Genomic investigation unveils colistin resistance mechanism in carbapenem-resistant Acinetobacter baumannii clinical isolates

Colistin resistance in is mediated by multiple mechanisms. Recently, mutations within two-component system and overexpression of gene due to upstream insertion of IS have been shown to play a major role. Thus, the aim of our study is to characterize colistin resistance mechanisms among the clinical isolates of in India. A total of 207 clinical isolates of collected from 2016 to 2019 were included in this study. Mutations within lipid A biosynthesis and genes were characterized by whole-genome shotgun sequencing. Twenty-eight complete genomes were further characterized by hybrid assembly approach to study insertional inactivation of genes and the association of IS . Several single point mutations (SNPs), like M12I in , A138T and A444V in , and E117K in were identified. We are the first to report two novel SNPs (T7I and V383I) in the gene. Among the five colistin-resistant isolates where complete genome was available, the analysis showed that three of the five isolates had IS insertion upstream of . No genes were identified among the isolates. We mapped the SNPs on the respective protein structures to understand the effect on the protein activity. We found that majority of the SNPs had little effect on the putative protein function; however, some SNPs might destabilize the local structure. Our study highlights the diversity of colistin resistance mechanisms occurring in and IS -driven overexpression is responsible for colistin resistance among the Indian isolates.IMPORTANCE is a Gram-negative, emerging and opportunistic bacterial pathogen that is often associated with a wide range of nosocomial infections. The treatment of these infections is hindered by increase in the occurrence of strains that are resistant to most of the existing antibiotics. The current drug of choice to treat the infection caused by is colistin, but unfortunately, the bacteria started to show resistance to the last-resort antibiotic. The loss of lipopolysaccharides and mutations in lipid A biosynthesis genes are the main reasons for the colistin resistance. The present study characterized 207 clinical isolates and constructed complete genomes of 28 isolates to recognize the mechanisms of colistin resistance. We showed the mutations in the colistin-resistant variants within genes essential for lipid A biosynthesis and that cause these isolates to lose the ability to produce lipopolysaccharides.