Universität zu Köln

Gerson, Stefanie, Betts, Jonathan W., Lucassen, Kai ORCID: 0000-0002-6335-7731, Nodari, Carolina Silva, Wille, Julia, Josten, Michaele, Goettig, Stephan, Nowak, Jennifer, Stefanik, Danuta, Roca, Ignasi ORCID: 0000-0002-1800-1576, Vila, Jordi, Cisneros, Jose M., La Ragione, Roberto M., Seifert, Harald and Higgins, Paul G. ORCID: 0000-0001-8677-9454 (2019). Investigation of Novel pmrB and eptA Mutations in Isogenic Acinetobacter baumannii Isolates Associated with Colistin Resistance and Increased Virulence In Vivo. Antimicrob. Agents Chemother., 63 (3). WASHINGTON: AMER SOC MICROBIOLOGY. ISSN 1098-6596

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Abstract

Colistin resistance in Acinetobacter baumannii is of great concern and is 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, and Delta L9-G12). Increased expression of pmrC was shown by semi-quantitative reverse transcription-PCR (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 Delta L9-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:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gerson, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Betts, Jonathan W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lucassen, Kai UNSPECIFIED orcid.org/0000-0002-6335-7731 UNSPECIFIED Nodari, Carolina Silva UNSPECIFIED UNSPECIFIED UNSPECIFIED Wille, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Josten, Michaele UNSPECIFIED UNSPECIFIED UNSPECIFIED Goettig, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Nowak, Jennifer UNSPECIFIED UNSPECIFIED UNSPECIFIED Stefanik, Danuta UNSPECIFIED UNSPECIFIED UNSPECIFIED Roca, Ignasi UNSPECIFIED orcid.org/0000-0002-1800-1576 UNSPECIFIED Vila, Jordi UNSPECIFIED UNSPECIFIED UNSPECIFIED Cisneros, Jose M. UNSPECIFIED UNSPECIFIED UNSPECIFIED La Ragione, Roberto M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Seifert, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Higgins, Paul G. UNSPECIFIED orcid.org/0000-0001-8677-9454 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-155797
DOI:	10.1128/AAC.01586-18
Journal or Publication Title:	Antimicrob. Agents Chemother.
Volume:	63
Number:	3
Date:	2019
Publisher:	AMER SOC MICROBIOLOGY
Place of Publication:	WASHINGTON
ISSN:	1098-6596
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language VENTILATOR-ASSOCIATED PNEUMONIA; PHOSPHOETHANOLAMINE MODIFICATION; IMPAIRED VIRULENCE; PMRCAB OPERON; LIPOPOLYSACCHARIDE; EMERGENCE; POLYMYXINS; THERAPY; FITNESS; EFFLUX Multiple languages Microbiology; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15579