Valnemulin restores colistin sensitivity against multidrug-resistant gram-negative pathogens
Chen Xu, Yuan Zhang, Lingman Ma, Guang-Fen Zhang, Chunli Li, Chenjie Zhang, Yunbing Li, Xiangkun Zeng, Yuanyuan Li, Ning Dong, Yuanyuan Li, Ning Dong
Abstract
Colistin is one of the last-resort antibiotics in treating infections caused by multidrug-resistant (MDR) pathogens. Unfortunately, the emergence of colistin-resistant gram-negative strains limit its clinical application. Here, we identify an FDA-approved drug, valnemulin (Val), exhibit a synergistic effect with colistin in eradicating both colistin-resistant and colistin-susceptible gram-negative pathogens both in vitro and in the mouse infection model. Furthermore, Val acts synergistically with colistin in eliminating intracellular bacteria in vitro. Functional studies and transcriptional analysis confirm that the combinational use of Val and colistin could cause membrane permeabilization, proton motive force dissipation, reduction in intracellular ATP level, and suppression in bacterial motility, which result in bacterial membrane disruption and finally cell death. Our findings reveal the potential of Val as a colistin adjuvant to combat MDR bacterial pathogens and treat recalcitrant infections. A colistin adjuvant valnemulin is identified to circumvent MDR bacterial pathogens and treat recalcitrant infections by causing membrane permeabilization, proton motive force dissipation, and reduction in intracellular ATP level.