Examinando por Autor "Vila, Alejandro J. [https://orcid.org/0000-0002-7978-3233]"

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    Ítem
    2-Mercaptomethyl thiazolidines (MMTZs) inhibit all metallo-β-lactamase classes by maintaining a conserved binding mode
    (American Chemical Society, 2021) Rossi, María Agustina; Martínez, Verónica; Villamil, Valentina; Spellberg, Brad J.; Drusano, George Louis; Banchio, Claudia; Bonomo, Robert A.; Hinchliffe, Philip; Moreno, Diego M. [https://orcid.org/0000-0001-5493-8537]; Mojica, María Fernanda [https://orcid.org/0000-0002-1380-9824]; Mahler, Graciela [https://orcid.org/0000-0003-0612-0516]; Vila, Alejandro J. [https://orcid.org/0000-0002-7978-3233]
    Metallo-β-lactamase (MBL) production in Gram-negative bacteria is an important contributor to β-lactam antibiotic resistance. Combining β-lactams with β-lactamase inhibitors (BLIs) is a validated route to overcoming resistance, but MBL inhibitors are not available in the clinic. On the basis of zinc utilization and sequence, MBLs are divided into three subclasses, B1, B2, and B3, whose differing active-site architectures hinder development of BLIs capable of “cross-class” MBL inhibition. We previously described 2-mercaptomethyl thiazolidines (MMTZs) as B1 MBL inhibitors (e.g., NDM-1) and here show that inhibition extends to the clinically relevant B2 (Sfh-I) and B3 (L1) enzymes. MMTZs inhibit purified MBLs in vitro (e.g., Sfh-I, Ki 0.16 μM) and potentiate β-lactam activity against producer strains. X-ray crystallography reveals that inhibition involves direct interaction of the MMTZ thiol with the mono- or dizinc centers of Sfh-I/L1, respectively. This is further enhanced by sulfur-π interactions with a conserved active site tryptophan. Computational studies reveal that the stereochemistry at chiral centers is critical, showing less potent MMTZ stereoisomers (up to 800-fold) as unable to replicate sulfur-π interactions in Sfh-I, largely through steric constraints in a compact active site. Furthermore, in silico replacement of the thiazolidine sulfur with oxygen (forming an oxazolidine) resulted in less favorable aromatic interactions with B2 MBLs, though the effect is less than that previously observed for the subclass B1 enzyme NDM-1. In the B3 enzyme L1, these effects are offset by additional MMTZ interactions with the protein main chain. MMTZs can therefore inhibit all MBL classes by maintaining conserved binding modes through different routes.
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    Ítem
    The urgent need for metallo-β-lactamase inhibitors: an unattended global threat
    (Elsevier Ltd, 2022-01) Rossi, María Agustina; Bonomo, Robert A.; Mojica, María Fernanda [https://orcid.org/0000-0002-1380-9824]; Vila, Alejandro J. [https://orcid.org/0000-0002-7978-3233]
    Debido a su tolerabilidad y eficacia superiores, los β-lactámicos son la clase de antibióticos más potentes y prescritos en la clínica. La aparición de resistencia a esos antibióticos, principalmente debido a la producción de enzimas bacterianas llamadas β-lactamasas, se ha resuelto parcialmente con la introducción de inhibidores de β-lactamasas, que restablecen la actividad de moléculas obsoletas. Esta solución es limitada porque los inhibidores de β-lactamasas actualmente disponibles solo funcionan contra las serina β-lactamasas, mientras que las metalo-β-lactamasas continúan propagándose, evolucionando y confiriendo resistencia a todos los β-lactámicos, incluidos los carbapenémicos. Además, el mayor uso de antibióticos para tratar la neumonía bacteriana secundaria en pacientes gravemente enfermos con COVID-19 podría exacerbar el problema de la resistencia a los antimicrobianos. En esta Opinión Personal, resumimos los principales avances logrados en esta área de investigación, enfatizamos los principales desafíos que deben resolverse y la importancia de la investigación sobre inhibidores de metalo-B-lactamasas en medio de la pandemia actual.