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Investigation of novel pmrB and eptA mutations in isogenic Acinetobacter baumannii isolates associated with colistin resistance and increased virulence in vivo

Gerson, Stefanie, Betts, Jonathan W., Lucaßen, Kai, Nodari, Carolina Silva, Wille, Julia, Josten, Michaele, Göttig, Stephan, Nowak, Jennifer, Stefanik, Danuta, Roca, Ignasi , Vila, Jordi, Cisneros, José M., La Ragione, Roberto M., Seifert, Harald and Higgins, Paul G. (2019) Investigation of novel pmrB and eptA mutations in isogenic Acinetobacter baumannii isolates associated with colistin resistance and increased virulence in vivo Antimicrobial Agents and Chemotherapy.

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Colistin resistance in Acinetobacter baumannii is of great concern and a threat to human health. In this study we investigate the mechanisms of colistin resistance in four isogenic pairs of A. baumannii isolates displaying an increase in colistin MICs. A mutation in pmrB was detected in each colistin-resistant isolate, three of which were novel (A28V, I232T, ΔL9-G12). Increased expression of pmrC was shown by qRT-PCR for three colistin-resistant isolates, and the addition of phosphoethanolamine (PEtN) to lipid A by PmrC was revealed by mass spectrometry. Interestingly, PEtN addition was also observed in some colistin-susceptible isolates, indicating that this resistance mechanism might be strain-specific and that other factors could contribute to colistin resistance. Furthermore, the introduction of pmrAB carrying the short amino acid deletion ΔL9-G12 into a pmrAB knockout strain resulted in increased pmrC expression and lipid A modification, but colistin MICs remained unchanged, further supporting the strain-specificity of this colistin resistance mechanism. Of note, a mutation in the pmrC-homologue eptA and a point mutation in ISAba1 upstream of eptA were associated with colistin-resistance and increased eptA expression, which is a hitherto undescribed resistance mechanism. Moreover, no cost of fitness was observed for colistin-resistant isolates, while the virulence of these isolates was increased in a Galleria mellonella infection model. Although the mutations in pmrB were associated with colistin resistance, PEtN addition appears not to be the sole factor leading to colistin resistance, indicating that the mechanism of colistin resistance is far more complex than previously suspected and is potentially strain-specific.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :
Gerson, Stefanie
Betts, Jonathan
Lucaßen, Kai
Nodari, Carolina Silva
Wille, Julia
Josten, Michaele
Göttig, Stephan
Nowak, Jennifer
Stefanik, Danuta
Roca, Ignasi
Vila, Jordi
Cisneros, José M.
La Ragione, Roberto
Seifert, Harald
Higgins, Paul G.
Date : 7 January 2019
DOI : 10.1128/AAC.01586-18
Copyright Disclaimer : Copyright © 2019 American Society for Microbiology. All Rights Reserved.
Depositing User : Clive Harris
Date Deposited : 31 Jan 2019 08:46
Last Modified : 08 Jul 2019 02:08

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