Journal ArticleDOI
2-Mercaptomethyl Thiazolidines (MMTZs) Inhibit All Metallo-β-Lactamase Classes by Maintaining a Conserved Binding Mode.
Philip Hinchliffe,Diego M. Moreno,Diego M. Moreno,Maria-Agustina Rossi,Maria F. Mojica,Maria F. Mojica,Maria F. Mojica,Verónica Martínez,Valentina Villamil,Brad Spellberg,George L. Drusano,Claudia Banchio,Claudia Banchio,Graciela Mahler,Robert A. Bonomo,Alejandro J. Vila,Alejandro J. Vila,James Spencer +17 more
TLDR
In this article, 2-mercaptomethyl thiazolidines (MMTZs) were used as B1 MBL inhibitors and showed that inhibition extends to B2 (Sfh-I) and B3 (L1) enzymes.Abstract:
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.read more
Citations
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Journal ArticleDOI
Multiscale Workflow for Modeling Ligand Complexes of Zinc Metalloproteins.
Zongfan Yang,Rebecca M. Twidale,Silvia Gervasoni,Silvia Gervasoni,Reynier Suardíaz,Charlotte K. Colenso,Eric J. M. Lang,James Spencer,Adrian J. Mulholland +8 more
TL;DR: In this paper, the authors evaluate the ability of alternative treatments, using (nonbonded) molecular mechanics (MM) and quantum mechanics/molecular mechanics (QM/MM) at semi-empirical (DFTB3) and density functional theory (DFT) levels of theory, to describe the zinc centers of ligand complexes of six metalloenzyme systems differing in coordination geometries, zinc stoichiometries (mono- and dinuclear), and the nature of interacting groups (specifically the presence of zinc-sulfur interactions).
Journal ArticleDOI
Structure and Mechanism-Guided Design of Dual Serine/Metallo-Carbapenemase Inhibitors.
TL;DR: This Perspective is the first systematic investigation of all chemotypes, modes of inhibition, and crystal structures of dual serine/metallo-carbapenemase inhibitors, and their mechanism of action to overcome the carbapenems resistance issue.
Journal ArticleDOI
The development of New Delhi metallo-β-lactamase-1 inhibitors since 2018.
TL;DR: In this article , the authors summarize NDM-1 inhibitors developed since 2018, classify these compounds by chemical scaffolds, and propose some inconsistencies and notable problems among these studies, which are expected to benefit future research.
Journal ArticleDOI
Time-resolved β-lactam cleavage by L1 metallo-β-lactamase
M. Wilamowski,D.A. Sherrell,Y. Kim,A. Lavens,Robert H. Henning,K. Lazarski,Austin K. Shigemoto,M. Endres,Natalia Maltseva,Gyorgy Babnigg,Shawn C. Burdette,Vukica Šrajer,Andrzej Joachimiak +12 more
TL;DR: In this paper , the structure, binding and cleavage of moxalactam antibiotic bound to L1 metallo-β-lactamase (MBL) from Stenotrophomonas maltophilia were revealed using time-resolved serial synchrotron crystallography.
Journal ArticleDOI
Recent advances in β-lactamase inhibitor chemotypes and inhibition modes.
TL;DR: In this paper , the authors summarized recent advances of inhibitor chemotypes targeting MBL and SBLs and their inhibition mechanisms, particularly including lead discovery and structural optimization strategies, with the aim to provide useful information for future efforts to develop new MBL/SBL inhibitors.
References
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