Abstract
The production of endogenous hydrogen sulfide (H2S) has been shown to confer antibiotic tolerance in all bacteria studied to date. Therefore, this mediator has been speculated to be a universal defense mechanism against antibiotics in bacteria. This is assuming that all bacteria produce endogenous H2S. In this study, we established that the pathogenic bacteria Acinetobacter baumannii does not produce endogenous H2S, giving us the opportunity to test the effect of exogenous H2S on antibiotic tolerance in a bacterium that does not produce it. By using a H2S-releasing compound to modulate the sulfide content in A. baumannii, we demonstrated that instead of conferring antibiotic tolerance, exogenous H2S sensitized A. baumannii to multiple antibiotic classes, and was able to revert acquired resistance to gentamicin. Exogenous H2S triggered a perturbation of redox and energy homeostasis that translated into hypersensitivity to antibiotic killing. We propose that H2S could be used as an antibiotic-potentiator and resistance-reversion agent in bacteria that do not produce it.
Highlights
Antimicrobial resistance (AMR) is rising and poses a major public health threat (Sugden et al, 2016)
We investigated the effect of exogenous H2S on A. baumannii, a critically important AMR bacteria that does not carry the genes coding for the H2S biosynthetic pathway, i.e., CBS, CSE or MST (Figure 1A)
To determine if H2S affects antibiotic sensitivity in A. baumannii, we conducted antibiotic time-kill experiments by Colony forming units (CFUs) determination overtime in the absence or presence of next made use of sodium hydrosulfide (NaHS). These experiments revealed that exogenous H2S did not confer protection against antibiotics in A. baumannii, but potentiated the killing effects of mechanistically unrelated antibiotics including gentamycin, colistin, rifampicin, and clarithromycin (Figure 2)
Summary
Antimicrobial resistance (AMR) is rising and poses a major public health threat (Sugden et al, 2016). The understanding of antibiotic modes of action (MOA), and bacteria mechanisms of resistance (MOR), is critically important in the efforts to develop alternative therapies. The formation of reactive oxygen species (ROS) has been proposed as a common effector mechanism in bacteria challenged with bactericidal antibiotics (Kohanski et al, 2007). Beyond the canonical drug-specific target-corruption MOA, the paradigm shifted toward systemlevel disruption of bacteria cellular homeostasis as a common mean of antibiotics-induced lethality (Kohanski et al, 2010). Several studies reported system level MOR involving oxidative stress defenses. In 2011, a novel resistance mechanism mediated by hydrogen sulfide (H2S) was described for several pathogenic bacteria, including Staphylococcus aureus, Pseudomonas
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