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Polsfuss, Silke, Sabine Hofmann-Thiel, Matthias Merker, David Krieger, Stefan Niemann, Holger Rüssmann, Nicolas Schönfeld, Harald Hoffmann, and Katharina Kranzer. "Emergence of Low-level Delamanid and Bedaquiline Resistance During Extremely Drug-resistant Tuberculosis Treatment." Clinical Infectious Diseases 69, no. 7 (February 2, 2019): 1229–31. http://dx.doi.org/10.1093/cid/ciz074.
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Abstract Two new drugs, delamanid and bedaquiline, have recently been approved for treatment of multidrug-resistant and extensively drug-resistant (XDR) tuberculosis. Here, we report a case of clofazimine, bedaquiline, and low-level delamanid resistances acquired during treatment of a patient with XDR tuberculosis.
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Migliori, G. B., R. Centis, L. D'Ambrosio, A. Spanevello, E. Borroni, D. M. Cirillo, and G. Sotgiu. "Totally Drug-Resistant and Extremely Drug-Resistant Tuberculosis: The Same Disease?" Clinical Infectious Diseases 54, no. 9 (April 9, 2012): 1379–80. http://dx.doi.org/10.1093/cid/cis128.
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Antonenko, Kate, Valentin Kresyun, and Peter Antonenko. "Mutations leading to drug-resistant Mycobacterium tuberculosis infection in Ukraine." Open Medicine 5, no. 1 (February 1, 2010): 30–35. http://dx.doi.org/10.2478/s11536-009-0114-6.
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AbstractThe goal of this research was detection of the drug-resistance level of Mycobacterium tuberculosis infection in the Odesa region of Southwest Ukraine, investigation of the level of mutation in katG and rpoB genes for M. tuberculosis with polymerase chain reaction (PCR), and spread of these mutations in different groups of patients with tuberculosis. An extremely high level of primary and acquired resistance of M. tuberculosis to first-line antituberculosis drugs has been found in the Southwest region of Ukraine. The PCR method has proved to have high sensitivity in the detection of mutations in katG and rpoB genes. The data showed significant spreading of M. tuberculosis strains with mutations in katG and rpoB genes in penitentiaries and an increased level of these mutations during tuberculosis treatment. The presence of mutations in rpoB and katG genes was associated with a more severe course of tuberculosis, increased risk of treatment default, persistence of positive smears on microscopy at discharge, and poor closing of tuberculous cavities. Extremely high level of mutations in the rpoB and katG genes of M. tuberculosis was observed in Beijing family strains. Our findings support the capability of the PCR method to detect M. tuberculosis that is resistant to drugs such as isoniazid and rifampicin.
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Allué-Guardia, Anna, Rajagopalan Saranathan, John Chan, and Jordi B. Torrelles. "Mycobacteriophages as Potential Therapeutic Agents against Drug-Resistant Tuberculosis." International Journal of Molecular Sciences 22, no. 2 (January 13, 2021): 735. http://dx.doi.org/10.3390/ijms22020735.
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The current emergence of multi-, extensively-, extremely-, and total-drug resistant strains of Mycobacterium tuberculosis poses a major health, social, and economic threat, and stresses the need to develop new therapeutic strategies. The notion of phage therapy against bacteria has been around for more than a century and, although its implementation was abandoned after the introduction of drugs, it is now making a comeback and gaining renewed interest in Western medicine as an alternative to treat drug-resistant pathogens. Mycobacteriophages are genetically diverse viruses that specifically infect mycobacterial hosts, including members of the M. tuberculosis complex. This review describes general features of mycobacteriophages and their mechanisms of killing M. tuberculosis, as well as their advantages and limitations as therapeutic and prophylactic agents against drug-resistant M. tuberculosis strains. This review also discusses the role of human lung micro-environments in shaping the availability of mycobacteriophage receptors on the M. tuberculosis cell envelope surface, the risk of potential development of bacterial resistance to mycobacteriophages, and the interactions with the mammalian host immune system. Finally, it summarizes the knowledge gaps and defines key questions to be addressed regarding the clinical application of phage therapy for the treatment of drug-resistant tuberculosis.
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Mumena, David Kajoba, Geoffrey Kwenda, Caroline Wangari Ngugi, and Andrew Kimanga Nyerere. "Drug-Resistant Tuberculosis Types and Their Treatment Regimens Using First-Line, Second-Line Injectable, Third-Line, Fluoroquinolones, Aminoglycosides, Cyclic Polypeptides, Novel and Repurposed Anti-Tuberculosis Drugs." Journal of Biomedical Research & Environmental Sciences 3, no. 8 (September 2022): 988–93. http://dx.doi.org/10.37871/jbres1542.
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Drug-Resistant Tuberculosis (DR-TB) causes high mortality and morbidity rates globally. DR-TB and COVID-19 pandemic are posing a major risk to global public health and economic security, and are jeopardizing efforts in the control, prevention and elimination of TB globally. Mycobacterium tuberculosis (MTB) has continued to evolve resistance to anti-TB drugs. Different types of DR-TB have been defined and they include; mono drug-resistant TB, Multi Drug-Resistant TB (MDR-TB), poly drug-resistant TB, pre-Extensively Drug-Resistant TB (pre-XDR TB), Extensively Drug-Resistant TB (XDR-TB), Extremely Drug-Resistant TB (XXDR-TB), and Totally Drug-Resistant TB (TDR-TB). DR-TB is caused by several factors which include: non-adherence, poor compliance, low efficacy anti-TB drugs, delayed diagnosis, interrupted supply, stock-outs, inadequate infection control, HIV co-infection, spontaneous mutations, and chromosomal replication errors. Global TB targets have gone off-track and years of progress reversed due to DR-TB and the COVID-19 pandemic. Treatment failure, death and costs incurred are higher among patients suffering from DR-TB than among those with susceptible TB. For this reason, susceptible TB needs to be diagnosed quickly and treated effectively to prevent its progression to DR-TB. Treatment for susceptible TB requires the use of first-line anti-TB drugs; rifampicin, isoniazid, pyrazinamide, and ethambutol. While DR-TB is treated using the second- and third-line anti-TB drugs. Effective treatment of TB is dependent on: prompt and accurate diagnosis of TB and recognition of drug-resistance; adherence to treatment; robust contact tracing and prophylactic treatment of TB contacts; and screening for TB infection in high-risk groups.
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Shen, Xin, Guo-miao Shen, Jie Wu, Xiao-hong Gui, Xia Li, Jian Mei, Kathryn DeRiemer, and Qian Gao. "Association between embB Codon 306 Mutations and Drug Resistance in Mycobacterium tuberculosis." Antimicrobial Agents and Chemotherapy 51, no. 7 (April 16, 2007): 2618–20. http://dx.doi.org/10.1128/aac.01516-06.
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ABSTRACT embB306 mutants were detected in both ethambutol (EMB)-resistant and EMB-susceptible strains of Mycobacterium tuberculosis. Multidrug-resistant (MDR) strains had a higher proportion of embB306 mutants than non-MDR strains (odds ratio, 6.78; P < 0.001). The embB306 locus is a candidate marker for rapid detection of MDR and extremely drug resistant tuberculosis.
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Pecho-Silva, Samuel, Ana Claudia Navarro-Solsol, Vicky Panduro-Correa, Jorge L. Maguina, Ali A. Rabaan, Luis Rene Quiroz-Ramirez, Kovy Arteaga-Livias, and Alfonso J. Rodriguez-Morales. "The first successful cochlear implant in Latin America after severe aminoglycoside-induced ototoxicity in a Peruvian patient cured of extensively drug-resistant tuberculosis." Revista del Cuerpo Médico Hospital Nacional Almanzor Aguinaga Asenjo 15, no. 4 (February 8, 2023): 622–25. http://dx.doi.org/10.35434/rcmhnaaa.2022.154.1501.
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Introduction: Multidrug-resistant tuberculosis is a significant public health problem for which drugs are used with many adverse effects. Among the devastating consequences of these diseases, there is a wide variation in the incidence of ototoxicity and hearing loss in patients with multidrug-resistant and extremely resistant tuberculosis. Cochlear implants may be indicated in patients with unilateral/severe bilateral hearing loss with no benefit from conventional hearing aids, but their use in patients with tuberculosis is rare. Case report: We present the first case of a right unilateral cochlear implant performed on a 34-year-old Peruvian patient who presented profound sensorineural hearing loss of cochlear origin. Conclusion: Cochlear implant surgery is an essential milestone in the treatment of patients with auditory sequelae of tuberculosis treatment. Close monitoring of possible complications of tuberculosis treatment should be strengthened in countries with a high incidence of multidrug-resistant and extremely resistant tuberculosis.
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Yadav, Snehlata, and Balasubramanian Narasimhan. "New Insights in Design and Development of Antitubercular Drugs." Current Bioactive Compounds 16, no. 1 (February 20, 2020): 13–23. http://dx.doi.org/10.2174/1573407215666190409153756.
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Background: Tuberculosis, an infectious disease caused mainly by the Mycobacterium tuberculosis accounts for the highest number of deaths worldwide. Despite curing millions, the currently used drug regimens are bounded by various limitations such as long course of therapy, emergence of resistance and permanent tissue damage. The treatment of multidrug-resistant and extremely drugresistant tuberculosis is a challenging task due to its reliance on second-line drugs which are less potent and more toxic than those used in the clinical management of drug-susceptible tuberculosis. Therefore, the major challenges in the upcoming years are to overcome the emergence of increased number of multidrug-resistant as well as extensively drug-resistant strains and the ineptness of the current treatment regimens against latent tuberculosis. Bedaquiline and Delamanid are the only new anti-TB drugs that have been currently approved since more than 40 years after discovery of isoniazid. Bedaquiline is the first diarylquinoline derivative that has showed resilient culture conversion at 24 weeks in phase IIb trials. Methods: Extensive literature search on the topic was undergone using a focused question. Results: Fifty-eight research articles from journals of repute are included in the review. The vaccine and peptide-based conjugates are recent developments against Mycobacterium for selective and specific targeting to the desired tissues. Conclusion: In this review, we have focused on the different classes of chemical as well as plant based compounds as potent antitubercular agents against multidrug-resistant tuberculosis strains. This review falls light on the importance of research been undergoing in different parts of the world to combat the ever increasing problem of mycobacterial resistance and the various treatment options available for the treatment of tuberculosis.
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Shaji, Jessy, and Mahmood Shaikh. "DRUG-RESISTANT TUBERCULOSIS: RECENT APPROACH IN POLYMER BASED NANOMEDICINE." International Journal of Pharmacy and Pharmaceutical Sciences 8, no. 10 (August 12, 2016): 1. http://dx.doi.org/10.22159/ijpps.2016v8i10.11295.
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<p>Tuberculosis (TB) had been a leading chronic bacterial infection since decades. Current therapeutic management of Mycobacterium tuberculosis (MTB) is inadequate due to the lengthy course of treatment, drug-related side effects and ill-planned therapy, and these factors can lead to therapeutic failure and the emergence of drug-resistant TB. The Multi-drug-resistant (MDR) TB needs a lengthy course of treatment with second-line antitubercular drugs (ATDs) having higher side effects and cost. The misuse of second-line ATDs may result in extremely drug-resistant (XDR) strain which is very difficult to treat and require high doses of drugs resulting in more toxicity and side effects. This review highlights the need for novel drug delivery for the treatment of drug-susceptible and resistant TB. The characteristics of the nanoparticulate system in ATDs delivery and its approach in the MDR and XDR TB are discussed. The lung is the site of infection in pulmonary TB and the targeted drug delivery to the site of infection helps in achieving increased efficacy with less dose further reducing the side effects and toxicity. The symbiotic association of nanotechnology and pulmonary drug delivery give rise to an efficient inhalable polymer based nanoparticulate system containing ATDs for the better management of drug-susceptible and resistant TB. Various ATDs loaded polymer based nanocarrier systems like Alginate, PLGA, Chitosan and Gelatin nanocarriers are discussed in detail. Thus, this review highlights the current research in pulmonary drug delivery of polymer based ATDs nanomedicine and their importance in control of drug-resistant TB.</p>
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Velayati, A. A., P. Farnia, M. A. Merza, G. K. Zhavnerko, P. Tabarsi, L. P. Titov, J. Ghanavei, et al. "New insight into extremely drug-resistant tuberculosis: using atomic force microscopy." European Respiratory Journal 36, no. 6 (November 30, 2010): 1490–93. http://dx.doi.org/10.1183/09031936.00064510.
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Saroha, Deepika, Divyani Garg, Ashok Kumar Singh, and Rajinder K. Dhamija. "Irreversible neuropathy in extremely-drug resistant tuberculosis: An unfortunate clinical conundrum." Indian Journal of Tuberculosis 67, no. 3 (July 2020): 389–92. http://dx.doi.org/10.1016/j.ijtb.2019.11.012.
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Sarkar, Susmita, and Mavanur R. Suresh. "An Overview Of Tuberculosis Chemotherapy – A Literature Review." Journal of Pharmacy & Pharmaceutical Sciences 14, no. 2 (April 27, 2011): 148. http://dx.doi.org/10.18433/j33591.
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Tuberculosis (TB) is a major threat in global public health. The emergence of HIV and also multi drug resistant (MDR) and extremely drug resistant (XDR)-TB poses a vital challenge to the control of the disease. For the last 40 years, no new anti-TB drug has been discovered.
This literature review provides a brief discussion of existing drugs and emerging drug targets, and also of the advantages of incorporating modern drug delivery systems and immune modulators in order to improve the existing treatment regimen in terms of better efficacy, reduced drug administration frequency, shortened period of treatment and reduced drug related toxicity. The investigation for new a drug target is essential in carrying on the fight against MDR and XDR-TB. However, owing to the enormous cost and time involved in new drug development, improvement of the existing treatment regimen is seen to be a valid alternative.
This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Maslow, Elizabeth R., Richard L. Lubman, and Peter F. Barnes. "Tuberculosis: An Update for Clinicians." Journal of Intensive Care Medicine 11, no. 5 (September 1996): 233–45. http://dx.doi.org/10.1177/088506669601100501.
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Tuberculosis is the most common cause of death due to a single pathogen world wide, and the number of tuberculosis cases in the United States has increased significantly since 1985. Drug-resistant tuberculosis is also increasing, and multidrug-resistant tuberculosis (resistant to isoniazid and rifampin) has fueled deadly epidemics in New York and Florida. The clinical manifestations of tuberculosis in patients with human immunodeficiency virus (HIV) infection are distinctive; chest radiographic findings include primary tuberculosis and an extremely high frequency of extrapulmonary tuberculosis. Promising new diagnostic tests for tuberculosis are based on amplification of mycobacterial DNA by polymerase chain reaction, but they have not yet been adapted to the clinical laboratory. Most tuberculosis patients in the United States should receive initial treatment with isoniazid, rifampin, pyrazinamide, and ethambutol. For drug-susceptible tuberculosis, these drugs are continued for 2 months, followed by isoniazid and rifampin for 4 months, which yields a cure rate of greater than 95%. For isoniazid-resistant organisms, rifampin, pyrazinamide, and ethambutol, with or without isoniazid, can be given for 6 months. For HIV-infected patients with drug-susceptible or isoniazid-resistant tuberculosis, we recommend continuation of therapy for a minimum of 9 months. Most forms of extrapulmonary tuberculosis due to drug-susceptible organisms are treated for 6 months, except for meningeal, miliary, and skeletal tuberculosis, for which a minimum of 12 months of therapy is recommended. To reduce nosocomial transmission of tuberculosis, health cafe facilities should institute administrative controls to reduce exposure to infectious patients, engineering controls to reduce the concentration of infectious droplet nuclei, and personal respiratory protection of health care workers with appropriate masks. Administrative controls are probably the most important part of a tuberculosis infection control program. Health care workers who were recently infected with Mycobacterium tuberculosis can be identified by serial skin testing, and those who convert their skin tests from negative to positive should receive chemoprophylaxis with isoniazid to prevent development of tuberculosis.
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Baveja, C. P., Gumma Vidyanidhi, Manisha Jain, Trishla Kumari, and V. K. Sharma. "Drug-resistant genital tuberculosis of the penis in a human immunodeficiency virus non-reactive individual." Journal of Medical Microbiology 56, no. 5 (May 1, 2007): 694–95. http://dx.doi.org/10.1099/jmm.0.46960-0.
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The genitourinary tract is the most common site for extrapulmonary tuberculosis (TB). Penile TB is extremely rare comprising less than 1 % of all genital TB cases in males. It most commonly presents either as a superficial ulcer on the glans or around the corona. Diagnosis of penile TB is often difficult because it can mimic numerous other diseases. The association of TB with AIDS, and the increasing incidence of multiple drug resistance has further compounded the problem. The case described herein involves a patient with multidrug-resistant smear-positive penile TB that was undiagnosed initially due to the lack of clinical suspicion of TB, and once diagnosed failed to respond to first line antitubercular drugs because of multiple drug resistance.
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Oudghiri, Amal, Ghizlane Momen, Achraf Aainouss, Amin Laglaoui, My Driss El Messaoudi, Mohammed El Mzibri, and Imane Chaoui. "Genotypic diversity of multi- and pre-extremely drug-resistant Mycobacterium tuberculosis isolates from Morocco." PLOS ONE 16, no. 7 (July 2, 2021): e0253826. http://dx.doi.org/10.1371/journal.pone.0253826.
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In Morocco, the prevalence of multidrug resistant tuberculosis (MDR-TB) continues to increase especially within previously treated cases; these MDR cases may evolve to extensively drug resistant tuberculosis (XDR-TB) raising major concern to TB control programs. From an epidemiological window, scarce informations are available about the genetic diversity of Mycobacterium tuberculosis (MTB) strains fueling these forms of resistance. The aim of this study was to assess to genetic diversity of MDR-MTB strains. Hence, this prospective study was conducted on patients diagnosed with MDR-TB at Pasteur Institute of Casablanca from 2010 to 2013. A total of 70 MDR-MTB isolates were genotyped by spoligotyping and 15-loci MIRU-VNTR methods. Spoligotyping generated four orphan patterns, five unique profiles whereas 61 strains were grouped in nine clusters (2 to 25 strains per cluster), the clustering rates being 87.1%. Subtyping by 15 loci MIRU-VNTR splitted all clusters already established by spoligotyping and generated 70 unique profiles not recognized in SITVIT2 database; clustering rate was equal to zero. HGDI analysis of 15 loci MIRU demonstrated that eight out of 15 loci were highly discriminant. Of note, all pre-XDR strains belongs to many clades, meaning that there no association between gyrA mutants and particular clade. Overall, the data generated by this study (i) describe the population structure of MDR MTBC in Morocco which is highly homogenous, (ii) confirm that TB in Morocco is almost exclusively transmitted by modern and evolutionary lineages with high level of biodiversity seen by MIRU, and (iii) validate the use of optimized 15-loci MIRU-VNTR format for future investigations in Morocco.
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Phua, Chee Kiang, Cynthia BE Chee, Angeline PG Chua, Suay Hong Gan, Aneez DB Ahmed, and Yee Tang Wang. "Managing a Case of Extensively Drug-Resistant (XDR) Pulmonary Tuberculosis in Singapore." Annals of the Academy of Medicine, Singapore 40, no. 3 (March 15, 2011): 132–35. http://dx.doi.org/10.47102/annals-acadmedsg.v40n3p132.
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Introduction: Extensively drug-resistant tuberculosis (XDR-TB) is an emerging global health risk. We present the first case report of XDR-TB in Singapore. Clinical Picture: A 41-year-old Indonesian lady with previously treated pulmonary tuberculosis presented with chronic cough. Her sputum was strongly acid-fast bacilli positive and grew Mycobacterium tuberculosis complex resistant to first and second-line TB medications. Treatment: She received 5 months of intensive multidrug treatment without sputum smear conversion. She then underwent resection of the diseased lung. The total cost incurred amounted to over S$100,000. Outcome: She achieved sputum smear/culture conversion post-surgery, but will require further medical therapy for at least 18 months. Conclusion: XDR-TB is poorly responsive to therapy and extremely expensive to manage. Its prevention by strict compliance to therapy is paramount. Key words: Directly observed therapy, Multidrug-resistant, Mycobacteria
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Teneva, Yoanna, Rumyana Simeonova, Violeta Valcheva, and Violina T. Angelova. "Recent Advances in Anti-Tuberculosis Drug Discovery Based on Hydrazide–Hydrazone and Thiadiazole Derivatives Targeting InhA." Pharmaceuticals 16, no. 4 (March 23, 2023): 484. http://dx.doi.org/10.3390/ph16040484.
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Tuberculosis is an extremely serious problem of global public health. Its incidence is worsened by the presence of multidrug-resistant (MDR) strains of Mycobacterium tuberculosis. More serious forms of drug resistance have been observed in recent years. Therefore, the discovery and/or synthesis of new potent and less toxic anti-tubercular compounds is very critical, especially having in mind the consequences and the delays in treatment caused by the COVID-19 pandemic. Enoyl-acyl carrier protein reductase (InhA) is an important enzyme involved in the biosynthesis of mycolic acid, a major component of the M. tuberculosis cell wall. At the same time, it is a key enzyme in the development of drug resistance, making it an important target for the discovery of new antimycobacterial agents. Many different chemical scaffolds, including hydrazide hydrazones and thiadiazoles, have been evaluated for their InhA inhibitory activity. The aim of this review is to evaluate recently described hydrazide-hydrazone- and thiadiazole-containing derivatives that inhibit InhA activity, resulting in antimycobacterial effects. In addition, a brief review of the mechanisms of action of currently available anti-tuberculosis drugs is provided, including recently approved agents and molecules in clinical trials.
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Arthur, Patrick K., Vincent Amarh, Precious Cramer, Gloria B. Arkaifie, Ethel J. S. Blessie, Mohammed-Sherrif Fuseini, Isaac Carilo, Rebecca Yeboah, Leonard Asare, and Brian D. Robertson. "Characterization of Two New Multidrug-Resistant Strains of Mycobacterium smegmatis: Tools for Routine In Vitro Screening of Novel Anti-Mycobacterial Agents." Antibiotics 8, no. 1 (January 2, 2019): 4. http://dx.doi.org/10.3390/antibiotics8010004.
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Mycobacterium tuberculosis is a pathogen of global public health concern. This threat is exacerbated by the emergence of multidrug-resistant and extremely-drug-resistant strains of the pathogen. We have obtained two distinct clones of multidrug-resistant Mycobacterium smegmatis after gradual exposure of Mycobacterium smegmatis mc2 155 to increasing concentrations of erythromycin. The resulting resistant strains of Mycobacterium smegmatis exhibited robust viability in the presence of high concentrations of erythromycin and were found to be resistant to a wide range of other antimicrobials. They also displayed a unique growth phenotype in comparison to the parental drug-susceptible Mycobacterium smegmatis mc2 155, and a distinct colony morphology in the presence of cholesterol. We propose that these two multidrug-resistant clones of Mycobacterium smegmatis could be used as model organisms at the inceptive phase of routine in vitro screening of novel antimicrobial agents targeted against multidrug-resistant Mycobacterial tuberculosis.
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Gul, Sana, Ruqaiya Khalil, Zaheer Ul-Haq, and Mohammad S. Mubarak. "Computational Overview of Mycobacterial Thymidine Monophosphate Kinase." Current Pharmaceutical Design 26, no. 15 (May 18, 2020): 1676–81. http://dx.doi.org/10.2174/1381612826666200403114152.
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: Tuberculosis (TB) ranks among the diseases with the highest morbidity rate with significantly high prevalence in developing countries. Globally, tuberculosis poses the most substantial burden of mortality. Further, a partially treated tuberculosis patient is worse than untreated; they may lead to standing out as a critical obstacle to global tuberculosis control. The emergence of multi-drug resistant (MDR) and extremely drug-resistant (XDR) strains, and co-infection of HIV further worsen the situation. The present review article discusses validated targets of the bacterial enzyme thymidine monophosphate kinase (TMPK). TMPKMTB enzyme belongs to the nucleoside monophosphate kinases (NMPKs) family. It is involved in phosphorylation of TMP to TDP, and TDP is phosphorylated to TTP. This review highlights structure elucidation of TMP enzymes and their inhibitors study on TMP scaffold, and it also discusses different techniques; including molecular docking, virtual screening, 3DPharmacophore, QSAR for finding anti-tubercular agents.
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Makarova, M. V., and L. D. Guntupova. "No ntuberculous Mycobacteria." BIOpreparations. Prevention, Diagnosis, Treatment 20, no. 2 (June 26, 2020): 97–102. http://dx.doi.org/10.30895/2221-996x-2020-20-2-97-102.
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There has been a sharp increase in the number of diseases associated with potentially pathogenic microorganisms of the genus Mycobacterium, which differ from Mycobacterium tuberculosis. These bacteria are known as atypical mycobacteria or nontuberculosis mycobacteria (NTM), and the diseases they cause are called mycobacteriosis. NTMs include more than 20 species of acid-resistant microorganisms that are widespread in the environment and that are not members of the M. tuberculosis complex. However, the role of certain types of NTMs in the pathogenesis of human diseases is rather ambiguous. The aim of the paper was to analyse the current rise in the incidence of NTM diseases, as well as the main areas of research on early diagnosis of mycobacteriosis and the detection and testing of drug susceptibility of these microorganisms. The paper summarises current views on NTM species differences, their prevalence and pathogenicity for humans and animals. The authors analysed the main efforts aimed at diagnosis and treatment of NTM diseases. The paper cites the results of the study of NTM susceptibility/resistance to anti-tuberculosis drugs. The diagnosis of mycobacteriosis remains extremely difficult, mainly because of the similarity of the clinico-radiological evidence with that of tuberculosis. Detection of NTM multiple and extensive drug resistance to the majority of anti-tuberculosis drugs complicates the treatment of the NTM disease. Further study of various aspects of NTM diseases is especially important given the increase in the incidence and prevalence of mycobacteriosis all over the world, challenging differential diagnosis, and detection of NTM extensive drug resistance.
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Danilenko, V. N. "Development of a technological platfom for creating innovative anti-tb drugs effective against multi-drug-resistant strains." Вестник Российской академии наук 89, no. 5 (May 6, 2019): 427–35. http://dx.doi.org/10.31857/s0869-5873895427-435.
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This article tackles the issue of the growing morbidity and mortality caused by multi-drug-resistant (extreme drug-resistant) tuberculosis (TB). This issue is aggravated by the alarming rise of immunocompromized patients and immigration worldwide. In order to solve this problem, an interdisciplinary approach is needed. Here we offer to: (1) develop innovative diagnostic techniques for identifying dangerous lineages of TB with mutations and drug resistance genes; (2) develop antibiotics with new modes of action effective against multiple drug resistance and extreme drug-resistant strains of TB and HIV; (3) develop new genetically engineered vaccines; and, (4) develop new vaccine adjuvants based on probiotic Lactobacillus and Bifidobacterium stains, with selective immunomodulatory activity.
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Cui, Ze-Jia, Wei-Tong Zhang, Qiang Zhu, Qing-Ye Zhang, and Hong-Yu Zhang. "Using a Heat Diffusion Model to Detect Potential Drug Resistance Genes of Mycobacterium tuberculosis." Protein & Peptide Letters 27, no. 8 (September 24, 2020): 711–17. http://dx.doi.org/10.2174/0929866527666200313113157.
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Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the oldest known and most dangerous diseases. Although the spread of TB was controlled in the early 20th century using antibiotics and vaccines, TB has again become a threat because of increased drug resistance. There is still a lack of effective treatment regimens for a person who is already infected with multidrug-resistant Mtb (MDR-Mtb) or extensively drug-resistant Mtb (XDRMtb). In the past decades, many research groups have explored the drug resistance profiles of Mtb based on sequence data by GWAS, which identified some mutations that were significantly linked with drug resistance, and attempted to explain the resistance mechanisms. However, they mainly focused on several significant mutations in drug targets (e.g. rpoB, katG). Some genes which are potentially associated with drug resistance may be overlooked by the GWAS analysis. Objective: In this article, our motivation is to detect potential drug resistance genes of Mtb using a heat diffusion model. Methods: All sequencing data, which contained 127 samples of Mtb, i.e. 34 ethambutol-, 65 isoniazid-, 53 rifampicin- and 45 streptomycin-resistant strains. The raw sequence data were preprocessed using Trimmomatic software and aligned to the Mtb H37Rv reference genome using Bowtie2. From the resulting alignments, SAMtools and VarScan were used to filter sequences and call SNPs. The GWAS was performed by the PLINK package to obtain the significant SNPs, which were mapped to genes. The P-values of genes calculated by GWAS were transferred into a heat vector. The heat vector and the Mtb protein-protein interactions (PPI) derived from the STRING database were inputted into the heat diffusion model to obtain significant subnetworks by HotNet2. Finally, the most significant (P < 0.05) subnetworks associated with different phenotypes were obtained. To verify the change of binding energy between the drug and target before and after mutation, the method of molecular dynamics simulation was performed using the AMBER software. Results: We identified significant subnetworks in rifampicin-resistant samples. Excitingly, we found rpoB and rpoC, which are drug targets of rifampicin. From the protein structure of rpoB, the mutation location was extremely close to the drug binding site, with a distance of only 3.97 Å. Molecular dynamics simulation revealed that the binding energy of rpoB and rifampicin decreased after D435V mutation. To a large extent, this mutation can influence the affinity of drug-target binding. In addition, topA and pyrG were reported to be linked with drug resistance, and might be new TB drug targets. Other genes that have not yet been reported are worth further study. Conclusion: Using a heat diffusion model in combination with GWAS results and protein-protein interactions, the significantly mutated subnetworks in rifampicin-resistant samples were found. The subnetwork not only contained the known targets of rifampicin (rpoB, rpoC), but also included topA and pyrG, which are potentially associated with drug resistance. Together, these results offer deeper insights into drug resistance of Mtb, and provides potential drug targets for finding new antituberculosis drugs.
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Duc, Nguyen Minh, Hanki Lee, Joo Won Suh, Vo Thi Bich Thuy, Nghiem Ngoc Minh, and Nguyen Phan Lan Hong. "The high-throughput screening system for inhibitor Mycobacterium tuberculosis compounds based on ATP hydrolysis activity of recombinant protein ClpC1." Vietnam Journal of Biotechnology 18, no. 2 (November 3, 2020): 239–47. http://dx.doi.org/10.15625/1811-4989/18/2/14908.
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The global Tuberculosis (TB) rate continues to increase by 1% per year with the widespread of drug-resistant TB. Therefore, the development and research to find new anti-TB drugs are becoming an extremely urgent mission. To be able to screen lead anti-tuberculosis drugs, currently, researchers have to carry out directly on the cells of Mycobacterium tuberculosis and to be performed in bio-security facilities level 3 or 4, to prevent infection from pathogens. However, our results demonstrated that the screening of anti-TB drug candidates can be implemented in bio-security facilities level 1 laboratory with the Escherichia coli cell extraction and recombinant ClpC1 protein - an integral part of the Mycobacterium tuberculosis genome. We focused on the ATP hydrolysis activity of ClpC1 to create a specific research direction for the high-throughput anti-tuberculosis drug screening system. ClpC1 protein was overexpressed and purified with functionally characterized (93.5 kDa). The steady-state growth of recombinant ClpC1 protein in Luria-Bertani (LB) broth High Salt medium was maintained and stabilized after extraction. The determined ATPase activity of ClpC1 was performed by measuring the released phosphate from the reaction. Ecumicin was chosen to be a control compound with expected ATP hydrolysis activities (Hill coefficient = 1,19 ± 0,217; Kd value = 0,52 ± 0,275). We tested this high throughput screening system with ten anti-TB drugs to evaluate the effectiveness of our screening system. Based on these results, we built a complete high-throughput screening system anti-tuberculosis drug safety and quickly.
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Lavrova, Anastasia I., and Eugene B. Postnikov. "An Improved Diagnostic of the Mycobacterium tuberculosis Drug Resistance Status by Applying a Decision Tree to Probabilities Assigned by the CatBoost Multiclassifier of Matrix Metalloproteinases Biomarkers." Diagnostics 12, no. 11 (November 17, 2022): 2847. http://dx.doi.org/10.3390/diagnostics12112847.
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In this work, we discuss an opportunity to use a set of the matrix metalloproteinases MMP-1, MMP-8, and MMP-9 and the tissue inhibitor TIMP, the concentrations of which can be easily obtained via a blood test from patients suffering from tuberculosis, as the biomarker for a fast diagnosis of the drug resistance status of Mycobacterium tuberculosis. The diagnostic approach is based on machine learning with the CatBoost system, which has been supplied with additional postprocessing. The latter refers not only to the simple probabilities of ML-predicted outcomes but also to the decision tree-like procedure, which takes into account the presence of strict zeros in the primary set of probabilities. It is demonstrated that this procedure significantly elevates the accuracy of distinguishing between sensitive, multi-, and extremely drug-resistant strains.
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Munro, A. W., K. J. McLean, K. R. Marshall, A. J. Warman, G. Lewis, O. Roitel, M. J. Sutcliffe, et al. "Cytochromes P450: novel drug targets in the war against multidrug-resistant Mycobacterium tuberculosis." Biochemical Society Transactions 31, no. 3 (June 1, 2003): 625–30. http://dx.doi.org/10.1042/bst0310625.
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Novel drug strategies are desperately needed to combat the global threat posed by multidrug-resistant strains of Mycobacterium tuberculosis (Mtb). The genome sequence of Mtb has revealed an unprecedented number of cytochrome P450 enzymes in a prokaryote, suggesting fundamental physiological roles for many of these enzymes. Several azole drugs (known inhibitors of cytochromes P450) have been shown to have potent anti-mycobacterial activity, and the most effective azoles have extremely tight binding constants for one of the Mtb P450s (CYP121). The structure of CYP121 has been determined at atomic resolution, revealing novel features of P450 structure, including mixed haem conformations and putative proton-relay pathways from protein surface to haem iron. The structure provides both a platform for investigation of structure/mechanism of cytochrome P450, and for design of inhibitor molecules as novel anti-tubercular agents.
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Kryzhanovsky, D. G., N. A. Marchenko, and V. A. Freivald. "Definition of drug resistance of Mycobacterium tuberculosis to antituberculosis drugs in patients with multidrugresistant tuberculosis and TB with extremely drug resistant depending on the case of the disease." Medicni perspektivi (Medical perspectives) 19, no. 4 (November 24, 2014): 84–89. http://dx.doi.org/10.26641/2307-0404.2014.4.35801.
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Lu, Yu, Meiqin Zheng, Bin Wang, Lei Fu, Weijie Zhao, Peng Li, Jian Xu, et al. "Clofazimine Analogs with Efficacy against Experimental Tuberculosis and Reduced Potential for Accumulation." Antimicrobial Agents and Chemotherapy 55, no. 11 (August 15, 2011): 5185–93. http://dx.doi.org/10.1128/aac.00699-11.
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ABSTRACTThe global tuberculosis crisis urgently demands new, efficacious, orally available drugs with the potential to shorten and simplify the long and complex treatments for drug-sensitive and drug-resistant disease. Clofazimine, a riminophenazine used for many years to treat leprosy, demonstrates efficacy in animal models of tuberculosis via a novel mode of action. However, clofazimine's physicochemical and pharmacokinetic properties contribute to side effects that limit its use; in particular, an extremely long half-life and propensity for tissue accumulation together with clofazimine's dye properties leads to unwelcome skin discoloration. We recently conducted a systematic structure-activity study of more than 500 riminophenazine analogs for anti-Mycobacterium tuberculosisactivity. We describe here the characteristics of 12 prioritized compounds in more detail. The new riminophenazine analogs demonstrated enhancedin vitroactivity compared to clofazimine against replicatingM. tuberculosisH37Rv, as well as panels of drug-sensitive and drug-resistant clinical isolates. The new compounds demonstrate at least equivalent activity compared to clofazimine against intracellularM. tuberculosisand, in addition, most of them were active against nonreplicatingM. tuberculosis. Eleven of these more water-soluble riminophenazine analogs possess shorter half-lives than clofazimine when dosed orally to mice, suggesting that they may accumulate less. Most importantly, the nine compounds that progressed to efficacy testing demonstrated inhibition of bacterial growth in the lungs that is superior to the activity of an equivalent dose of clofazimine when administered orally for 20 days in a murine model of acute tuberculosis. The efficacy of these compounds, along with their decreased potential for accumulation and therefore perhaps also for tissue discoloration, warrants further study.
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Grenkova, T. A., A. I. Chizhov, M. P. Gusarova, and N. V. Gudova. "Study of the Effectiveness against Test Strain Mycobacterium terrae DSM 43227 of Some Substances Containing Fragment of Phenolic." Epidemiology and Vaccine Prevention 15, no. 4 (August 20, 2016): 37–41. http://dx.doi.org/10.31631/2073-3046-2016-15-4-37-41.
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Relevance. Multi-drug-resistant Mycobacterium tuberculosis has been an important problem in public health around the world. However, development of effective methods and means of disinfection is now extremely urgent. Phenol is probably the oldest known disinfectant. Disinfectants based on substances containing phenolic practically used in almost every countries of the worldwide for the disinfection of medical devices, surfaces and hand hygiene. Goal. Comparative study of the activity of certain disinfectants containing phenol fragment against the test strain. Materials and methods. Multi-drug-resistant M. terrae, M. avium-intracellulara and M. tuberculosis have similar characteristics of resistance to chemical disinfectants, herefore M. terrae DSM 43227 used as the test strain. We studied five used in Russia for the production of disinfectants and antiseptics. substances containing a phenolic. Results. The disinfectant effect of substances with phenol compounds was detected in lower concentrations (from 0.02% for 2-benzil-4-chlorphenol to 1.0% for ortophenylphenol) than with substances containing glutaraldehyde or chloramine B compounds. Conclusions. Saving disinfecting effectiveness at low concentrations of the active substances in the working solutions can be recommended disinfectants based on phenolic compounds for disinfection measures in the complex of measures for prevention of occurrence and spread of tuberculosis.
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Oliveira, Gabriel S., Raquel P. Costa, Paula Gomes, Maria Salomé Gomes, Tânia Silva, and Cátia Teixeira. "Antimicrobial Peptides as Potential Anti-Tubercular Leads: A Concise Review." Pharmaceuticals 14, no. 4 (April 2, 2021): 323. http://dx.doi.org/10.3390/ph14040323.
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Despite being considered a public health emergency for the last 25 years, tuberculosis (TB) is still one of the deadliest infectious diseases, responsible for over a million deaths every year. The length and toxicity of available treatments and the increasing emergence of multidrug-resistant strains of Mycobacterium tuberculosis renders standard regimens increasingly inefficient and emphasizes the urgency to develop new approaches that are not only cost- and time-effective but also less toxic. Antimicrobial peptides (AMP) are small cationic and amphipathic molecules that play a vital role in the host immune system by acting as a first barrier against invading pathogens. The broad spectrum of properties that peptides possess make them one of the best possible alternatives for a new “post-antibiotic” era. In this context, research into AMP as potential anti-tubercular agents has been driven by the increasing danger revolving around the emergence of extremely-resistant strains, the innate resistance that mycobacteria possess and the low compliance of patients towards the toxic anti-TB treatments. In this review, we will focus on AMP from various sources, such as animal, non-animal and synthetic, with reported inhibitory activity towards Mycobacterium tuberculosis.
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Silva, Aleidy, Bai-Yu Lee, Daniel L. Clemens, Theodore Kee, Xianting Ding, Chih-Ming Ho, and Marcus A. Horwitz. "Output-driven feedback system control platform optimizes combinatorial therapy of tuberculosis using a macrophage cell culture model." Proceedings of the National Academy of Sciences 113, no. 15 (March 28, 2016): E2172—E2179. http://dx.doi.org/10.1073/pnas.1600812113.
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Tuberculosis (TB) remains a major global public health problem, and improved treatments are needed to shorten duration of therapy, decrease disease burden, improve compliance, and combat emergence of drug resistance. Ideally, the most effective regimen would be identified by a systematic and comprehensive combinatorial search of large numbers of TB drugs. However, optimization of regimens by standard methods is challenging, especially as the number of drugs increases, because of the extremely large number of drug–dose combinations requiring testing. Herein, we used an optimization platform, feedback system control (FSC) methodology, to identify improved drug–dose combinations for TB treatment using a fluorescence-based human macrophage cell culture model of TB, in which macrophages are infected with isopropyl β-D-1-thiogalactopyranoside (IPTG)-inducible green fluorescent protein (GFP)-expressing Mycobacterium tuberculosis (Mtb). On the basis of only a single screening test and three iterations, we identified highly efficacious three- and four-drug combinations. To verify the efficacy of these combinations, we further evaluated them using a methodologically independent assay for intramacrophage killing of Mtb; the optimized combinations showed greater efficacy than the current standard TB drug regimen. Surprisingly, all top three- and four-drug optimized regimens included the third-line drug clofazimine, and none included the first-line drugs isoniazid and rifampin, which had insignificant or antagonistic impacts on efficacy. Because top regimens also did not include a fluoroquinolone or aminoglycoside, they are potentially of use for treating many cases of multidrug- and extensively drug-resistant TB. Our study shows the power of an FSC platform to identify promising previously unidentified drug–dose combinations for treatment of TB.
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Martin, Carlos, Nacho Aguilo, Dessislava Marinova, and Jesus Gonzalo-Asensio. "Update on TB Vaccine Pipeline." Applied Sciences 10, no. 7 (April 10, 2020): 2632. http://dx.doi.org/10.3390/app10072632.
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In addition to antibiotics, vaccination is considered among the most efficacious methods in the control and the potential eradication of infectious diseases. New safe and effective vaccines against tuberculosis (TB) could be a very important tool and are called to play a significant role in the fight against TB resistant to antimicrobials. Despite the extended use of the current TB vaccine Bacillus Calmette-Guérin (BCG), TB continues to be transmitted actively and continues to be one of the 10 most important causes of death in the world. In the last 20 years, different TB vaccines have entered clinical trials. In this paper, we review the current use of BCG and the diversity of vaccines in clinical trials and their possible indications. New TB vaccines capable of protecting against respiratory forms of the disease caused by sensitive or resistant Mycobacterium tuberculosis strains would be extremely useful tools helping to prevent the emergence of multi-drug resistance.
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Zitko, Jan, and Martin Doležal. "Old Drugs and New Targets as an Outlook for the Treatment of Tuberculosis." Current Medicinal Chemistry 25, no. 38 (January 7, 2019): 5142–67. http://dx.doi.org/10.2174/0929867324666170920154325.
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Background: Despite of the globally positive trends in the epidemiology of tuberculosis, the increasing rates of drug-resistant strains are urging to introduce new antituberculars into clinical practice. Development of a new chemical entity from hit to marketed drug is an extremely time and resources consuming process with uncertain outcome. Repurposing of clinically used drugs can be a cheaper alternative to develop new drugs effective in the treatment of tuberculosis. Objective: To extract the latest information on new mechanisms of action described or proposed for clinically used antitubercular drugs. To identify drugs from various pharmacodynamic groups as candidates for repurposing to become effective in combatting tuberculosis. Attention will be paid to elucidate the connection between repurposed drugs and new antituberculars in clinical practice or in clinical trials. Methods: Scientific databases were searched for the keywords. Results: We reviewed the latest aspects of usage and new mechanisms of action for both first-line and second-line antitubercular drugs in clinical practice. Further, we found that surprisingly large number of clinically used drugs from various pharmacodynamic groups have potential to be used in the treatment of tuberculosis, including antimicrobial drugs not typically used against tuberculosis, statins, CNS drugs (tricyclic phenothiazines, antidepressants, anticonvulsants), non-steroidal anti-inflammatory drugs, kinase inhibitors, and others (metformin, disulfiram, verapamil, lansoprazole). Repurposed drugs may become effective antituberculars, acting either by direct effects on mycobacteria or as adjunct, host-directed therapy. Conclusion: In this review, we showed that proper research of old drugs is a very efficient tool to develop new antituberculars.
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Ugwu, D. I., B. E. Ezema, F. U. Eze, and D. I. Ugwuja. "Synthesis and Structural Activity Relationship Study of Antitubercular Carboxamides." International Journal of Medicinal Chemistry 2014 (December 30, 2014): 1–18. http://dx.doi.org/10.1155/2014/614808.
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The unusual structure and chemical composition of the mycobacterial cell wall, the tedious duration of therapy, and resistance developed by the microorganism have made the recurrence of the disease multidrug resistance and extensive or extreme drug resistance. The prevalence of tuberculosis in synergy with HIV/AIDS epidemic augments the risk of developing the disease by 100-fold. The need to synthesize new drugs that will shorten the total duration of effective treatment and/or significantly reduce the dosage taken under DOTS supervision, improve on the treatment of multidrug-resistant tuberculosis which defies the treatment with isoniazid and rifampicin, and provide effective treatment for latent TB infections which is essential for eliminating tuberculosis prompted this review. In this review, we considered the synthesis and structure activity relationship study of carboxamide derivatives with antitubercular potential.
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Nanovic, Zorica, Biserka Kaeva Jovkovska, Gorica Breskovska, and Milena Petrovska. "Key Issues in the Management of Multi-Drug Resistant Tuberculosis: A Case Report." Open Access Macedonian Journal of Medical Sciences 6, no. 7 (July 14, 2018): 1282–88. http://dx.doi.org/10.3889/oamjms.2018.290.
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BACKGROUND: Global tuberculosis (TB) epidemic is being driven to an increasing extent by the emergence and spread of drug-resistant strains of Mycobacterium tuberculosis complex (MTBC). We present a case of primary multidrug-resistant tuberculosis (MDR-TB), highlighting Macedonian MDR-TB management issues.CASE REPORT: A 39-year old previously healthy Caucasian male, with no previous history of TB or close contact to TB, was admitted in referral TB-hospital due to respiratory bleeding. Chest X-ray revealed opacity with cavernous lesions in the right upper lobe. Sputum samples showed no presence of acid-fast bacilli (AFB) on fluorescence microscopy, but molecular tests (real-time PCR-based assay and multiplex PCR-based reverse hybridisation Line Probe Assay) confirmed the presence of MTBC, also revealing rifampicin and isoniazid resistance and absence of resistance to second-line anti-tubercular drugs. The strain was considered multidrug-resistant, lately confirmed by conventional methods in liquid and solid culture. Following the protocol of the World Health Organization, we started the longer treatment of MDR-TB comprised of at least five effective anti-tubercular drugs. Due to patient’s extreme non-adherence, we had to delay and modify the regimen (i.e. omitting parenteral aminoglycoside) and to discharge him from the hospital a month after directly observed therapy (DOT) in negative pressure room. As there is no legal remedy in our country regarding involuntary isolation, our patient continued the regimen under ambulatory control of referral TB-hospital. Ignoring the risk of additional acquisition of drug resistance and prolonged exposure of the community to MDR-TB strain - for which he was repeatedly advised - he decided to cease the therapy six months after beginning.CONCLUSION: The benefit of molecular tests in the early diagnosis of TB and drug resistance is unequivocal for adequate treatment of resistant forms of TB. Whole genome sequencing ensures additional knowledge of circulating strains and their resistance patterns. These are essentials of effective TB control programs and can provide evidence to medical and legal authorities for more active policies of screening, involuntary confinement and compliance with therapy, and alternative modalities for successful treatment, as a part of infection control.
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Gupta, Shradheya R. R., Ekta Gupta, Avnam Ohri, Sandeep Kumar Shrivastava, Sumita Kachhwaha, Vinay Sharma, Rupesh Kumar Mishra, and Ravi Ranjan Kumar Niraj. "Comparative Proteome Analysis of Mycobacterium Tuberculosis Strains - H37Ra, H37Rv, CCDC5180, and CAS/NITR204: A Step Forward to Identify Novel Drug Targets." Letters in Drug Design & Discovery 17, no. 11 (October 23, 2020): 1422–31. http://dx.doi.org/10.2174/1570180817999200531165148.
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Background: Mycobacterium tuberculosis is a causative agent of tuberculosis. It is a non-motile, acid-fast, obligatory aerobic bacterium. Finding novel drug targets in Mycobacterium tuberculosis has become extremely important as the bacterium is evolving into a more dangerous multi-drug resistant pathogen. The predominant strains in India belong to the Central-Asian, East- African Indian, and Beijing clad. For the same reason, the whole proteomes of a non-virulent strain (H37Ra), a virulent (H37Rv) and two clinical strains, a Central-Asian clad (CAS/NITR204) and a Beijing clad (CCDC5180) have been selected for comparative study. Selecting a phylogenetically close and majorly studied non-virulent strain is helpful in removing the common and undesired proteins from the study. Objective: The study compares the whole proteome of non-virulent strain with the other three virulent strains to find a unique protein responsible for virulence in virulent strains. It is expected that the drugs developed against identified targets will be specific to the virulent strains. Additionally, to assure minimal toxicity to the host, we also screened the human proteome. Methods: Comparative proteome analysis was used for target identification and in silico validation of identified target protein Rv2466c, identification of the respective ligand of the identified target protein and binding interaction study using Molecular docking and Molecular Dynamic Simulation study were used in this study. Results and Discussion: Finally, eleven proteins were found to be unique in virulent strain only and out of which, Rv2466c (PDB-ID: 4ZIL) was found to be an essential protein and identified as a putative drug target protein for further study. The compound glutathione was found to be a suitable inhibitor for Rv2466c. In this study, we used a comparative proteomics approach to identify novel target proteins. Conclusion: This study is unique as we are assured that the study will move forward the research in a new direction to cure the deadly disease (tuberculosis) caused by Mycobacterium tuberculosis. Rv2466c was identified as a novel drug target and glutathione as a respective ligand of Rv2466c. Discovery of the novel drug target as well as the drug will provide a solution to drug resistance as well as the infection caused by Mycobacterium tuberculosis.
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Elger, B. S., F. Mirzayev, S. Afandiyev, and E. Gurbanova. "Ethical issues in tuberculosis screening and the use of new drugs for prisoners." International Journal of Tuberculosis and Lung Disease 24, no. 5 (May 1, 2020): 57–60. http://dx.doi.org/10.5588/ijtld.17.0899.
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SETTING: Prisons are known to have extremely high tuberculosis (TB) and multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB prevalence and poor treatment outcomes.OBJECTIVE: To examine the screening and M/XDR-TB treatment with new TB drugs in prisons from the perspective of international ethical and legal requirements.DESIGN: WHO recommendations on TB screening in prisons and M/XDR-TB treatment as well as the international human rights law on prisoners were analysed.RESULTS: Prisoners have a human right to access at least the same level of TB care as in their communities. Screening for TB in prisons, which may run contrary to a given individual's choice to be tested, may be justified by the positive obligation to prevent other prisoners from contracting a possibly deadly disease. Introduction of new TB drugs in prisons is necessary, ethically sound and should start in parallel with introduction in a civilian sector in strict compliance with the WHO recommendations.CONCLUSION: Access to screening for TB, as well as effective treatment according to WHO recommendations, must be ensured by countries on the basis of international human rights conventions.
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Будрицкий, А. М., В. А. Серёгина, and Н. С. Правада. "Structure and Dynamics of Drug Resistance in Patients with Respiratory Tuberculosis." Клиническая инфектология и паразитология, no. 1 (April 12, 2021): 17–28. http://dx.doi.org/10.34883/pi.2021.10.1.022.
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Несмотря на достигнутые успехи эпидемиологической ситуации по туберкулезу в нашей стране, остается чрезвычайно актуальной проблема наличия у пациентов лекарственной устойчивости (ЛУ) микобактерий туберкулеза (МБТ). В работе проанализирована структура и динамика ЛУ пациентов, получивших лечение в Богушевской областной противотуберкулезной больнице (БОТБ) с 2012 по 2016 г. В течение этих лет наблюдается отчетливая тенденция к увеличению количества пациентов с полиустойчивостью, множественной лекарственной устойчивостью (МЛУ) МБТ как в абсолютных цифрах по годам, так и в процентном отношении от случаев лекарственной устойчивости к каждому году. Процент пациентов с наличием пре-широкой лекарственной устойчивости к инъекционным аминогликозидам (пре-ШЛУInj) от всех пациентов с наличием лекарственной устойчивости МБТ ежегодно довольно высокий (от 16,5 до 46,5). Процент пациентов с наличием пре-широкой лекарственной устойчивости к фторхинолонам (пре-ШЛУFg) МБТ от всех пациентов с наличием лекарственной устойчивости МБТ ежегодно низкий (от 0,9 до 5,9). У пациентов с полиустойчивостью МБТ значительно увеличилось разнообразие сочетаний лекарственной устойчивости МБТ к противотуберкулезным препаратам при одновременном увеличении их количества. У пациентов с наличием МЛУ МБТ выявлена наиболее часто встречающаяся комбинация в виде HREZ. Группа пациентов с пре-ШЛУInj МБТ отличалась большим разнообразием комбинаций противотуберкулезных препаратов. Причем ежегодно из них встречались две комбинации (HRSEKm, HREKm). Число пациентов с комбинацией HRSEKm на протяжении пяти лет в этой группе уменьшилось, а число пациентов с комбинацией HREKm значительно увеличилось. Варианты пре-ШЛУFg МБТ встречались редко и не каждый год и были представлены двумя комбинациями: HREOfх, HRZEOfх. В группе пациентов с широкой лекарственной устойчивостью (ШЛУ) МБТ одновременно встречалась лекарственная устойчивость к 9 противотуберкулезным препаратам. Во всех случаях комбинаций преобладала устойчивость к Km, Am, Ofх, Pas. Despite the success achieved in the epidemiological situation of tuberculosis in our country, the problem of the presence of drug resistance (DR) in patients with Mycobacterium tuberculosis (MBT) remains extremely urgent. The paper analyzes the structure and dynamics of DR patients who received treatment at the Bogushevsk Regional TB Hospital (BRTH) from 2012 to 2016. During these years there was a clear trend towards an increase in the number of patients with poly-resistance, multiple drug resistance (MDR) of the MBT, both in absolute numbers by year, and as a percentage of cases of drug resistance per each year. The annual percentage of patients with pre-extensive drug resistance to injectable aminoglycosides (pre-XDRIni) from all patients with MBT drug resistance is quite high (from 16.5% to 46.5%). The annual percentage of patients with pre-extensive drug resistance to fluoroquinolones (pre-XDRInj) of MBT from all patients with drug resistance of MBT is low (from 0.9 to 5.9). In patients with MBT poly-resistance, the variety of combinations of MBT drug resistance to anti-tuberculosis drugs increased significantly while their number also increased. In MBT patients with MDR, the most common combination identified was HREZ. The group of MBT patients with pre-extensive drug resistance to injectable aminoglycosides was distinguished by a wide variety of combinations of anti-tuberculosis drugs. Moreover, two combinations were encountered annually (HRSEKm, HREKm). The number of patients with the HRSEKm combination decreased over the course of five years in this group while the number of patients with HREKm combination increased significantly. Pre-extensive drug resistance to fluoroquinolones variants were rare and did not occur every year. They were represented by two combinations: HREOfx, HRZEOfx. In the group of patients with extensively drug-resistant MBT, simultaneous drug resistance to 9 anti- tuberculosis drugs was encountered. In all cases of combinations, resistance to Km, Am, Ofх, Pas prevailed.
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Esposito, Susanna. "TUBERCULOSIS IN CHILDREN." Mediterranean Journal of Hematology and Infectious Diseases 5, no. 1 (November 4, 2013): e2013064. http://dx.doi.org/10.4084/mjhid.2013.064.
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Tuberculosis (TB) in children is a neglected aspect of the TB epidemic despite it constituting 20% or more of all TB cases in many countries with high TB incidence. Childhood TB is a direct consequence of adult TB but remains overshadowed by adult TB because it is usually smear-negative. Infants and young children are more likely to develop life-threatening forms of TB than older children and adults due to their immature immune systems. Therefore, prompt diagnoses are extremely important although difficult since clinical and radiological signs of TB can be non-specific and variable in children. Despite undeniable advances in identifying definite, probable, or possible TB markers, pediatricians still face many problems when diagnosing TB diagnosis. Moreover, curing TB can be difficult when treatment is delayed and when multi-drug resistant (MDR) pathogens are the cause of the disease. In these cases, the prognosis in children is particularly poor because MDR-TB treatment and treatment duration remain unclear. New studies of diagnostic tests and optimal treatment in children are urgently needed with the final goal of developing an effective anti-TB vaccine.
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Moni, Esther Del florence Ndedi, Patrick Hervé Diboue Betote, Christelle Wayoue Kom, Chimène Félicite Mekoulou Benga, Armelle Deutou Tchamgoue, and Maximilienne Ascension Nyegue. "Inhibitory effects of hydroethanolic extracts from three Cameroonian medicinal plants on proteins inflammation and growth of multi-resistant strains of Mycobacterium tuberculosis." Journal of Drug Delivery and Therapeutics 11, no. 4-S (August 15, 2021): 15–21. http://dx.doi.org/10.22270/jddt.v11i4-s.4930.
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The present work aimed to determine the phytochemical components and evaluate the in vitro anti-inflammatory and anti-mycobacterial effects of hydroethanolic extracts of Allium sativum L bulbs, Drypetes gossweileri S. MOORE stem-barks and Pentadiplandra brazzeana Baill roots against several resistant strains of Mycobacterium tuberculosis. The phytochemical screenings of extracts were carried out according the colorimetric and precipitation tests to reveal the presence of phytochemical compounds. The anti-inflammatory effects of extracts were evaluated using in vitro Bovine Serum Albumin denaturation and proteinase inhibitory action assays. The inhibitory parameters of hydro-ethanol extracts were evaluated by the microdilution method agaisnt Mycobacterium tuberculosis. The phytochemical screening of hydro-ethanol extracts revealed the presence of phenols, polyphenols, flavonoids, alkaloids, cathechic tannins, triterpens, steroids, anthocyanins and leucoanthocyanins. The anti-inflammatory activity of hydro-ethanol extracts of D. gossweileri, P. brazzeana and A. sativum have shown the inhibitory concentrations 50 (IC50) values ranging from 356.70, 183.30 and 226.30 mg/mL for BSA denaturation and 31.92, 33.62 and 56.93 mg/mL for proteinase inhibitory action respectively. The hydroethanolic extracts of D. gossweileri, P. brazzeana and A. sativum exhibited moderate and weak anti-mycobacterial activities with the minimum inhibitory concentrations (MICs) ranging from 312.5 to 2500 μg/mL. A. sativum hydro-ethanol extract has shown the highest anti-mycobacterial activity with MIC of 312.5 μg/mL against isoniazid resistant of M. tuberculosis and extremely resistant drug strain of M. tuberculosis. These results suggest that hydro-ethanol extracts of A. sativum, D. gossweileri and P. brazzeana are efficient against tuberculosis caused by multi-resistant Mycobacterium tuberculosis strains and are able to resorb the inflammation induced during infection.
Keywords: Anti-inflammatory activity, Anti-mycobacterial effect, Hydroethanolic extracts, Medicinal plants, Phytochemical screening.
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Arbex, Marcos Abdo, Hélio Ribeiro de Siqueira, Lia D'Ambrosio, and Giovanni Battista Migliori. "The challenge of managing extensively drug-resistant tuberculosis at a referral hospital in the state of São Paulo, Brazil: a report of three cases." Jornal Brasileiro de Pneumologia 41, no. 6 (December 2015): 554–59. http://dx.doi.org/10.1590/s1806-37562015000000299.
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ABSTRACT Here, we report the cases of three patients diagnosed with extensively drug-resistant tuberculosis and admitted to a referral hospital in the state of São Paulo, Brazil, showing the clinical and radiological evolution, as well as laboratory test results, over a one-year period. Treatment was based on the World Health Organization guidelines, with the inclusion of a new proposal for the use of a combination of antituberculosis drugs (imipenem and linezolid). In the cases studied, we show the challenge of creating an acceptable, effective treatment regimen including drugs that are more toxic, are more expensive, and are administered for longer periods. We also show that treatment costs are significantly higher for such patients, which could have an impact on health care systems, even after hospital discharge. We highlight the fact that in extreme cases, such as those reported here, hospitalization at a referral center seems to be the most effective strategy for providing appropriate treatment and increasing the chance of cure. In conclusion, health professionals and governments must make every effort to prevent cases of multidrug-resistant and extensively drug-resistant tuberculosis.
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Li, Lei, Eungyu Lee, and Neil Shaw. "Expression, purification and crystallization of phosphoribosyl transferase from a mycobacteriophage." Acta Crystallographica Section F Structural Biology Communications 74, no. 3 (February 26, 2018): 161–65. http://dx.doi.org/10.1107/s2053230x18002480.
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Tuberculosis (TB) continues to remain a leading cause of death globally. Of particular concern is the emergence and rise in incidence of multidrug-resistant and extremely drug-resistant cases of TB. To counter this threat, it is important to explore alternative therapies, including phage therapy. Phage BTCU-1 specifically infectsMycobacteriumspp. and kills the majority of them. Intriguingly, many proteins from the phage do not share high amino-acid sequence identity with proteins from species other than phages. Here, the expression, purification and crystallization of one such protein, a putative phosphoribosyl transferase from phage BTCU-1, is reported. The crystals belonged to space groupC2221, with unit-cell parametersa= 59.71,b= 64.42,c = 65.32 Å, α = β = γ = 90°. The crystals diffracted X-rays to 2.2 Å resolution.
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Daneshfar, Sara, Azar Dokht Khosravi, and Mohammad Hashemzadeh. "Drug susceptibility profiling and genetic determinants of drug resistance in Mycobacterium simiae isolates obtained from regional tuberculosis reference laboratories of Iran." PLOS ONE 17, no. 8 (August 12, 2022): e0267320. http://dx.doi.org/10.1371/journal.pone.0267320.
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Background Among Non-tuberculous mycobacteria (NTM) which generally cause opportunistic infections, especially in immunocompromised hosts, Mycobacterium simiae (M. simiae) is one of the most important NTM, associated with pulmonary disease. The main concern about M. simiae infections is the extreme resistance of this NTM to antibiotics. There are limited studies about drug susceptibility testing (DST) and the causes of drug resistance in M. simiae. Hence, the current study aimed to identify the M. simiae isolates and to assess the drug resistance of the isolates using phenotypic and molecular methods. Materials and methods In this study, 50 clinical pulmonary isolates suspected of NTM were collected from regional tuberculosis reference laboratories in Iran. The isolates were identified as M. simiae by using standard biochemical tests and molecular methods. DST was performed for identified M. simiae isolates and additional 35 M. simiae isolates from the department archive, against eight drugs. The mutations in gyrA, gyrB, and rrl genes in clarithromycin and moxifloxacin resistant isolates were investigated by polymerase chain reaction (PCR) followed by sequencing. Results Out of 50 suspected NTM isolates, 25 isolates were detected as M. simiae species based on the biochemical tests, and 18 isolates were verified based on the rpoB gene sequence analysis to achieve a total of 53 isolates when the archive isolates were included. DST results showed that all 53 isolates were resistant to isoniazid, rifampin, and clofazimine. The rate of resistance to ethambutol and linezolid were 34 (64%), and 40 (76%) respectively. The highest susceptibility rate was demonstrated for amikacin 53 (100%) and clarithromycin 45(85%), followed by moxifloxacin 35(66%). Sequence analysis showed mutations in positions 2058 and 2059 of the rrl gene, as well non-synonymous mutation at codons 389, 444, and 571 of the gyrB gene. Sequence analysis showed no mutation in the gyrA gene. drug-resistant isolates with mutations showed higher MICs compared to non-mutant resistant isolates. Conclusions This study revealed amikacin, clarithromycin, and moxifloxacin as the most effective antibiotics. However, since M. simiae exhibited a high level of antibiotic resistance in vitro, therefore, species identification and determining the antibiotic susceptibility pattern of the isolates are essential before treatment.
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Bespyatykh, Julia, Egor Shitikov, Dmitry Bespiatykh, Andrei Guliaev, Ksenia Klimina, Vladimir Veselovsky, Georgij Arapidi, et al. "Metabolic Changes of Mycobacterium tuberculosis during the Anti-Tuberculosis Therapy." Pathogens 9, no. 2 (February 18, 2020): 131. http://dx.doi.org/10.3390/pathogens9020131.
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Tuberculosis, caused by Mycobacterium tuberculosis complex bacteria, remains one of the most pressing health problems. Despite the general trend towards reduction of the disease incidence rate, the situation remains extremely tense due to the distribution of the resistant forms. Most often, these strains emerge through the intra-host microevolution of the pathogen during treatment failure. In the present study, the focus was on three serial clinical isolates of Mycobacterium tuberculosis Beijing B0/W148 cluster from one patient with pulmonary tuberculosis, to evaluate their changes in metabolism during anti-tuberculosis therapy. Using whole genome sequencing (WGS), 9 polymorphisms were determined, which occurred in a stepwise or transient manner during treatment and were linked to the resistance (GyrA D94A; inhA t-8a) or virulence. The effect of the inhA t-8a mutation was confirmed on both proteomic and transcriptomic levels. Additionally, the amount of RpsL protein, which is a target of anti-tuberculosis drugs, was reduced. At the systemic level, profound changes in metabolism, linked to the evolution of the pathogen in the host and the effects of therapy, were documented. An overabundance of the FAS-II system proteins (HtdX, HtdY) and expression changes in the virulence factors have been observed at the RNA and protein levels.
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Das, Rina, Gyati S. Asthana, Krishan A. Suri, Dinesh Mehta, and Abhay Asthana. "Recent Developments in Azole Compounds as Antitubercular Agent." Mini-Reviews in Organic Chemistry 16, no. 3 (January 25, 2019): 290–306. http://dx.doi.org/10.2174/1570193x15666180622144414.
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Tuberculosis (TB) is a global health disaster and is a wide-reaching hitch. The improper use of antibiotics in chemotherapy of TB patients led to the current problem of tuberculosis therapy which gives rise to Multi-Drug Resistant (MDR) strains. Nitrogen heterocycles including azole compounds are an important class of therapeutic agent with electron-rich property. Azole-based derivatives easily bind with the enzymes and receptors in organisms through noncovalent interactions, thereby possessing various applications in medicinal chemistry. Research on azoles derivatives have been expansively carried out and have become one of the extremely active area in recent years and the progress is quite rapid. A genuine attempt to review chemistry of azoles and to describe various azole-based compounds synthesized in the last two decades having promising antitubercular potential is described in the present article. It is hopeful that azole compounds may continue to serve as an important direction for the exploitation of azole-based antitubercular drugs with better curative effect, lower toxicity, less side effects, especially fewer resistances and so on.
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Pavlenko, E. P., N. V. Rachina, and S. V. Epifanova. "The surfactant inhaled therapy in a complex lung tuberculosis treatment: clinical reviews." Meditsinskiy sovet = Medical Council, no. 23 (January 18, 2023): 118–24. http://dx.doi.org/10.21518/2079-701x-2022-16-23-118-124.
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The article describes the clinical case reports of patients with respiratory tuberculosis who were hospitalized at the Regional Clinical Antituberculosis Center in Kursk. One of them was in the pediatric department for patients with tuberculosis of respiratory organs and the other in the 1st department for patients with multidrug-resistant tuberculosis. As pathogenetic therapy in the complex treatment of pulmonary tuberculosis, in the intensive phase of anti-tuberculosis chemotherapy, we added inhalation therapy with surfactant (medicinal product surfactant-BL lyophilisate for emulsion preparation, 75 mg, manufactured by Biosurf LLC, Russia) according to the instructions to the drug. Treatment of pulmonary tuberculosis is performed by multiple inhalations of surfactant-BL as part of complex therapy against the background of fully deployed antituberculosis drugs (ATD), i.e. when the patient empirically or based on data on drug sensitivity of the pathogen is selected 4-6 ATD that are well tolerated by the patient in the prescribed dose and combination. It should be noted that an adult patient during the intensive phase of anti-tuberculosis chemotherapy had COVID-19. Against the background of inhalation therapy with surfactant, it was possible to stabilize the clinical and radiological condition of the patients, and to improve their condition. Clinically it was expressed in reduction of coughing, increase of tolerance to physical exertion. For example, according to spirometry data on the admission of an adult patient and in dynamics, the vital capacity index (VCI) increased from an extremely sharp decrease (31.25%) to 75%, which corresponded to a very mild decrease. At the moment the patient from the children’s ward is completing a course of antituberculosis therapy with small residual changes in the lungs, and the adult patient was operated on at the Russian Ministry of Health at the Federal State Budgetary Institution “National Research Center of Pulmonary Medicine” for installation of a bronchial valve. Based on the above, we can conclude about the successful, pathogenetically sound use of surfactant-BL in patients with respiratory tuberculosis in both children and adults.
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Foo, Caroline Shi-Yan, Benoit Lechartier, Gaëlle S. Kolly, Stefanie Boy-Röttger, João Neres, Jan Rybniker, Andréanne Lupien, Claudia Sala, Jérémie Piton, and Stewart T. Cole. "Characterization of DprE1-Mediated Benzothiazinone Resistance in Mycobacterium tuberculosis." Antimicrobial Agents and Chemotherapy 60, no. 11 (August 15, 2016): 6451–59. http://dx.doi.org/10.1128/aac.01523-16.
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ABSTRACTBenzothiazinones (BTZs) are a class of compounds found to be extremely potent against both drug-susceptible and drug-resistantMycobacterium tuberculosisstrains. The potency of BTZs is explained by their specificity for their target decaprenylphosphoryl-d-ribose oxidase (DprE1), in particular by covalent binding of the activated form of the compound to the critical cysteine 387 residue of the enzyme. To probe the role of C387, we used promiscuous site-directed mutagenesis to introduce other codons at this position intodprE1ofM. tuberculosis. The resultant viable BTZ-resistant mutants were characterizedin vitro,ex vivo, and biochemically to gain insight into the effects of these mutations on DprE1 function and onM. tuberculosis. Five different mutations (C387G, C387A, C387S, C387N, and C387T) conferred various levels of resistance to BTZ and exhibited different phenotypes. The C387G and C387N mutations resulted in a lower growth rate of the mycobacterium on solid medium, which could be attributed to the significant decrease in the catalytic efficiency of the DprE1 enzyme. All five mutations rendered the mycobacterium less cytotoxic to macrophages. Finally, differences in the potencies of covalent and noncovalent DprE1 inhibitors in the presence of C387 mutations were revealed by enzymatic assays. As expected from the mechanism of action, the covalent inhibitor PBTZ169 only partially inhibited the mutant DprE1 enzymes compared to the near-complete inhibition with a noncovalent DprE1 inhibitor, Ty38c. This study emphasizes the importance of the C387 residue for DprE1 activity and for the killing action of covalent inhibitors such as BTZs and other recently identified nitroaromatic inhibitors.
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Vyazovaya, Anna, Igor Mokrousov, Natalia Solovieva, Alexander Mushkin, Olga Manicheva, Boris Vishnevsky, Viacheslav Zhuravlev, and Olga Narvskaya. "Tuberculous Spondylitis in Russia and Prominent Role of Multidrug-Resistant Clone Mycobacterium tuberculosis Beijing B0/W148." Antimicrobial Agents and Chemotherapy 59, no. 4 (February 2, 2015): 2349–57. http://dx.doi.org/10.1128/aac.04221-14.
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ABSTRACTExtrapulmonary and, in particular, spinal tuberculosis (TB) constitutes a minor but significant part of the total TB incidence. In spite of this, almost no studies on the genetic diversity and drug resistance ofMycobacterium tuberculosisisolates from spinal TB patients have been published to date. Here, we report results of the first Russian and globally largest molecular study ofM. tuberculosisisolates recovered from patients with tuberculous spondylitis (TBS). The majority of 107 isolates were assigned to the Beijing genotype (n= 80); the other main families were T (n= 11), Ural (n= 7), and LAM (n= 4). Multidrug resistance (MDR) was more frequently found among Beijing (90.5%) and, intriguingly, Ural (71.4%) isolates than other genotypes (5%;P< 0.001). The extremely drug-resistant (XDR) phenotype was exclusively found in the Beijing isolates (n= 7). A notable prevalence of therpoB531andkatG315mutations in Beijing strains that were similarly high in both TBS (this study) and published pulmonary TB (PTB) samples from Russia shows that TBS and PTB Beijing strains follow the same paradigm of acquisition of rifampin (RIF) and isoniazid (INH) resistance. The 24-locus mycobacterial interspersed repetitive unit–variable-number tandem-repeat (MIRU-VNTR) subtyping of 80 Beijing isolates further discriminated them into 24 types (Hunter Gaston index [HGI] = 0.83); types 100-32 and 94-32 represented the largest groups. A genotype of Russian successful clone B0/W148 was identified in 30 of 80 Beijing isolates. In conclusion, this study highlighted a crucial impact of the Beijing genotype and the especially prominent role of its MDR-associated successful clone B0/W148 cluster in the development of spinal MDR-TB in Russian patients.
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Prowse, Stephen J., and John S. MacKenzie. "Emerging Infectious Disease." Microbiology Australia 30, no. 4 (2009): 112. http://dx.doi.org/10.1071/ma09112.
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The term ?emerging diseases? has become synonymous with new, previously unknown infectious agents, or with known infectious agents which are either spreading geographically or increasing in incidence. An analysis by Jones et al (2008) showed that since 1940 there has been a steady increase in new diseases, and new diseases are continuing to emerge today. Most of these new diseases are of minor importance with respect to human or animal health, but occasionally important, highly pathogenic diseases arise, such as we have seen in recent years with SARS and Nipah virus, or with new variants or strains of known diseases such as avian H5N1 influenza, the current pandemic strain of H1N1 2009 influenza virus, and extremely drug resistant tuberculosis.
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Ame, Mohammedkemal Mustefa. "Review on the Global Public Health Issue of Antibiotic Resistance and Potential Solutions." Public Health Open Access 7, no. 1 (2023): 1–11. http://dx.doi.org/10.23880/phoa-16000233.
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Both industrialized and developing nations are extremely concerned about the worldwide spread of infectious diseases and the rise of antibiotic resistance. It is common for bacteria to develop resistance to antibiotics, and this phenomenon has been observed after the introduction of every antimicrobial drug into clinical practice. When bacteria adapt, the effectiveness of medications used to treat the infection is decreased or eliminated. This phenomenon is known as resistance. As a result, the germs continue to grow and cause additional damage. Due to the fact that the current antibiotics in clinical use were produced through changes to the existing classes and have demonstrated short effect cycles, a report indicated that there would be a global antibiotic shortage. The main contributing variables include population density and mobility, proper use of human antibiotics, and sub-therapeutic and excessive use of antibiotics in food animals. Manufacturers of extended-spectrum beta-lactamases and drug resistance Major concerns to global public health include Neisseria gonorrhoeae, tuberculosis, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. At the moment, antibiotic resistance places a significant clinical and financial burden. Due to the requirement for more expensive medications for the second line of therapy and significantly longer hospital stays, antibiotic resistance has a significant financial impact on the patient and family, the hospital, and society. According to the Centers for Disease Control and Prevention, antibiotic resistance causes 23,000 fatalities and over 2 million illnesses annually in the United States alone. With 27.3 deaths per 100,000 people, Africa has the highest mortality rate from AMR infections in the whole globe.
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Ndjeka, N., J. Hughes, A. Reuter, F. Conradie, M. Enwerem, H. Ferreira, N. Ismail, et al. "Implementing novel regimens for drug-resistant TB in South Africa: what can the world learn?" International Journal of Tuberculosis and Lung Disease 24, no. 10 (October 1, 2020): 1073–80. http://dx.doi.org/10.5588/ijtld.20.0174.
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Worldwide uptake of new drugs in the treatment of rifampicin-resistant tuberculosis (RR-TB) has been extremely low. In June 2018, ahead of the release of the updated WHO guidelines for the management of RR-TB, South Africa announced that bedaquiline (BDQ) would be provided to virtually all RR-TB patients on shorter or longer regimens. South Africa has been the global leader in accessing BDQ for patients with RR-TB, who now represent 60% of the global BDQ cohort. The use of BDQ within a shorter modified regimen has generated the programmatic data underpinning the most recent change in WHO guidelines endorsing a shorter, injectable-free regimen. Progressive policies on access to new drugs have resulted in improved favourable outcomes and a reduction in mortality among RR-TB patients in South Africa. This supported global policy change. The strategies underpinning these bold actions include close collaboration between the South African National TB Programme and partners, introduction of new TB diagnostic tools in closely monitored conditions and the use of locally generated programmatic evidence to inform country policy changes. In this paper, we summarise a decade´s work that led to the bold decision to use a modified, short, injectable-free regimen with BDQ and linezolid under carefully monitored programmatic conditions.