Antibiotic killing through oxidized nucleotides

Abstract

The alarming global rise of antibiotic resistance among bacterial pathogens necessitates not only urgent discovery of new antibiotics but also practical strategies to preserve those that are currently used (1, 2). A system-level understanding of the killing mechanisms of bactericidal antibiotics holds the promise of shortening treatment time courses and decreasing the chances that sensitive bacteria will evolve resistance during treatment (3). As different classes of bactericidal antibiotics have different primary cellular target(s), it is not surprising that a significant aspect of the bacterial killing mechanism is specific to the essential function targeted by each antibiotic class: β-lactams induce a futile cycle of cell wall synthesis (4), aminoglycosides induce mistranslation of peptides that compromise inner membrane integrity (5), and fluoroquinolones cause DNA breaks by inhibiting DNA gyrase or topoisomerase IV (6). However, regardless of the primary cellular target, different bactericidal antibiotics all induce a similar cascade of events that contribute to their lethality in Escherichia coli : accelerated respiration (7); changes in iron and redox metabolism (8); formation of reactive oxygen species (9); oxidative damage of DNA (10), RNA, and proteins (11); and cell death. Interestingly, the same killing cascade is seen in a number of antibiotic-independent killing phenomena, for example, T6SS-effector dependent killing (12) and expression of a toxic fusion protein (13). In PNAS, Fan et al. (14) explore whether different classes of bactericidal antibiotics used to treat Mycobacterium tuberculosis , the causative agent of tuberculosis, share a common killing cascade. They used bactericidal antibiotics of the aminoglycoside and fluoroquinolone classes that were also used in previous bactericidal antibiotic lethality studies in E. coli . They discovered that lethal oxidative DNA damage does occur in nongrowing M. tuberculosis cells treated with different bactericidal antibiotics. They also used rifampicin, an RNA polymerase inhibitor that is not bactericidal in … [↵][1]1To whom correspondence should be addressed. Email: evgeny.nudler{at}nyumc.org. [1]: #xref-corresp-1-1