Global control of antibiotic resistance and virulence
Acinetobacter baumannii has a protective cell envelope that thwarts antibiotic and immune attack. Understanding this defense is critical to developing improved antimicrobial treatments. We have uncovered a set of global regulators that control envelope synthesis and enable resistance and pathogenicity in A. baumannii. One key global system, known as BfmRS, lowers susceptibility to a wide range of drugs, antagonizes innate immune killing, and facilitates development of lethal disease in mice (PLoS Pathogens, 2018). The system is therefore at the heart of antibiotic treatment failure and represents a target for blocking nosocomial disease. We study how the global BfmRS regulon controls broad-range drug resistance and pathogenicity, and how it senses and responds to antimicrobial and infection-related stresses.
A unique cell division strategy
Cell division is poorly understood in Acinetobacter, which lack several key enzymes driving division in well-studied bacteria. Addressing this problem can pave the way to novel, narrow-spectrum inhibitors. We used a chemical-genetic approach known as phenotypic signature analysis to mine the substantial “dark matter” of unannotated genes in A. baumannii for division factors. We discovered an essential protein that we named AdvA (Nature Communications 2020) that is found primarily in Acinetobacter and its close relatives and is critical for orchestration of cell division. We study the structure and activities of the protein, its network of molecular interactions, and how these enable a novel strategy for coordinating cell division.
Targeting the A. baumannii cell wall
The Gram-negative bacterial cell wall is essential to microbial growth, resilience, and adaptation to changing environments. Cell wall biosynthesis is carefully controlled to enhance antibiotic resistance and promote infection. We study how A. baumannii assembles and recycles its cell wall, and how it uses cell-wall synthesis enzymes in unappreciated ways to maintain envelope integrity, cell shape, and drug resistance.
