Outer membrane permeability of mcr-positive bacteria reveals potent synergy of colistin and macromolecular antibiotics against colistin-resistant Acinetobacter baumannii

Colistin (CT) is the last-resort of antibiotic against multidrug-resistance (MDR) <i>Acinetobacter baumannii</i> (<i>A. baumannii</i>) infection. However, colistin resistance is increasingly reported in <i>A. baumannii</i> isolates partially due to the global emergence and dissemination of plasmid-borne mobile colistin resistance (<i>mcr</i>) gene and is a threat to human health. Thus, available treatment strategies urgently required in the fight against colistin-resistant <i>A. baumannii</i>. Here, we showed that <i>mcr</i> confers damaged outer membrane (OM) permeability in <i>A. baumannii</i>, which could compromise the viability of <i>A. baumannii</i>. Consistently, <i>A. baumannii</i> with colistin resistance exhibits increased susceptibility to macromolecular antibiotics such as rifampicin (RIF) and erythromycin (ERY). Moreover, the combination therapy of colistin and rifampicin demonstrates efficacy against colistin-resistant <i>A. baumannii</i>, regardless of the presence of <i>mcr</i>. Altogether, our data suggest that the synergy of colistin in combination with macromolecular hydrophobic antibiotics poses a promising therapeutic alternative for colistin-resistant <i>A. baumannii</i>.