The project aims to define the functional basis of Acinetobacter baumannii intrinsic resistance to three clinically-relevant antibiotics (meropenem, colistin, and tobramycin) at a comprehensive scale. The work will identify resistance functions at genome-scale using transposon mutant sequencing, and will validate results through single mutant testing. The study will employ new technology that makes it possible to include mutants inactivating essential genes, which is usually missing from such studies. Top, validated mutants exhibiting increased sensitivity to one or more of the antibiotics will be further evaluated for whether they act through established or novel resistance mechanisms.
The premise of the proposed work is that undermining resistance mechanisms represents an important approach to overcoming the antibiotic resistance crisis. A relatively complete identification of resistance functions and understanding of their mechanisms of action is crucial in implementing this strategy. The proposed experiments identify such resistance functions at a comprehensive scale for three antibiotics of clinical importance in treating infections by the notorious nosocomial pathogen Acinetobacter baumannii.