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

Paul, A and Nair, RR and Jakkala, K and Pradhan, A and Ajitkumar, P (2022) 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. In: Antimicrobial Agents and Chemotherapy, 66 (5).

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Abstract

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 H2O2, 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. Elevated levels of superoxide and the consequential formation of high levels of H2O2 and Fe(II) led to the generation of hydroxyl radical, facilitating de novo high frequency emergence of antibiotic resisters. The M. smegmatis cultures, exposed to nontoxic concentrations of the ROS scavenger, thiourea (TU), and the NADH oxidase (one of the superoxide producers) inhibitor, diphenyleneiodonium chloride (DPI), showed a reduction in the levels of the three ROS, Fe(II), and antibiotic resister generation frequency. The non-antibiotic- exposed cultures grown in the absence/presence of TU/DPI did not show increased ROS, Fe(II) levels, or antibiotic resister generation frequency. The antibioticsurviving population showed significantly increased expression and activity of superoxide- producing genes and decreased expression of antioxidant and DNA repair genes, revealing an environment conducive for the acquisition and retention of mutations. Since we recently reported significant comparability between the antibiotic-survival gene expression profiles of the saprophyte-cum-opportunistic pathogens M. smegmatis and the M. tuberculosis in tuberculosis patients undergoing treatment, we discuss the clinical relevance of the findings on the mechanism of emergence of antibiotic-resistant mycobacterial strains. © 2022 American Society for Microbiology.

Item Type:	Journal Article
Publication:	Antimicrobial Agents and Chemotherapy
Publisher:	American Society for Microbiology
Additional Information:	The copyright for this article belongs to the American Society for Microbiology.
Keywords:	antiinfective agent; ferrous ion; hydrogen peroxide; hydroxyl radical; reactive oxygen metabolite; rifampicin; superoxide, genetics; human; metabolism; Mycobacterium smegmatis; Mycobacterium tuberculosis; tuberculosis, Anti-Bacterial Agents; Ferrous Compounds; Humans; Hydrogen Peroxide; Hydroxyl Radical; Mycobacterium smegmatis; Mycobacterium tuberculosis; Reactive Oxygen Species; Rifampin; Superoxides; Tuberculosis
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	06 Jun 2022 05:07
Last Modified:	06 Jun 2022 05:07
URI:	https://eprints.iisc.ac.in/id/eprint/73114

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