Antibiotic susceptibility signatures identify potential antimicrobial targets in the Acinetobacter baumannii cell envelope

• Published in: Nature communications 2020-09, Vol.11 (1), p.4522-16, Article 4522
• Main Authors: Geisinger, Edward, Mortman, Nadav J., Dai, Yunfei, Cokol, Murat, Syal, Sapna, Farinha, Andrew, Fisher, Delaney G., Tang, Amy Y., Lazinski, David W., Wood, Stephen, Anthony, Jon, van Opijnen, Tim, Isberg, Ralph R.
• Format: Article
• Language: English
• Subjects: 45; 45/22; 45/23; 45/41; 45/47; 45/70; 49; 49/111; 49/23; 49/40; 631/326/22; 631/326/325; 631/326/88; 631/80/641/151; Acinetobacter baumannii; Acinetobacter baumannii - drug effects; Acinetobacter baumannii - genetics; Acinetobacter Infections - drug therapy; Acinetobacter Infections - microbiology; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotic resistance; Antibiotics; Antiinfectives and antibacterials; Antimicrobial agents; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Cell division; Cell Wall - drug effects; Cell Wall - genetics; Cell Wall - metabolism; Cell walls; Cross Infection - drug therapy; Cross Infection - microbiology; DNA Mutational Analysis; DNA Transposable Elements - genetics; DNA, Bacterial - genetics; Drug resistance; Drug Resistance, Multiple, Bacterial - drug effects; Drug Resistance, Multiple, Bacterial - genetics; Drug Synergism; Elongation; Hospitals; Humanities and Social Sciences; Humans; Hydrolase; Lipooligosaccharides; Microbial Sensitivity Tests; Morphology; multidisciplinary; Mutants; Mutation; Nosocomial infection; Pathogens; Proteins; Science; Science (multidisciplinary); Signatures; Susceptibility; Synthesis; Target recognition; β-Lactam antibiotics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18301-2

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. A unique cell envelope contributes to the antibiotic resistance of the pathogen Acinetobacter baumannii. Here, Geisinger et al. identify A. baumannii mutants with altered antibiotic susceptibility, infer the function of uncharacterized proteins involved in envelope synthesis, and predict antibiotic synergies.