Journal articles: 'Mycobacterium smegmatis - Moxifloxacin'

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Maurer, Florian P., Vera L. Bruderer, Claudia Ritter, Claudio Castelberg, Guido V. Bloemberg, and Erik C. Böttger. "Lack of Antimicrobial Bactericidal Activity in Mycobacterium abscessus." Antimicrobial Agents and Chemotherapy 58, no. 7 (April 21, 2014): 3828–36. http://dx.doi.org/10.1128/aac.02448-14.

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ABSTRACTAntibiotic therapy of infections caused by the emerging pathogenMycobacterium abscessusis challenging due to the organism's natural resistance toward most clinically available antimicrobials. We investigated the bactericidal activity of antibiotics commonly administered inM. abscessusinfections in order to better understand the poor therapeutic outcome. Time-kill curves were generated for clinicalM. abscessusisolates,Mycobacterium smegmatis, andEscherichia coliby using antibiotics commonly categorized as bactericidal (amikacin and moxifloxacin) or bacteriostatic (tigecycline and linezolid). In addition, the impact of aminoglycoside-modifying enzymes on the mode of action of substrate and nonsubstrate aminoglycosides was studied by usingM. smegmatisas a model organism. While amikacin and moxifloxacin were bactericidal againstE. coli, none of the tested compounds showed bactericidal activity againstM. abscessus. Further mechanistic investigations of the mode of action of aminoglycosides inM. smegmatisrevealed that the bactericidal activity of tobramycin and gentamicin was restored by disruption of the chromosomalaac(2′) gene in the mycobacterial genome. The lack of bactericidal antibiotics in currently recommended treatment regimens provides a reasonable explanation for the poor therapeutic outcome inM. abscessusinfection. Our findings suggest that chromosomally encoded drug-modifying enzymes play an important role in the lack of aminoglycoside bactericidal activity against rapidly growing mycobacteria.

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Pasca, Maria Rosalia, Paola Guglierame, Fabio Arcesi, Marco Bellinzoni, Edda De Rossi, and Giovanna Riccardi. "Rv2686c-Rv2687c-Rv2688c, an ABC Fluoroquinolone Efflux Pump in Mycobacterium tuberculosis." Antimicrobial Agents and Chemotherapy 48, no. 8 (August 2004): 3175–78. http://dx.doi.org/10.1128/aac.48.8.3175-3178.2004.

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ABSTRACT The Mycobacterium tuberculosis Rv2686c-Rv2687c-Rv2688c operon, encoding an ABC transporter, conferred resistance to ciprofloxacin and, to a lesser extent, norfloxacin, moxifloxacin, and sparfloxacin to Mycobacterium smegmatis. The resistance level decreased in the presence of the efflux pump inhibitors reserpine, carbonyl cyanide m-chlorophenylhydrazone, and verapamil. Energy-dependent efflux of ciprofloxacin from M. smegmatis cells containing the Rv2686c-Rv2687c-Rv2688c operon was observed.

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Malik, Muhammad, Tao Lu, Xilin Zhao, Anubha Singh, Christopher M. Hattan, John Domagala, Robert Kerns, and Karl Drlica. "Lethality of Quinolones against Mycobacterium smegmatis in the Presence or Absence of Chloramphenicol." Antimicrobial Agents and Chemotherapy 49, no. 5 (May 2005): 2008–14. http://dx.doi.org/10.1128/aac.49.5.2008-2014.2005.

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ABSTRACT Quinolones were examined for rapid lethal activity against Mycobacterium smegmatis in the presence and absence of chloramphenicol, an inhibitor of protein synthesis. C-8 methoxy, C-6 fluorine, and particular C-7 ring substituents enhanced rapid killing. With the surprising exception of moxifloxacin, higher quinolone concentrations were required for lethal activity in the presence of chloramphenicol than in its absence. Moxifloxacin was also unusual in lacking the time lag characteristic of fluoroquinolone lethality. Several fluoroquinolone dimers, which represent quinolones with large C-7 substituents, showed modest bacteriostatic activity. Unlike other quinolones, the dimers failed to display lethal activity. The insensitivity of moxifloxacin to chloramphenicol has not been observed with other bacteria and may therefore reflect unique aspects of mycobacterial gyrase.

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Long, Quanxin, Qinglin Du, Tiwei Fu, Karl Drlica, Xilin Zhao, and Jianping Xie. "Involvement of Holliday Junction Resolvase in Fluoroquinolone-Mediated Killing of Mycobacterium smegmatis." Antimicrobial Agents and Chemotherapy 59, no. 3 (December 22, 2014): 1782–85. http://dx.doi.org/10.1128/aac.04434-14.

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ABSTRACTThe absence of the Holliday-junction Ruv resolvase ofMycobacterium smegmatisincreased the bacteriostatic and bactericidal activities of the fluoroquinolone moxifloxacin, an important antituberculosis agent. The treatment ofruvAB-deficient cells with thiourea and 2,2′-bipyridyl lowered moxifloxacin lethality to wild-type levels, indicating that the absence ofruvABstimulates a lethal pathway involving reactive oxygen species. A hexapeptide that traps the Holliday junction substrate of RuvAB potentiated moxifloxacin-mediated lethality, supporting the development of small-molecule enhancers for moxifloxacin activity against mycobacteria.

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Danilchanka, Olga, Mikhail Pavlenok, and Michael Niederweis. "Role of Porins for Uptake of Antibiotics by Mycobacterium smegmatis." Antimicrobial Agents and Chemotherapy 52, no. 9 (June 16, 2008): 3127–34. http://dx.doi.org/10.1128/aac.00239-08.

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ABSTRACT The outer membrane of mycobacteria presents an effective permeability barrier for many antibiotics. Transport pathways across this membrane are unknown for most drugs. Here, we examined which antibiotics utilize the porin pathway across the outer membrane of the model organism Mycobacterium smegmatis. Deletion of the porins MspA and MspC drastically increased the resistance of M. smegmatis ML10 to β-lactam antibiotics, while its β-lactamase activity remained unchanged. These results are consistent with the ninefold-reduced outer membrane permeability of the M. smegmatis porin mutants for cephaloridine and strongly indicate that β-lactam antibiotics rely on the porin pathway. The porin mutant ML10 accumulated less chloramphenicol and norfloxacin and was less susceptible to these antibiotics than wild-type M. smegmatis. These results demonstrated that small and hydrophilic antibiotics use the Msp porins for entering the cell. In contrast to norfloxacin, the hydrophobic moxifloxacin was 32-fold more effective in inhibiting the growth of M. smegmatis, presumably because it was able to diffuse through the lipid membrane. Structural models indicated that erythromycin, kanamycin, and vancomycin are too large to move through the MspA channel. This study presents the first experimental evidence that hydrophilic fluoroquinolones and chloramphenicol diffuse through porins in mycobacteria. Thus, mutations resulting in less efficient porins or lower porin expression levels are likely to represent a mechanism for the opportunistic pathogens M. avium, M. chelonae, and M. fortuitum, which have Msp-like porins, to acquire resistance to fluoroquinolones.

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Luo, Tao, Jinning Yuan, Xuan Peng, Guoping Yang, Youjun Mi, Changfeng Sun, Chuhan Wang, Chunxi Zhang, and Lang Bao. "Double mutation in DNA gyrase confers moxifloxacin resistance and decreased fitness of Mycobacterium smegmatis." Journal of Antimicrobial Chemotherapy 72, no. 7 (April 6, 2017): 1893–900. http://dx.doi.org/10.1093/jac/dkx110.

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Swaminath, Sharmada, Avraneel Paul, Atul Pradhan, Jees Sebastian, Rashmi Ravindran Nair, and Parthasarathi Ajitkumar. "Mycobacterium smegmatis moxifloxacin persister cells produce high levels of hydroxyl radical, generating genetic resisters selectable not only with moxifloxacin, but also with ethambutol and isoniazid." Microbiology 166, no. 2 (February 1, 2020): 180–98. http://dx.doi.org/10.1099/mic.0.000874.

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Lu, T. "Effect of chloramphenicol, erythromycin, moxifloxacin, penicillin and tetracycline concentration on the recovery of resistant mutants of Mycobacterium smegmatis and Staphylococcus aureus." Journal of Antimicrobial Chemotherapy 52, no. 1 (June 12, 2003): 61–64. http://dx.doi.org/10.1093/jac/dkg268.

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Ajitkumar, Parthasarathi, Avraneel Paul, RashmiRavindran Nair, and Kishor Jakkala. "Mycobacterium smegmatis strains genetically resistant to moxifloxacin emerge de novo from the moxifloxacin-surviving population containing high levels of superoxide, H₂O₂, hydroxyl radical, and Fe (II)." International Journal of Mycobacteriology 11, no. 2 (2022): 150. http://dx.doi.org/10.4103/ijmy.ijmy_58_22.

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Malik, Muhammad, Kalyan Chavda, Xilin Zhao, Nirali Shah, Syed Hussain, Natalia Kurepina, Barry N. Kreiswirth, Robert J. Kerns, and Karl Drlica. "Induction of Mycobacterial Resistance to Quinolone Class Antimicrobials." Antimicrobial Agents and Chemotherapy 56, no. 7 (May 7, 2012): 3879–87. http://dx.doi.org/10.1128/aac.00474-12.

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ABSTRACTAn agar plate assay was developed for detecting the induction of drug-resistant mycobacterial mutants during exposure to inhibitors of DNA gyrase. WhenMycobacterium smegmatison drug-containing agar, resistant colonies arose over a period of 2 weeks. ArecAdeficiency reduced mutant recovery, consistent with involvement of the SOS response in mutant induction. The C-8-methoxy compounds gatifloxacin and moxifloxacin allowed the recovery of fewer resistant mutants than either ciprofloxacin or levofloxacin when present at the same multiple of the MIC; a quinolone-like 8-methoxy-quinazoline-2,4-dione was more effective at restricting the emergence of resistant mutants than its cognate fluoroquinolone. Thus, the structure of fluoroquinolone-like compounds affects mutant recovery. A spontaneous mutator mutant ofM. smegmatis, obtained by growth in medium containing both isoniazid and rifampin, increased mutant induction during exposure to ciprofloxacin. Moreover, the mutator increased the size of spontaneous resistant mutant subpopulations, as detected by population analysis. Induction of ciprofloxacin resistance was also observed withMycobacterium tuberculosisH37Rv. When measured with clinical isolates, no difference in mutant recovery was observed between multidrug-resistant (MDR) and pansusceptible isolates. This finding is consistent with at least some MDR isolates ofM. tuberculosislacking mutators detectable by the agar plate assay. Collectively, the data indicate that the use of fluoroquinolones against tuberculosis may induce resistance and that the choice of quinolone may be important for restricting the recovery of induced mutants.

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Rai, Deepika, and Sarika Mehra. "The mycobacterial efflux pump EfpA can induce high drug tolerance to many anti-tuberculosis drugs, including moxifloxacin, in Mycobacterium smegmatis." Antimicrobial Agents and Chemotherapy, August 23, 2021. http://dx.doi.org/10.1128/aac.00262-21.

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Active efflux of drugs across the membrane is a major survival strategy of bacteria against many drugs. In this work, we characterize an efflux pump EfpA, from the major facilitator superfamily, that is highly conserved among both slow growing and fast-growing mycobacterium species and has been found to be upregulated in many clinical isolates of Mycobacterium tuberculosis . The gene encoding EfpA from Mycobacterium smegmatis was over-expressed under both constitutive and an inducible promoter. Expression of efpA gene under both the promoters resulted in greater than 32-fold increased drug tolerance of M. smegmatis cells to many first-line (rifampicin, isoniazid and streptomycin) and second-line (amikacin) anti-tuberculosis drugs. Notably, drug tolerance of M. smegmatis cells to moxifloxacin increased by more than 180-fold when efpA was over-expressed. The increase in minimum inhibitory concentration (MIC) correlated with the decreased uptake of drugs including norfloxacin, moxifloxacin and ethidium bromide and the high MIC could be reversed in the presence of an efflux pump inhibitor. A correlation was observed between the MIC of drugs and the efflux pump expression level, suggesting that the latter could be modulated by varying the expression level of the efflux pump. The expression of high levels of efpA did not impact the fitness of the cells when supplemented with glucose.The efpA gene is conserved across both pathogenic and non-pathogenic mycobacteria. The efpA gene from the Mycobacterium bovis BCG/ M. tuberculosis , which is 80% identical to efpA from M. smegmatis , also led to decreased antimicrobial efficacy to many drugs, although the fold-change was lower. When over-expressed in M. bovis BCG, an 8-fold higher drug tolerance to moxifloxacin was observed . This is the first report of an efflux pump from mycobacterium species that leads to higher drug tolerance to moxifloxacin, a promising new drug for the treatment of tuberculosis.

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Paul, Avraneel, Rashmi Ravindran Nair, Kishor Jakkala, Atul Pradhan, and Parthasarathi Ajitkumar. "Elevated Levels of Three Reactive Oxygen Species and Fe(II) in the Antibiotic-Surviving Population of Mycobacteria Facilitate De Novo Emergence of Genetic Resisters to Antibiotics." Antimicrobial Agents and Chemotherapy, April 18, 2022. http://dx.doi.org/10.1128/aac.02285-21.

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We had earlier reported the de novo emergence of genetic resisters of Mycobacterium tuberculosis and Mycobacterium smegmatis to rifampicin and moxifloxacin from the antibiotic-surviving population containing elevated levels of the non-DNA-specific mutagenic reactive oxygen species (ROS) hydroxyl radical. Since hydroxyl radical is generated by Fenton reaction between Fe(II) and H 2 O 2 , which is produced by superoxide dismutation, we here report significantly elevated levels of these three ROS and Fe(II) in the M. smegmatis rifampicin-surviving population.

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Cvetnić, Luka, Miroslav Benić, Željko Cvetnić, Sanja Duvnjak, Irena Reil, Maja Zdelar-Tuk, Marija Cvetnić, et al. "Bovine mastitis caused by rapid-growth environmental mycobacteria." Veterinarska stanica 53, no. 5 (January 5, 2022). http://dx.doi.org/10.46419/vs.53.5.11.

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Rapid-growth mycobacteria were isolated from two cases of cow mastitis with similar clinical appearance and within a narrow time frame. Mycobacteria were isolated on blood esculine agar. The isolated mycobacteria were Gram stained, Ziehl-Nielsen stained and tested for growth at 25°C, 37°C and 42°C, iron uptake, growth on Löwenstein-Jensen (LJ) agar with and without 5% NaCl, arylsulphatase (3 days), tween 80 hydrolysis, tellurite reduction, nitrate reductase and niacin synthesis. Molecular identification was performed using the Mycobacteria GenoType CM and AS tests (Hain Diagnostika, Nehren, Germany). One isolate was additionally sequenced for the hsp65, rpoB, 16S rRNA gene sequence and transcribed spacer sequence (ITS) DNA. Susceptibility testing of isolates was performed on the Sensititre Rapmycol plate (TREK Diagnostic Systems Ltd.) for trimethoprim/sulfamethoxasole, linezolid, ciprofloxacin, imipenem, moxifloxacin, cefepime, cefoxitin, amoxicillin / clavulanic acid, amikacin, ceftriaxone, doxycycline, minocycline, tigecycline, tobramycine and clarythromycine. Gram-positive acid-resistant rods were observed in stained smears. Both strains grew at 25°C, 37°C and 42°C on LJ medium, and on LJ medium containing 5 % NaCl. The conventional biochemical tests for iron uptake, arylsulphatase (3 days), Tween 80 hydrolysis, tellurite reduction and nitrate reductase were positive, while the niacin test was negative. Both isolates were identified by the GenoType Mycobacterium CM as Mycobacterium fortuitum II/ Mycobacterium mageritense, while application of the GenoType Mycobacterium AS kit identified both isolates as belonging to the species Mycobacterium smegmatis. Analysis of the isolate sequences (strain DS) for 16S ribosomal RNA confirmed a 100% identical result with Mycobacterium smegmatis strain INHR2. According to the CLSI criteria, both strains were sensitive to sulfametoxazole/trimethoprim, linezolid, doxicycline, amikacin and tobramycin. The strains differed in their sensitivity to cefoxitim, and both strains were resistant to clarithromycin. There was a strong difference between the isolates in sensitivity toward cefoxitime and tigecycline.

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Pradhan, Atul, Sharmada Swaminath, Kishor Jakkala, and Parthasarathi Ajitkumar. "A method for the enrichment, isolation and validation of Mycobacterium smegmatis population surviving in the presence of bactericidal concentrations of rifampicin and moxifloxacin." FEMS Microbiology Letters 368, no. 14 (July 2021). http://dx.doi.org/10.1093/femsle/fnab090.

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ABSTRACT The bacterial populations surviving in the presence of antibiotics contain cells that have gained genetic resistance, phenotypic resistance and tolerance to antibiotics. Isolation of live bacterial population, surviving against antibiotics, from the milieu of high proportions of dead/damaged cells will facilitate the study of the cellular/molecular processes used by them for survival. Here we present a Percoll gradient centrifugation based method for the isolation of enriched population of Mycobacterium smegmatis surviving in the presence of bactericidal concentrations of rifampicin and moxifloxacin. From the time of harvest, throughout the enrichment and isolation processes, and up to the lysis of the cells for total RNA preparation, we maintained the cells in the presence of the antibiotic to avoid changes in their metabolic status. The total RNA extracted from the enriched population of live antibiotic-surviving population showed structural integrity and purity. We analysed the transcriptome profile of the antibiotic-surviving population and compared it with the orthologue genes of Mycobacterium tuberculosis that conferred antibiotic tolerance on tubercle bacilli isolated from the tuberculosis patients under treatment with four antitubercular antibiotics. Statistically significant comparability between the gene expression profiles of the antibiotic tolerance associated genes of M. smegmatis and M. tuberculosis validated the reliability/utility of the method.

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Jakkala, Kishor, Avraneel Paul, Atul Pradhan, Rashmi Ravindran Nair, Deepti Sharan, Sharmada Swaminath, and Parthasarathi Ajitkumar. "Unique Mode of Cell Division by the Mycobacterial Genetic Resister Clones Emerging De Novo from the Antibiotic-Surviving Population." mSphere 5, no. 6 (November 18, 2020). http://dx.doi.org/10.1128/msphere.00994-20.

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ABSTRACT The emergence of antibiotic genetic resisters of pathogenic bacteria poses a major public health challenge. The mechanism by which bacterial antibiotic genetic resister clones formed de novo multiply and establish a resister population remained unknown. Here, we delineated the unique mode of cell division of the antibiotic genetic resisters of Mycobacterium smegmatis and Mycobacterium tuberculosis formed de novo from the population surviving in the presence of bactericidal concentrations of rifampicin or moxifloxacin. The cells in the rifampicin/moxifloxacin-surviving population generated elevated levels of hydroxyl radical-inflicting mutations. The genetic mutants selected against rifampicin/moxifloxacin became multinucleated and multiseptated and developed multiple constrictions. These cells stochastically divided multiple times, producing sister-daughter cells phenomenally higher in number than what could be expected from their generation time. This caused an abrupt, unexpectedly high increase in the rifampicin/moxifloxacin resister colonies. This unique cell division behavior was not shown by the rifampicin resisters formed naturally in the actively growing cultures. We could detect such abrupt increases in the antibiotic resisters in others’ and our earlier data on the antibiotic-exposed laboratory/clinical M. tuberculosis strains, M. smegmatis and other bacteria in in vitro cultures, infected macrophages/animals, and tuberculosis patients. However, it went unnoticed/unreported in all those studies. This phenomenon occurring in diverse bacteria surviving against different antibiotics revealed the broad significance of the present study. We speculate that the antibiotic-resistant bacillary clones, which emerge in patients with diverse bacterial infections, might be using the same mechanism to establish an antibiotic resister population quickly in the continued presence of antibiotics. IMPORTANCE The bacterial pathogens that are tolerant to antibiotics and survive in the continued presence of antibiotics have the chance to acquire genetically resistant mutations against the antibiotics and emerge de novo as antibiotic resisters. Once the antibiotic resister clone has emerged, often with compromise on growth characteristics, for the protection of the species, it is important to establish an antibiotic-resistant population quickly in the continued presence of the antibiotic. In this regard, the present study has unraveled multinucleation and multiseptation followed by multiple constrictions as the cellular processes used by the bacteria for quick multiplication to establish antibiotic-resistant populations. The study also points out the same phenomenon occurring in other bacterial systems investigated in our laboratory and others’ laboratories. Identification of these specific cellular events involved in quick multiplication offers additional cellular processes that can be targeted in combination with the existing antibiotics’ targets to preempt the emergence of antibiotic-resistant bacterial strains.

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Journal articles on the topic 'Mycobacterium smegmatis - Moxifloxacin'

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