Reactive oxygen species as the long arm of bactericidal antibiotics

Abstract

Stress tolerance in bacterial populations is the ability to restore homeostasis after protracted exposure to lethal agents. The longer a bacterial population can withstand a lethal agent, the more tolerant it is considered to be. In the last two decades, antibiotic tolerance was given special attention because of a possible link between the tolerance level of bacterial pathogens and infection outcome in the clinic (1). Much like the evolution of antibiotic resistance, bacterial pathogens can evolve into a state of high-level tolerance (2). Unlike the limited number of mutations that provide antibiotic resistance, a wide range of mutations can increase the bacterial level of tolerance. This observation distinguishes a fundamental difference between the mechanisms of tolerance and resistance. Whereas de novo acquisition of resistance is based on specific changes at the antibiotic binding site, numerous mutations that slow the growth rate or extend the lag time increase the bacterial tolerance level. In both slow-growth and extended-lag mutants, the antibiotic target is less abundant and, therefore, primary damage accumulates more slowly (3). However, for most antibiotics, it is not the primary damage per se that kills the bacterial cell, but rather a downstream cascade of events that ends in secondary damage types (4⇓–6). In theory, one would expect an additional evolutionary trajectory toward a high state of tolerance, driven by secondary damage attenuating mutations. However, the inherent difficulty of the study of secondary damage in isolation is the dearth of currently available research. Measuring tolerance is more difficult than it may initially seem. The common practice of quantifying bacterial survival at time intervals by removal of antibiotic and cell plating on recovery plates is inherently flawed. While it accurately quantifies the amount of cell regrowth on the plates, the quantification of bacterial survival does not accurately reveal the … [↵][1]1To whom correspondence should be addressed. Email: evgeny.nudler{at}nyumc.org. [1]: #xref-corresp-1-1