Identification of combinatorial colistin resistance mutations in Shewanella algae

Background Colistin 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 in Shewanella algae, partly due to complex epistatic interactions among multiple genes. Methodology/Principal Findings This study sequenced, assembled, and compared the genomes of 23 mcr-negative colistin-resistant Shewanella algae from 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 in Shewanella algae. Conclusions/Significance This study demonstrates a computational approach for identifying epistatic-interacted mutations. Author summary Shewanella algae is an emerging pathogen related to Neglected Tropical Diseases (NTDs), including cobra-bite wound infections, marine injuries or ingestion of contaminated seafood. Shewanella algae is intrinsic resistant to various classes of β-lactams. Additionally, growing resistance to colistin in mcr-negative Shewanella algae further limits therapeutic options, especially in resource-limited regions. Currently, little is known about the genetic mechanisms underlying colistin resistance in Shewanella algae, partly due to complex epistatic interactions among multiple genes. We conduct comparative genomics to identify combinatorial colistin resistance mutations in mcr-negative colistin-resistant Shewanella algae and a combination of three mutations (PmrB451, PmrE168, PmrH292) is strongly associated with colistin-resistance.