Identification of an anti-virulence drug that reverses antibiotic resistance in multidrug resistant bacteria

The persistent incidence of high levels of multidrug-resistant (MDR) bacteria seriously endangers global public health. In response to MDR-associated infections, new antibacterial drugs and strategies are particularly needed. Screening to evaluate a potential compound to reverse antibiotic resistance is a good strategy to alleviate this crisis. In this paper, using high-throughput screening methods, we identified that oxyclozanide potentiated tetracycline antibiotics act against MDR bacterial pathogens by promoting intracellular accumulation of tetra-cycline in resistant bacteria. Furthermore, mechanistic studies demonstrated that oxyclozanide could directly kill bacteria by disrupting bacterial membrane and inducing the overproduction of bacterial reactive oxygen species. Oxyclozanide effectively reduced the production of virulence proteins in S. aureus and neutralized the produced alpha-hemolysin, thereby effectively alleviating the inflammatory response caused by bacteria. Finally, oxyclozanide significantly reversed tetracycline resistance in animal infection assays. In summary, these results demonstrated the capacity of oxyclozanide as a novel antibiotic adjuvant, antibacterial and anti-virulence multifunctional compound to circumvent MDR bacteria and improve the therapeutic effect of persistent infections caused by MDR bacteria worldwide.

Automated summary

The persistent incidence of multidrug-resistant bacteria poses a serious threat to global public health. In this study, oxyclozanide was found to potentiate the activity of tetracycline antibiotics against drug-resistant bacteria by promoting intracellular accumulation of tetracycline. Oxyclozanide was also shown to directly kill bacteria, reduce virulence protein production, and alleviate inflammation caused by bacteria. In animal infection assays, oxyclozanide effectively reversed tetracycline resistance.