Phenotype microarray analysis of the AdeRS two-component system in Acinetobacter baumannii

Acinetobacter baumannii is a nosocomial pathogen capable of resistance to multiple antimicrobials. The AdeRS two-component system (TCS) is associated with antimicrobial resistance by controlling the AdeABC efflux pump. To elucidate modulation by AdeRS, we made an A. baumannii mutant lacking the AdeRS TCS and characterized it using phenotype microarray (PM) analysis. After disrupting the adeRS operon, lower expression of AdeABC efflux pump was observed in the mutant strain. PM analysis showed that the AdeRS deletion strain and parental strain presented different tolerances to 91 compounds. Tolerance to 54 of the 91 compounds could be restored by complementing the AdeRS deleted strain with a plasmid carrying the adeRS gene. Compared to the parental strain, the AdeRS deletion strain was more sensitive to various inhibitors that target on-protein synthesis and function of cell membrane permeability. Tolerance to phleomycin of the AdeRS deletion strain reduced greatly and was further confirmed with minimum inhibitory concentration (MIC) determination and spot assay. The efflux pump inhibitor, NMP, could reduce phleomycin MIC four-fold at least for 29 (34.8%) of 81 tigecycline-resistant extensively drug-resistant A. baumannii (TGC-resistant XDRAB) clinical isolates. Our results suggested that the AdeRS TCS of A. baumannii was important for both elimination of antibiotics and tolerance to particular compounds.