Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes
| Autor: | Valerie Castillo, Alejandro J. Vila, Graciela Mahler, Javier M. González, Maria F. Mojica, Cecilia Saiz, Magda Kosmopoulou, Mariano M. González, James Spencer, Catherine L. Tooke, Philip Hinchliffe, Robert A. Bonomo, Leticia I. Llarrull |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular antibiotic resistance Stereochemistry metallo-β-lactamase Otras Ciencias Biológicas 030106 microbiology Biology beta-Lactamases bisthiazolidines purl.org/becyt/ford/1 [https] Ciencias Biológicas 03 medical and health sciences chemistry.chemical_compound carbapenemase Bacterial Proteins Escherichia Catalytic Domain Hydrolase inhibitors Carboxylate purl.org/becyt/ford/1.6 [https] chemistry.chemical_classification Multidisciplinary Bicyclic molecule Hydrolysis biology.organism_classification In vitro Anti-Bacterial Agents Kinetics Enzyme Biochemistry chemistry PNAS Plus Drug Design Thiol Thiazolidines Enantiomer beta-Lactamase Inhibitors CIENCIAS NATURALES Y EXACTAS |
| Zdroj: | Hinchliffe, P, Gonzalez, M M, Mojica, M F, Gonzalez, J M, Castillo, V, Saiz, C, Kosmopoulou, M, Tooke, C, Llarrull, L, Mahler, G, Bonomo, R A, Villa, A J & Spencer, J 2016, ' Cross-class metallo-β-lactamase inhibition by bisthiazolidines reveals multiple binding modes ', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 26, pp. E3745-E3754 . https://doi.org/10.1073/pnas.1601368113 CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| Popis: | Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics and are unaffected by clinically available β-lactamase inhibitors (βLIs). Active-site architecture divides MBLs into three classes (B1, B2, and B3), complicating development of βLIs effective against all enzymes. Bisthiazolidines (BTZs) are carboxylate-containing, bicyclic compounds, considered as penicillin analogs with an additional free thiol. Here, we show both L- and D-BTZ enantiomers are micromolar competitive βLIs of all MBL classes in vitro, with Ki sof6-15 μM or 36-84 μM for subclass B1 MBLs (IMP-1 and BcII, respectively), and 10-12 μM for the B3 enzyme L1. Against the B2 MBL Sfh-I, the L-BTZ enantiomers exhibit 100-fold lower Ki s (0.26-0.36 μM) than D-BTZs (26-29 μM). Importantly, cell-based time-kill assays show BTZs restore β-lactam susceptibility of Escherichia coli-producing MBLs (IMP-1, Sfh-1, BcII, and GOB-18) and, significantly, an extensively drug-resistant Stenotrophomonas maltophilia clinical isolate expressing L1. BTZs therefore inhibit the full range of MBLs and potentiate β-lactam activity against producer pathogens. X-ray crystal structures reveal insights into diverse BTZ binding modes, varying with orientation of the carboxylate and thiol moieties. BTZs bind the di-zinc centers of B1 (IMP-1; BcII) and B3 (L1) MBLs via the free thiol, but orient differently depending upon stereochemistry. In contrast, the L-BTZ carboxylate dominates interactions with the monozinc B2 MBL Sfh-I, with the thiol uninvolved. D-BTZ complexes most closely resemble β-lactam binding to B1 MBLs, but feature an unprecedented disruption of the D120-zinc interaction. Cross-class MBL inhibition therefore arises from the unexpected versatility of BTZ binding. Fil: Hinchliffe, Philip. University of Bristol; Reino Unido Fil: Gonzalez, Javier Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Mojica, María. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Estados Unidos. Case Western Reserve University; Estados Unidos Fil: Gonzalez, Javier Marcelo. Universidad Nacional de Santiago del Estero. Instituto de Bionanotecnología del Noa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Bionanotecnología del Noa; Argentina Fil: Castillo, Valerie. Universidad de la República; Uruguay Fil: Saiz Garcia, Cecilia. Universidad de la República; Uruguay Fil: Kosmopoulou, Magda. University of Bristol; Reino Unido Fil: Tooke, Catherine. University of Bristol; Reino Unido Fil: Llarrull, Leticia Irene. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Mahler, Graciela. Universidad de la República; Uruguay Fil: Bonomo, Robert. Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Estados Unidos. Case Western Reserve University; Estados Unidos Fil: Vila, Alejandro Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Spencer, James. University of Bristol; Reino Unido |
| Databáze: | OpenAIRE |
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