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Macrolide Resistance and In Vitro Potentiation by Peptidomimetics in Porcine Clinical Escherichia coli.
Ma, Yibing; Pirolo, Mattia; Subramani, Prabha; Gehring, Ronette; Damborg, Peter; Franzyk, Henrik; Guardabassi, Luca.
Afiliación
  • Ma Y; Department of Veterinary and Animal Sciences, University of Copenhagengrid.5254.6, Copenhagen, Denmark.
  • Pirolo M; Department of Veterinary and Animal Sciences, University of Copenhagengrid.5254.6, Copenhagen, Denmark.
  • Subramani P; Department of Veterinary and Animal Sciences, University of Copenhagengrid.5254.6, Copenhagen, Denmark.
  • Gehring R; Institute of Risk Assessment Sciences, Utrecht Universitygrid.5477.1, Utrecht, The Netherlands.
  • Damborg P; Department of Veterinary and Animal Sciences, University of Copenhagengrid.5254.6, Copenhagen, Denmark.
  • Franzyk H; Department of Drug Design and Pharmacology, University of Copenhagengrid.5254.6, Copenhagen, Denmark.
  • Guardabassi L; Department of Veterinary and Animal Sciences, University of Copenhagengrid.5254.6, Copenhagen, Denmark.
mSphere ; 7(5): e0040222, 2022 Oct 26.
Article en En | MEDLINE | ID: mdl-36154672
ABSTRACT
Escherichia coli is intrinsically resistant to macrolides due to outer membrane impermeability, but may also acquire macrolide resistance genes by horizontal transfer. We evaluated the prevalence and types of acquired macrolide resistance determinants in pig clinical E. coli, and we assessed the ability of peptidomimetics to potentiate different macrolide subclasses against strains resistant to neomycin, a first-line antibiotic in the treatment of pig-enteric infections. The erythromycin MIC distribution was determined in 324 pig clinical E. coli isolates, and 62 neomycin-resistant isolates were further characterized by genome sequencing and MIC testing of azithromycin, spiramycin, tilmicosin, and tylosin. The impact on potency achieved by combining these macrolides with three selected peptidomimetic compounds was determined by checkerboard assays in six strains representing different genetic lineages and macrolide resistance gene profiles. Erythromycin MICs ranged from 16 to >1,024 µg/mL. Azithromycin showed the highest potency in wild-type strains (1 to 8 µg/mL), followed by erythromycin (16 to 128 µg/mL), tilmicosin (32 to 256 µg/mL), and spiramycin (128 to 256 µg/mL). Isolates with elevated MIC mainly carried erm(B), either alone or in combination with other acquired macrolide resistance genes, including erm(42), mef(C), mph(A), mph(B), and mph(G). All peptidomimetic-macrolide combinations exhibited synergy (fractional inhibitory concentration index [FICI] < 0.5) with a 4- to 32-fold decrease in the MICs of macrolides. Interestingly, the MICs of tilmicosin in wild-type strains were reduced to concentrations (4 to 16 µg/mL) that can be achieved in the pig intestinal tract after oral administration, indicating that peptidomimetics can potentially be employed for repurposing tilmicosin in the management of E. coli enteritis in pigs. IMPORTANCE Acquired macrolide resistance is poorly studied in Escherichia coli because of intrinsic resistance and limited antimicrobial activity in Gram-negative bacteria. This study reveals new information on the prevalence and distribution of macrolide resistance determinants in a comprehensive collection of porcine clinical E. coli from Denmark. Our results contribute to understanding the correlation between genotypic and phenotypic macrolide resistance in E. coli. From a clinical standpoint, our study provides an initial proof of concept that peptidomimetics can resensitize E. coli to macrolide concentrations that may be achieved in the pig intestinal tract after oral administration. The latter result has implications for animal health and potential applications in veterinary antimicrobial drug development in view of the high rates of antimicrobial-resistant E. coli isolated from enteric infections in pigs and the lack of viable alternatives for treating these infections.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Espiramicina / Infecciones por Escherichia coli / Peptidomiméticos Tipo de estudio: Risk_factors_studies Límite: Animals Idioma: En Revista: MSphere Año: 2022 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Espiramicina / Infecciones por Escherichia coli / Peptidomiméticos Tipo de estudio: Risk_factors_studies Límite: Animals Idioma: En Revista: MSphere Año: 2022 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA