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

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  • Authors: Christine J. Boinett1​,2​,3​ ,  Amy K. Cain1​,4​ ,  Jane Hawkey5​,6​,7​ ,  Nhu Tran Do Hoang2​ ,  Nhu Nguyen Thi Khanh8​ ,  Duy Pham Thanh2​ ,  Janina Dordel1​,9​ ,  James I. Campbell2​,3​ ,  Nguyen Phu Huong Lan2​,10​ ,  Matthew Mayho1​ ,  Gemma C. Langridge1​,11​ ,  James Hadfield1​ ,  Nguyen Van Vinh Chau10​ ,  Guy E. Thwaites2​,3​ ,  Julian Parkhill1​ ,  Nicholas R. Thomson1​,12​ ,  Kathryn E. Holt5​,6​ , Stephen Baker2​,3​,13​,*
    • VIEW AFFILIATIONS
    • 1​ 1​Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK 2​ 2​Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam 3​ 3​Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK 4​ 4​Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi 5​ 5​Centre for Systems Genomics, University of Melbourne, Melbourne, Victoria, Australia 6​ 6​Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia 7​ 7​Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Melbourne, Victoria, Australia 8​ 8​School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia 9​ 9​Department of Biology, Drexel University, Philadelphia 19104, PA, USA 10​ 10​Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam 11​ 11​Norwich Medical School, University of East Anglia, Norwich, UK 12​ 12​Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 13​ 13​Medicine, The University of Cambridge, Cambridge, UK
  • *Correspondence: Stephen Baker [email protected]
  • First Published Online: 05 February 2019, Microbial Genomics , 2019 5, doi: 10.1099/mgen.0.000246
  • Subject: Research Article - Responses to Human Interventions - Antibiotics
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Clinical and laboratory-induced colistin-resistance mechanisms in Acinetobacter baumannii, Page 1 of 1

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  • 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.

  • All supporting data, code and protocols have been provided within the article or through supplementary data files. Eight supplementary tables and one supplementary figure are available with the online version of this article.

© 2019 The Authors | Published by the Microbiology Society

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2019-04-25
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