Modeling of GyrA, MexB, FtsI, AtpD Protein Variants In Multidrug Resistant Acinetobacter baumannii

Abstract

Acinetobacter baumannii is a Gram-negative nosocomial pathogen known to manifest numerous drug resistances against major antibiotic classes. Compounded by its pathogenicity and virulence, it is considered globally as a top priority threat among the ESKAPE pathogens. The GyrA, MexB, FtsI and AtpD proteins in A. baumannii strain PR07 have been proven to mutate under exposure to ciprofloxacin, meropenem, imipenem and erythromycin, respectively. While the genomic data is useful, the impact of the mutations on the protein structure and function is not well understood. To obtain a deeper understanding, the protein structures were analyzed using structural bioinformatics tools. Here, the PR07 GyrA, MexB, FtsI and AtpD protein sequence data from NCBI were compared between ESKAPE pathogens and other A. baumannii species. MexB and AtpD structures were retrieved from the PDB database, while AlphaFold was used to construct protein structure predictions for GyrA and FtsI. MSA analyses identified mutations GyrA S81L, MexB S181L, FtsI P508, FtsI A515V, FtsI A579T and AtpD A166V mutations to be unique among the selected bacteria species. The mutation sites for all four target proteins were found to be within proximity to the potential binding sites. GyrA S81L, MexB S181L, FtsI A515V and FtsI A579T rigid protein models have shown loss of inter-residue polar hydrogen bonds, while AtpD A166V caused no observable changes. The mutations reported in PR07 therefore may potentially be significant contributors to its acquired resistance towards the target antibiotics.