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Mechanisms of intrinsic resistance and acquired susceptibility of Pseudomonas aeruginosa isolated from cystic fibrosis patients to temocillin, a revived antibiotic

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Chalhoub, Houssein [UCL] Pletzer, Daniel Weingart, Helge Braun, Yvonne Tunney, Michael M. Rodriguez-Villalobos, Hector [UCL] Tulkens, Paul M. [UCL] Van Bambeke, Françoise [UCL]

The β-lactam antibiotic temocillin (6-α-methoxy-ticarcillin) shows stability to most extended spectrum β-lactamases, but is considered inactive against Pseudomonas aeruginosa. Mutations in the MexAB-OprM efflux system, naturally occurring in cystic fibrosis (CF) isolates, have been previously shown to reverse this intrinsic resistance. In the present study, we measured temocillin activity in a large collection (n=333) of P. aeruginosa CF isolates. 29% of the isolates had MICs ≤ 16 mg/L (proposed clinical breakpoint for temocillin). Mutations were observed in mexA or mexB in isolates for which temocillin MIC was ≤ 512 mg/L (nucleotide insertions or deletions, premature termination, tandem repeat, nonstop, and missense mutations). A correlation was observed between temocillin MICs and efflux rate of N-phenyl-1-naphthylamine (MexAB-OprM fluorescent substrate) and extracellular exopolysaccharide abundance (contributing to a mucoid phenotype). OpdK or OpdF anion-specific porins expression decreased temocillin MIC by ~1 two-fold dilution only. Contrarily to the common assumption that temocillin is inactive on P. aeruginosa, we show here clinically-exploitable MICs on a non-negligible proportion of CF isolates, explained by a wide diversity of mutations in mexA and/or mexB. In a broader context, this work contributes to increase our understanding of MexAB-OprM functionality and help delineating how antibiotics interact with MexA and MexB.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2017
Language Anglais
Journal information "Scientific Reports" - Vol. 7, p. 40208 [1-14] (2017)
Peer reviewed yes
Publisher Nature Publishing Group ((United Kingdom) London)
e-issn 2045-2322
Publication status Publié
Affiliations UCL - SSS/LDRI - Louvain Drug Research Institute
UCL - SSS/IREC/MBLG - Pôle de Microbiologie médicale
UCL - (SLuc) Service de microbiologie
Links
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Bibliographic reference Chalhoub, Houssein ; Pletzer, Daniel ; Weingart, Helge ; Braun, Yvonne ; Tunney, Michael M. ; et. al. Mechanisms of intrinsic resistance and acquired susceptibility of Pseudomonas aeruginosa isolated from cystic fibrosis patients to temocillin, a revived antibiotic. In: Scientific Reports, Vol. 7, p. 40208 [1-14] (2017)
Permanent URL http://hdl.handle.net/2078.1/180970