Contents
Academic literature on the topic 'Drug-tolerant Mtb'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the lists of relevant articles, books, theses, conference reports, and other scholarly sources on the topic 'Drug-tolerant Mtb.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Journal articles on the topic "Drug-tolerant Mtb"
1
Mishra, Richa, Sakshi Kohli, Nitish Malhotra, Parijat Bandyopadhyay, Mansi Mehta, MohamedHusen Munshi, Vasista Adiga, et al. "Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis." Science Translational Medicine 11, no. 518 (November 13, 2019): eaaw6635. http://dx.doi.org/10.1126/scitranslmed.aaw6635.
Full textAbstract:
The capacity of Mycobacterium tuberculosis (Mtb) to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in Mtb populations is one of the factors that drives antibiotic tolerance during infection. However, the mechanisms underpinning this variation in bacterial population remain poorly understood. Here, we show that phagosomal acidification alters the redox physiology of Mtb to generate a population of replicating bacteria that display drug tolerance during infection. RNA sequencing of this redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster biogenesis, hydrogen sulfide (H2S) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when Mtb infected macrophages with actively replicating HIV-1, suggesting that redox heterogeneity could contribute to high rates of TB therapy failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant Mtb, ameliorated lung pathology, and reduced postchemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (Cmax and AUClast) exhibited no major drug-drug interaction when coadministered with first line anti-TB drugs in mice. Our data establish a link between phagosomal pH, redox metabolism, and drug tolerance in replicating Mtb and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure.
2
Vilchèze, Catherine, Travis Hartman, Brian Weinrick, Paras Jain, Torin R. Weisbrod, Lawrence W. Leung, Joel S. Freundlich, and William R. Jacobs. "Enhanced respiration prevents drug tolerance and drug resistance in Mycobacterium tuberculosis." Proceedings of the National Academy of Sciences 114, no. 17 (April 10, 2017): 4495–500. http://dx.doi.org/10.1073/pnas.1704376114.
Full textAbstract:
Persistence, manifested as drug tolerance, represents a significant obstacle to global tuberculosis control. The bactericidal drugs isoniazid and rifampicin kill greater than 99% of exponentially growing Mycobacterium tuberculosis (Mtb) cells, but the remaining cells are persisters, cells with decreased metabolic rate, refractory to killing by these drugs, and able to generate drug-resistant mutants. We discovered that the combination of cysteine or other small thiols with either isoniazid or rifampicin prevents the formation of drug-tolerant and drug-resistant cells in Mtb cultures. This effect was concentration- and time-dependent, relying on increased oxygen consumption that triggered enhanced production of reactive oxygen species. In infected murine macrophages, the addition of N-acetylcysteine to isoniazid treatment potentiated the killing of Mtb. Furthermore, we demonstrate that the addition of small thiols to Mtb drug treatment shifted the menaquinol/menaquinone balance toward a reduced state that stimulates Mtb respiration and converts persister cells to metabolically active cells. This prevention of both persister cell formation and drug resistance leads ultimately to mycobacterial cell death. Strategies to enhance respiration and initiate oxidative damage should improve tuberculosis chemotherapies.
3
Lim, Juhyeon, Jae Jin Lee, Sun-Kyung Lee, Seoyong Kim, Seok-Yong Eum, and Hyungjin Eoh. "Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia." Proceedings of the National Academy of Sciences 118, no. 35 (August 23, 2021): e2105800118. http://dx.doi.org/10.1073/pnas.2105800118.
Full textAbstract:
Mycobacterium tuberculosis (Mtb) infection is difficult to treat because Mtb spends the majority of its life cycle in a nonreplicating (NR) state. Since NR Mtb is highly tolerant to antibiotic effects and can mutate to become drug resistant (DR), our conventional tuberculosis (TB) treatment is not effective. Thus, a novel strategy to kill NR Mtb is required. Accumulating evidence has shown that repetitive exposure to sublethal doses of antibiotics enhances the level of drug tolerance, implying that NR Mtb is formed by adaptive metabolic remodeling. As such, metabolic modulation strategies to block the metabolic remodeling needed to form NR Mtb have emerged as new therapeutic options. Here, we modeled in vitro NR Mtb using hypoxia, applied isotope metabolomics, and revealed that phosphoenolpyruvate (PEP) is nearly completely depleted in NR Mtb. This near loss of PEP reduces PEP-carbon flux toward multiple pathways essential for replication and drug sensitivity. Inversely, supplementing with PEP restored the carbon flux and the activities of the foregoing pathways, resulting in growth and heightened drug susceptibility of NR Mtb, which ultimately prevented the development of DR. Taken together, PEP depletion in NR Mtb is associated with the acquisition of drug tolerance and subsequent emergence of DR, demonstrating that PEP treatment is a possible metabolic modulation strategy to resensitize NR Mtb to conventional TB treatment and prevent the emergence of DR.
4
Liu, Yancheng, Shumin Tan, Lu Huang, Robert B. Abramovitch, Kyle H. Rohde, Matthew D. Zimmerman, Chao Chen, Véronique Dartois, Brian C. VanderVen, and David G. Russell. "Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo." Journal of Experimental Medicine 213, no. 5 (April 25, 2016): 809–25. http://dx.doi.org/10.1084/jem.20151248.
Full textAbstract:
Successful chemotherapy against Mycobacterium tuberculosis (Mtb) must eradicate the bacterium within the context of its host cell. However, our understanding of the impact of this environment on antimycobacterial drug action remains incomplete. Intriguingly, we find that Mtb in myeloid cells isolated from the lungs of experimentally infected mice exhibit tolerance to both isoniazid and rifampin to a degree proportional to the activation status of the host cells. These data are confirmed by in vitro infections of resting versus activated macrophages where cytokine-mediated activation renders Mtb tolerant to four frontline drugs. Transcriptional analysis of intracellular Mtb exposed to drugs identified a set of genes common to all four drugs. The data imply a causal linkage between a loss of fitness caused by drug action and Mtb’s sensitivity to host-derived stresses. Interestingly, the environmental context exerts a more dominant impact on Mtb gene expression than the pressure on the drugs’ primary targets. Mtb’s stress responses to drugs resemble those mobilized after cytokine activation of the host cell. Although host-derived stresses are antimicrobial in nature, they negatively affect drug efficacy. Together, our findings demonstrate that the macrophage environment dominates Mtb’s response to drug pressure and suggest novel routes for future drug discovery programs.
5
Fattorini, Lanfranco, Giovanni Piccaro, Alessandro Mustazzolu, and Federico Giannoni. "TARGETING DORMANT BACILLI TO FIGHT TUBERCULOSIS." Mediterranean Journal of Hematology and Infectious Diseases 5, no. 1 (November 19, 2013): e2013072. http://dx.doi.org/10.4084/mjhid.2013.072.
Full textAbstract:
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which kills about 2 million people annually. Furthermore, 2 billion people worldwide are latently infected with this organism, with 10% of them reactivating to active TB due to re-growth of nonreplicating (dormant) Mtb residing in their tissues. Because of the huge reservoir of latent TB it is important to find novel drugs/drug combinations killing dormant bacilli (microaerophiles, anaerobes and drug-tolerant persisters) surviving for decades in a wide spectrum of granulomatous lesions in the lungs of TB patients. Antibiotic treatment of drug-susceptible TB requires administration of isoniazid, rifampin, pyrazinamide, ethambutol for 2 months, followed by isoniazid and rifampin for 4 months. To avoid reactivation of dormant Mtb to active pulmonary TB, up to 9 months of treatment with isoniazid is required. Therefore, a strategy to eliminate dormant bacilli needs to be developed to shorten therapy of active and latent TB and reduce the reservoir of people with latent TB. Finding drugs with high rate of penetration into the caseous granulomas and understanding the biology of dormant bacilli and in particular of persister cells, phenotypically resistant to antibiotics, will be essential to eradicate Mtb from humans. In recent years unprecedented efforts have been done in TB drug discovery, aimed at identifying novel drugs and drug combinations killing both actively replicating and nonreplicating Mtb in vitro, in animal models and in clinical trials in humans.
6
Saito, Kohta, Thulasi Warrier, Selin Somersan-Karakaya, Lina Kaminski, Jianjie Mi, Xiuju Jiang, Suna Park, et al. "Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations." Proceedings of the National Academy of Sciences 114, no. 24 (May 30, 2017): E4832—E4840. http://dx.doi.org/10.1073/pnas.1705385114.
Full textAbstract:
Mycobacterium tuberculosis (Mtb) encounters stresses during the pathogenesis and treatment of tuberculosis (TB) that can suppress replication of the bacteria and render them phenotypically tolerant to most available drugs. Where studied, the majority of Mtb in the sputum of most untreated subjects with active TB have been found to be nonreplicating by the criterion that they do not grow as colony-forming units (cfus) when plated on agar. However, these cells are viable because they grow when diluted in liquid media. A method for generating such “differentially detectable” (DD) Mtb in vitro would aid studies of the biology and drug susceptibility of this population, but lack of independent confirmation of reported methods has contributed to skepticism about their existence. Here, we identified confounding artifacts that, when avoided, allowed development of a reliable method of producing cultures of ≥90% DD Mtb in starved cells. We then characterized several drugs according to whether they contribute to the generation of DD Mtb or kill them. Of the agents tested, rifamycins led to DD Mtb generation, an effect lacking in a rifampin-resistant strain with a mutation in rpoB, which encodes the canonical rifampin target, the β subunit of RNA polymerase. In contrast, thioridazine did not generate DD Mtb from starved cells but killed those generated by rifampin.
7
Genestet, Charlotte, Elisabeth Hodille, Alexia Barbry, Jean-Luc Berland, Jonathan Hoffmann, Emilie Westeel, Fabiola Bastian, et al. "Rifampicin exposure reveals within-host Mycobacterium tuberculosis diversity in patients with delayed culture conversion." PLOS Pathogens 17, no. 6 (June 24, 2021): e1009643. http://dx.doi.org/10.1371/journal.ppat.1009643.
Full textAbstract:
Mycobacterium tuberculosis (Mtb) genetic micro-diversity in clinical isolates may underline mycobacterial adaptation to tuberculosis (TB) infection and provide insights to anti-TB treatment response and emergence of resistance. Herein we followed within-host evolution of Mtb clinical isolates in two cohorts of TB patients, either with delayed Mtb culture conversion (> 2 months), or with fast culture conversion (< 2 months). We captured the genetic diversity of Mtb isolates obtained in each patient, by focusing on minor variants detected as unfixed single nucleotide polymorphisms (SNPs). To unmask antibiotic tolerant sub-populations, we exposed these isolates to rifampicin (RIF) prior to whole genome sequencing (WGS) analysis. Thanks to WGS, we detected at least 1 unfixed SNP within the Mtb isolates for 9/15 patients with delayed culture conversion, and non-synonymous (ns) SNPs for 8/15 patients. Furthermore, RIF exposure revealed 9 additional unfixed nsSNP from 6/15 isolates unlinked to drug resistance. By contrast, in the fast culture conversion cohort, RIF exposure only revealed 2 unfixed nsSNP from 2/20 patients. To better understand the dynamics of Mtb micro-diversity, we investigated the variant composition of a persistent Mtb clinical isolate before and after controlled stress experiments mimicking the course of TB disease. A minor variant, featuring a particular mycocerosates profile, became enriched during both RIF exposure and macrophage infection. The variant was associated with drug tolerance and intracellular persistence, consistent with the pharmacological modeling predicting increased risk of treatment failure. A thorough study of such variants not necessarily linked to canonical drug-resistance, but which are prone to promote anti-TB drug tolerance, may be crucial to prevent the subsequent emergence of resistance. Taken together, the present findings support the further exploration of Mtb micro-diversity as a promising tool to detect patients at risk of poorly responding to anti-TB treatment, ultimately allowing improved and personalized TB management.
8
Iacobino, Angelo, Lanfranco Fattorini, and Federico Giannoni. "Drug-Resistant Tuberculosis 2020: Where We Stand." Applied Sciences 10, no. 6 (March 22, 2020): 2153. http://dx.doi.org/10.3390/app10062153.
Full textAbstract:
The control of tuberculosis (TB) is hampered by the emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, defined as resistant to at least isoniazid and rifampin, the two bactericidal drugs essential for the treatment of the disease. Due to the worldwide estimate of almost half a million incident cases of MDR/rifampin-resistant TB, it is important to continuously update the knowledge on the mechanisms involved in the development of this phenomenon. Clinical, biological and microbiological reasons account for the generation of resistance, including: (i) nonadherence of patients to their therapy, and/or errors of physicians in therapy management, (ii) complexity and poor vascularization of granulomatous lesions, which obstruct drug distribution to some sites, resulting in resistance development, (iii) intrinsic drug resistance of tubercle bacilli, (iv) formation of non-replicating, drug-tolerant bacilli inside the granulomas, (v) development of mutations in Mtb genes, which are the most important molecular mechanisms of resistance. This review provides a comprehensive overview of these issues, and releases up-dated information on the therapeutic strategies recently endorsed and recommended by the World Health Organization to facilitate the clinical and microbiological management of drug-resistant TB at the global level, with attention also to the most recent diagnostic methods.
9
Yadav, Pramod. "Challenges & Solutions for Recent Advancements in Multi-Drugs Resistance Tuberculosis: A Review." Microbiology Insights 16 (January 2023): 117863612311524. http://dx.doi.org/10.1177/11786361231152438.
Full textAbstract:
In MDR-TB, mycobacterium is resistant to battlefront drugs like rifampicin and isoniazid. Now it’s an urgent global challenge for treatment & diagnosis because more than 50% of drugs are resistant. Till today's information, 5 reasons are liable for MDR: (1) Errors of physicians/patients in therapy management, (2) Complexity and poor vascularization of granulomatous lesions, which obstruct drug distribution to some sites, leading to resistance development, (3) Intrinsic drug resistance of tubercle bacilli, (4) Formation of non-replicating, drug-tolerant bacilli inside the granulomas, (5) Development of mutations in Mtb genes, which are the foremost important molecular mechanisms of resistance. the most contribution of this work is a brief & clear explanation of things chargeable for resistant development, and recent diagnostic & treatment methods for MDR-TB. This study shall help researchers & scientists to develop replacement rapid diagnostic tools, drugs, and treatment protocols.
10
Choudhury, Sreetama, Ajay Suresh Akhade, and Naeha Subramanian. "Dual RNA-seq as an effective tool to simultaneously identify transcriptional changes in host macrophages and invading intracellular pathogens." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 227.27. http://dx.doi.org/10.4049/jimmunol.204.supp.227.27.
Full textAbstract:
Abstract Intracellular pathogens have evolved strategies to subvert the host immune response and establish infection leading to disease. For example, Mycobacterium tuberculosis (MTB) has been recently reported to effectively counteract immunological and anti-tubercular challenges by activating resistance mechanisms that enable the pathogen to attain an immune tolerant state. A systems scale approach using dual RNA Sequencing revealed key transcriptional factors that enabled researchers to discover a drug combination that delivers more effective killing of MTB. On the basis of our preliminary findings we hypothesize that similar to MTB, Salmonella spp. have evolved to escape host macrophage responses by down-regulating the expression of flagellin, a potent activator of the NLRC4 inflammasome, by taking advantage of a natural host negative feedback mechanism that allows the pathogen to reside intracellularly within macrophages. However, how Salmonella and host transcriptional networks rewire over the course of infection to permit development of an immune-evasive phenotype in the pathogen remains unknown. Using dual RNA-Seq and regulatory network analysis, we propose to simultaneously identify the molecular changes that occur in both the host and the pathogen during infection. We aim to conduct a temporal study to find transcriptional changes at different time points post infection that lead to development of a permissive host environment and allow Salmonella to undergo immune escape within macrophages. Our study will help identify the key regulators that shape host-pathogen crosstalk over the course of Salmonella infection with potentially important implications for bacterial pathogenesis and immunity.