Elevated Levels of Three Reactive Oxygen Species and Fe(II) in the Antibiotic-Surviving Population of Mycobacteria Facilitate <i>De Novo</i> Emergence of Genetic Resisters to Antibiotics

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Abstract

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 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. Elevated levels of superoxide and the consequential formation of high levels of H ₂ O ₂ 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 antibiotic-surviving 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.

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A common mechanism of cellular death induced by bactericidal antibiotics.

Michael A Kohanski, Daniel Dwyer, Boris Hayete … (2007)

Antibiotic mode-of-action classification is based upon drug-target interaction and whether the resultant inhibition of cellular function is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, in contrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanism of hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damage cellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.

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Molecular mechanisms of antibiotic resistance.

Jessica M. A. Blair, Mark Webber, Alison Baylay … (2015)

Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.

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Antibiotics and Bacterial Resistance in the 21st Century

Richard Fair, Yitzhak Tor (2014)

Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed.