Enterobacterial common antigen biosynthesis inYersinia pestisis tied to antimicrobial peptide resistance

Abstract

AbstractResistance to antimicrobial peptides (AMPs) plays an important role in allowingYersinia pestisto maintain a successful infection in the flea vectorXenopsylla cheopis. Mutants that are unable to modify lipid A in their outer membrane with aminoarabinose (Ara4N), showed increased sensitivity to AMPs such as polymyxin B (PB), as well as decreased survival in fleas. A deletion mutant ofwecE, a gene involved in biosynthesis of enterobacterial common antigen (ECA), also displayed hypersusceptibility to PB in vitro. Additional mutants in the ECA biosynthetic pathway were generated, some designed to cause accumulation of intermediate products that sequester undecaprenyl phosphate (Und-P), a lipid carrier that is also used in numerous other pathways, including for peptidoglycan, O-antigen, and Ara4N biosynthesis. Mutants that accumulate Und-PP-linked intermediates (ECA-lipid II) showed increased susceptibility to PB, reduced Ara4N-modified lipid A, altered cell morphology, and decreased ability to maintain flea infections. These effects are consistent with a model whereY. pestishas a sufficiently limited free Und-P pool such that sequestration of Und-P as ECA-lipid II prevents adequate Ara4N biosynthesis, ultimately resulting in AMP hypersusceptibility.