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

Christine J. Boinett, Amy K. Cain, Jane Hawkey, Nhu Tran Do Hoang, Nhu Nguyen Thi Khanh, Duy Pham Thanh, Janina Dordel, James I. Campbell, Nguyen Phu Huong Lan, Matthew Mayho, Gemma C. Langridge, James Hadfield, Nguyen Van Vinh Chau, Guy E. Thwaites, Julian Parkhill, Nicholas R. Thomson, Kathryn E. Holt, Stephen Baker

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Number of pages10
JournalMicrobial genomics
Volume5
Issue number2
DOIs
Publication statusPublished - 1 Feb 2019
Externally publishedYes

Keywords

  • Acinetobacter baumannii
  • colistin resistance
  • multi-drug resistance
  • RNAseq
  • TraDIS
  • whole-genome sequencing

Cite this

Boinett, C. J., Cain, A. K., Hawkey, J., Do Hoang, N. T., Khanh, N. N. T., Thanh, D. P., ... Baker, S. (2019). Clinical and laboratory-induced colistin-resistance mechanisms in Acinetobacter baumannii. Microbial genomics, 5(2). https://doi.org/10.1099/mgen.0.000246
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. ; Baker, Stephen. / Clinical and laboratory-induced colistin-resistance mechanisms in Acinetobacter baumannii. In: Microbial genomics. 2019 ; Vol. 5, No. 2.
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Boinett, CJ, Cain, AK, Hawkey, J, Do Hoang, NT, Khanh, NNT, Thanh, DP, Dordel, J, Campbell, JI, Lan, NPH, Mayho, M, Langridge, GC, Hadfield, J, Chau, NVV, Thwaites, GE, Parkhill, J, Thomson, NR, Holt, KE & Baker, S 2019, 'Clinical and laboratory-induced colistin-resistance mechanisms in Acinetobacter baumannii' Microbial genomics, vol. 5, no. 2. https://doi.org/10.1099/mgen.0.000246

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.; Baker, Stephen.

In: Microbial genomics, Vol. 5, No. 2, 01.02.2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Boinett, Christine J.

AU - Cain, Amy K.

AU - Hawkey, Jane

AU - Do Hoang, Nhu Tran

AU - Khanh, Nhu Nguyen Thi

AU - Thanh, Duy Pham

AU - Dordel, Janina

AU - Campbell, James I.

AU - Lan, Nguyen Phu Huong

AU - Mayho, Matthew

AU - Langridge, Gemma C.

AU - Hadfield, James

AU - Chau, Nguyen Van Vinh

AU - Thwaites, Guy E.

AU - Parkhill, Julian

AU - Thomson, Nicholas R.

AU - Holt, Kathryn E.

AU - Baker, Stephen

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N2 - 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.

AB - 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.

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KW - colistin resistance

KW - multi-drug resistance

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