Clinical and laboratory-induced colistin-resistance mechanisms in Acinetobacter baumannii

Boinett, Christine J, Cain, Amy K, Hawkey, Jane, Do Hoang, Nhu Tran, Khanh, Nhu Nguyen Thi, Thanh, Duy Pham, Dordel, Janina, Campbell, James I, Lan, Nguyen Phu Huong, Mayho, Matthew, Langridge, Gemma C, Hadfield, James, Chau, Nguyen Van Vinh, Thwaites, Guy E, Parkhill, Julian, Thomson, Nicholas R, Holt, Kathryn E and Baker, Stephen (2019) Clinical and laboratory-induced colistin-resistance mechanisms in Acinetobacter baumannii. Microbial Genomics, 5 (2). pp. 1-10. ISSN 2057-5858

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Abstract

The increasing incidence and emergence of multi-drug resistant (MDR) Acinetobacter baumannii has become a major global health concern. Colistin is a historic antimicrobial that has become commonly used as a treatment for MDR A. baumannii infections. The increase in colistin usage has been mirrored by an increase in colistin resistance. We aimed to identify the mechanisms associated with colistin resistance in A. baumannii using multiple high-throughput-sequencing technologies, including transposon-directed insertion site sequencing (TraDIS), RNA sequencing (RNAseq) and whole-genome sequencing (WGS) to investigate the genotypic changes of colistin resistance in A. baumannii. Using TraDIS, we found that genes involved in drug efflux (adeIJK), and phospholipid (mlaC, mlaF and mlaD) and lipooligosaccharide synthesis (lpxC and lpsO) were required for survival in sub-inhibitory concentrations of colistin. Transcriptomic (RNAseq) analysis revealed that expression of genes encoding efflux proteins (adeI, adeC, emrB, mexB and macAB) was enhanced in in vitro generated colistin-resistant strains. WGS of these organisms identified disruptions in genes involved in lipid A (lpxC) and phospholipid synthesis (mlaA), and in the baeS/R two-component system (TCS). We additionally found that mutations in the pmrB TCS genes were the primary colistin-resistance-associated mechanisms in three Vietnamese clinical colistin-resistant A. baumannii strains. Our results outline the entire range of mechanisms employed in A. baumannii for resistance against colistin, including drug extrusion and the loss of lipid A moieties by gene disruption or modification.

Item Type: Article
Faculty \ School: Faculty of Science > School of Computing Sciences
Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: LivePure Connector
Date Deposited: 04 Mar 2019 16:30
Last Modified: 13 May 2020 23:57
URI: https://ueaeprints.uea.ac.uk/id/eprint/70099
DOI: 10.1099/mgen.0.000246

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