Synergistic combinations of anthelmintic salicylanilides oxyclozanide, rafoxanide, and closantel with colistin eradicates multidrug-resistant colistin-resistant Gram-negative bacilli.

Repurposing nonantibiotic drugs for antimicrobial therapy presents a viable approach to drug discovery. Development of therapeutic strategies that overcome existing resistance mechanisms is important especially against those bacterial infections in which treatment options are limited, such as against multidrug-resistant Gram-negative bacilli. Herein, we provide in vitro data that suggest the addition of anthelmintic salicylanilides, including oxyclozanide, rafoxanide, and closantel, in colistin therapy to treat multidrug-resistant colistin-susceptible but more importantly colistin-resistant Gram-negative bacilli. As a stand-alone agent, the three salicylanilides suffered from limited outer membrane permeation in Pseudomonas aeruginosa, with oxyclozanide also susceptible to efflux. Synergy was apparent for the combinations against multidrug-resistant clinical isolates of P. aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae. Susceptibility breakpoints for colistin, but also with polymyxin B, were reached upon addition of 1 µg ml