In order to mitigate antibiotic resistance, a new strategy to increase antibiotic potency and reverse drug resistance is needed. Herein, the translocation mechanism of an antimicrobial guanidinium‐functionalized polycarbonate is leveraged in combination with traditional antibiotics to afford a potent treatment for drug‐resistant bacteria. Particularly, this polymer–antibiotic combination approach reverses rifampicin resistance phenotype in Acinetobacter baumannii demonstrating a 2.5 × 105‐fold reduction in minimum inhibitory concentration (MIC) and a 4096‐fold reduction in minimum bactericidal concentration (MBC). This approach also enables the repurposing of auranofin as an antibiotic against multidrug‐resistant (MDR) Gram‐negative bacteria with a 512‐fold MIC and 128‐fold MBC reduction, respectively. Finally, the in vivo efficacy of polymer–rifampicin combination is demonstrated in a MDR bacteremia mouse model. This combination approach lays foundational ground rules for a new class of antibiotic adjuvants capable of reversing drug resistance phenotype and repurposing drugs against MDR Gram‐negative bacteria.

The production of endogenous hydrogen sulfide (H 2 S) 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 H 2 S. In this study, we established that the pathogenic bacteria Acinetobacter baumannii does not produce endogenous H 2 S, giving us the opportunity to test the effect of exogenous H 2 S on antibiotic tolerance in a bacterium that does not produce it. By using a H 2 S-releasing compound to modulate the sulfide content in A. baumannii, we demonstrated that instead of conferring antibiotic tolerance, exogenous H 2 S sensitized A. baumannii to multiple antibiotic classes, and was able to revert acquired resistance to gentamicin. Exogenous H 2 S triggered a perturbation of redox and energy homeostasis that translated into hypersensitivity to antibiotic killing. We propose that H 2 S could be used as an antibiotic-potentiator and resistance-reversion agent in bacteria that do not produce it.

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