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| Título: | Penicillin-Binding Protein Occupancy Dataset for 18 β-Lactams and 4 β-Lactamase Inhibitors in Neisseria gonorrhoeae |
Autor: | López-Argüello, Silvia; Montaner, Maria; Mármol-Salvador, Amanda; Velázquez-Escudero, Ana; Docobo-Pérez, Fernando CSIC ORCID; Oliver, Antonio; Moyà, Bartolomé | Palabras clave: | Penicillin-binding proteins (PBP) N. gonorrhoeae Gonococcus β-lactams β-lactam resistance |
Fecha de publicación: | 15-jun-2023 | Editor: | American Society for Microbiology | Citación: | Microbiology Spectrum 11(3): e00692-23 (2023) | Resumen: | The lack of effective first-line antibiotic treatments against Neisseria gonorrhoeae, and the worldwide dissemination of resistant strains, are the main drivers of a worsening global health crisis. β-lactam antibiotics have been the backbone of therapeutic armamentarium against gonococci. However, we are lacking critical insights to design rationally optimized therapies. In the present work, we generated the first PBP-binding data set on 18 currently available and clinically relevant β-lactams and 4 β-lactamase inhibitors in two N. gonorrhoeae ATCC type collection strains, 19424 and 49226 (PBP2 type XXII and A39T change in mtrR). PBP binding (IC50) was determined via the Bocillin FL binding assay in isolated membrane preparations. Three clusters of differential PBP IC50s were identified and were mostly consistent across both strains, but with quantitative differences. Carbapenems were coselective for PBP2 and PBP3 (0.01 to 0.03 mg/L). Third- and fourth-generation cephalosporins cefixime, cefotaxime, ceftazidime, cefepime, and ceftriaxone showed the lowest IC50 values for PBP2 (0.01 mg/L), whereas cefoxitin, ceftaroline, and ceftolozane required higher concentrations (0.04 to >2 mg/L). Aztreonam was selective for PBP2 in both strains (0.03 to 0.07 mg/L); amdinocillin bound this PBP at higher concentrations (1.33 to 2.94 mg/L). Penicillins specifically targeted PBP2 in strain ATCC 19424 (0.02 to 0.19 mg/L) and showed limited inhibition in strain ATCC 49226 (0.01 to >2 mg/L). Preferential PBP2 binding was observed by β-lactam-based β-lactamase inhibitors sulbactam and tazobactam (1.07 to 6.02 mg/L); meanwhile, diazabicyclooctane inhibitors relebactam and avibactam were selective for PBP3 (1.27 to 5.40 mg/L). This data set will set the bar for future studies that will help the rational use and translational development of antibiotics against multidrug-resistant (MDR) N. gonorrhoeae. | Descripción: | © 2023 López-Argüello et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. | Versión del editor: | https://doi.org/10.1128/spectrum.00692-23 | URI: | http://hdl.handle.net/10261/352227 | DOI: | 10.1128/spectrum.00692-23 | E-ISSN: | 2165-0497 |
| Aparece en las colecciones: | (IBIS) Artículos |
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| Penicillin-Binding_MS_2023_OA.pdf | 1,12 MB | Adobe PDF | Visualizar/Abrir |
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