Antibiotic susceptibility signatures identify potential antimicrobial targets in the Acinetobacter baumannii cell envelope
Edward Geisinger, Nadav J. Mortman, Yunfei Dai, Murat Cokol, Sapna Syal, Andrew Farinha, Delaney G. Fisher, Amy Y. Tang, David W. Lazinski, Stephen Wood, Jon Anthony, Tim van Opijnen, Ralph R. Isberg
Abstract
A unique, protective cell envelope contributes to the broad drug resistance of the nosocomial pathogen Acinetobacter baumannii. Here we use transposon insertion sequencing to identify A. baumannii mutants displaying altered susceptibility to a panel of diverse antibiotics. By examining mutants with antibiotic susceptibility profiles that parallel mutations in characterized genes, we infer the function of multiple uncharacterized envelope proteins, some of which have roles in cell division or cell elongation. Remarkably, mutations affecting a predicted cell wall hydrolase lead to alterations in lipooligosaccharide synthesis. In addition, the analysis of altered susceptibility signatures and antibiotic-induced morphology patterns allows us to predict drug synergies; for example, certain beta-lactams appear to work cooperatively due to their preferential targeting of specific cell wall assembly machineries. Our results indicate that the pathogen may be effectively inhibited by the combined targeting of multiple pathways critical for envelope growth.