Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement
With tuberculosis, the emergence of fluoroquinolone resistance erodes the ability of treatment to interrupt the progression of MDR-TB to XDR-TB. One way to reduce the emergence of resistance is to identify heteroresistant infections in which subpopulations of resistant mutants are likely to expand a...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2022.938032/full |
| _version_ | 1798044072879849472 |
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| author | Amit Singh Amit Singh Xilin Zhao Xilin Zhao Karl Drlica |
| author_facet | Amit Singh Amit Singh Xilin Zhao Xilin Zhao Karl Drlica |
| author_sort | Amit Singh |
| collection | DOAJ |
| description | With tuberculosis, the emergence of fluoroquinolone resistance erodes the ability of treatment to interrupt the progression of MDR-TB to XDR-TB. One way to reduce the emergence of resistance is to identify heteroresistant infections in which subpopulations of resistant mutants are likely to expand and make the infections fully resistant: treatment modification can be instituted to suppress mutant enrichment. Rapid DNA-based detection methods exploit the finding that fluoroquinolone-resistant substitutions occur largely in a few codons of DNA gyrase. A second approach for restricting the emergence of resistance involves understanding fluoroquinolone lethality through studies of antimicrobial tolerance, a condition in which bacteria fail to be killed even though their growth is blocked by lethal agents. Studies with Escherichia coli guide work with Mycobacterium tuberculosis. Lethal action, which is mechanistically distinct from blocking growth, is associated with a surge in respiration and reactive oxygen species (ROS). Mutations in carbohydrate metabolism that attenuate ROS accumulation create pan-tolerance to antimicrobials, disinfectants, and environmental stressors. These observations indicate the existence of a general death pathway with respect to stressors. M. tuberculosis displays a variation on the death pathway idea, as stress-induced ROS is generated by NADH-mediated reductive stress rather than by respiration. A third approach, which emerges from lethality studies, uses a small molecule, N-acetyl cysteine, to artificially increase respiration and additional ROS accumulation. That enhances moxifloxacin lethality with M. tuberculosis in culture, during infection of cultured macrophages, and with infection of mice. Addition of ROS stimulators to fluoroquinolone treatment of tuberculosis constitutes a new direction for suppressing the transition of MDR-TB to XDR-TB. |
| first_indexed | 2024-04-11T22:57:45Z |
| format | Article |
| id | doaj.art-ef224366fc674555b8ce0548ce28129b |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-04-11T22:57:45Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-ef224366fc674555b8ce0548ce28129b2022-12-22T03:58:22ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882022-09-011210.3389/fcimb.2022.938032938032Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancementAmit Singh0Amit Singh1Xilin Zhao2Xilin Zhao3Karl Drlica4Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, IndiaCentre for Infectious Disease Research, Indian Institute of Science, Bangalore, IndiaPublic Health Research Institute and Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers University, Newark, NJ, United StatesState Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, ChinaPublic Health Research Institute and Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Rutgers University, Newark, NJ, United StatesWith tuberculosis, the emergence of fluoroquinolone resistance erodes the ability of treatment to interrupt the progression of MDR-TB to XDR-TB. One way to reduce the emergence of resistance is to identify heteroresistant infections in which subpopulations of resistant mutants are likely to expand and make the infections fully resistant: treatment modification can be instituted to suppress mutant enrichment. Rapid DNA-based detection methods exploit the finding that fluoroquinolone-resistant substitutions occur largely in a few codons of DNA gyrase. A second approach for restricting the emergence of resistance involves understanding fluoroquinolone lethality through studies of antimicrobial tolerance, a condition in which bacteria fail to be killed even though their growth is blocked by lethal agents. Studies with Escherichia coli guide work with Mycobacterium tuberculosis. Lethal action, which is mechanistically distinct from blocking growth, is associated with a surge in respiration and reactive oxygen species (ROS). Mutations in carbohydrate metabolism that attenuate ROS accumulation create pan-tolerance to antimicrobials, disinfectants, and environmental stressors. These observations indicate the existence of a general death pathway with respect to stressors. M. tuberculosis displays a variation on the death pathway idea, as stress-induced ROS is generated by NADH-mediated reductive stress rather than by respiration. A third approach, which emerges from lethality studies, uses a small molecule, N-acetyl cysteine, to artificially increase respiration and additional ROS accumulation. That enhances moxifloxacin lethality with M. tuberculosis in culture, during infection of cultured macrophages, and with infection of mice. Addition of ROS stimulators to fluoroquinolone treatment of tuberculosis constitutes a new direction for suppressing the transition of MDR-TB to XDR-TB.https://www.frontiersin.org/articles/10.3389/fcimb.2022.938032/fullantimycobacterialoxidative stressfluoroquinolonerespirationN-acetyl cysteineredox biosensor |
| spellingShingle | Amit Singh Amit Singh Xilin Zhao Xilin Zhao Karl Drlica Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement Frontiers in Cellular and Infection Microbiology antimycobacterial oxidative stress fluoroquinolone respiration N-acetyl cysteine redox biosensor |
| title | Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement |
| title_full | Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement |
| title_fullStr | Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement |
| title_full_unstemmed | Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement |
| title_short | Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement |
| title_sort | fluoroquinolone heteroresistance antimicrobial tolerance and lethality enhancement |
| topic | antimycobacterial oxidative stress fluoroquinolone respiration N-acetyl cysteine redox biosensor |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2022.938032/full |
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