Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 61, Issue 3, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01737-16
Keywords
Acinetobacter; antibiotic resistance; basic amino acid channels; carbapenem outer membrane channels; carbapenem resistance; Gram-negative bacteria; outer membrane proteins
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Funding
- Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT) [PICT-2011-1020]
- CONICET (PIP) [1055]
- Ministerio de Ciencia, Tecnologia e Innovacion Productiva
- Provincia de Santa Fe, Argentina
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The number and type of outer membrane (OM) channels responsible for carbapenem uptake in Acinetobacter are still not well defined. Here, we addressed these questions by using Acinetobacter baylyi as a model species and a combination of methodologies aimed to characterize OM channels in their original membrane environment. Kinetic and competition analyses of imipenem (IPM) uptake by A. baylyi whole cells allowed us to identify different carbapenem-specific OM uptake sites. Comparative analyses of IPM uptake by A. baylyi wild-type (WT) cells and Delta carO mutants lacking CarO indicated that this OM protein provided a carbapenem uptake site displaying saturable kinetics and common binding sites for basic amino acids compatible with a specific channel. The kinetic analysis uncovered another carbapenem-specific channel displaying a somewhat lower affinity for IPM than that of CarO and, in addition, common binding sites for basic amino acids as determined by competition studies. The use of A. baylyi gene deletion mutants lacking OM proteins proposed to function in carbapenem uptake in Acinetobacter baumannii indicated that CarO and OprD/OccAB1 mutants displayed low but consistent reductions in susceptibility to different carbapenems, including IPM, meropenem, and ertapenem. These two mutants also showed impaired growth on L-Arg but not on other carbon sources, further supporting a role of CarO and OprD/OccAB1 in basic amino acid and carbapenem uptake. A multiple-carbapenem-channel scenario may provide clues to our understanding of the contribution of OM channel loss or mutation to the carbapenem-resistant phenotype evolved by pathogenic members of the Acinetobacter genus.
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