Identification of combinatorial colistin resistance mutations inShewanella algae

Abstract

AbstractBackgroundColistin is one of the last-line antimicrobial agents against drug-resistant gram-negative bacteria. Currently, little is known about the genetic mechanisms underlying colistin resistance inShewanella algae, partly due to complex epistatic interactions among multiple genes.Methodology/Principal FindingsThis study sequenced, assembled, and compared the genomes of 23 mcr-negative colistin-resistantShewanella algaefrom marine, clam, oyster, and human. Comparative genomics and computational approach were applied to find combinatorial mutations. A combination of three mutations (PmrB451, PmrE168, PmrH292) was found to be strongly associated with colistin resistance inShewanella algae.Conclusions/SignificanceThis study demonstrates a computational approach for identifying epistatic-interacted mutations.Author summaryShewanella algaeis an emerging pathogen related to Neglected Tropical Diseases (NTDs), including cobra-bite wound infections, marine injuries or ingestion of contaminated seafood.Shewanella algaeis intrinsic resistant to various classes of β-lactams. Additionally, growing resistance to colistin inmcr-negativeShewanella algaefurther limits therapeutic options, especially in resource-limited regions. Currently, little is known about the genetic mechanisms underlying colistin resistance inShewanella algae, partly due to complex epistatic interactions among multiple genes. We conduct comparative genomics to identify combinatorial colistin resistance mutations inmcr-negative colistin-resistantShewanella algaeand a combination of three mutations (PmrB451, PmrE168, PmrH292) is strongly associated with colistin-resistance.