In order to describe possible reaction mechanisms involving amino acids, and the evolution of protonation state acid side chains in solution, a reactive force field (ReaxFF-based description) for peptide protein simulations has been developed as an expansion previously reported glycine parameters. This consists adding training set more than five hundred molecular systems, including all acids some short structures, which have investigated by means quantum mechanical calculations. The...

Synonymous mutations result from the degeneracy of genetic code. Most amino acids are encoded by two or more codons, and that change a codon to another synonymous do not acid in gene product. Historically, such have been considered silent because they were assumed no very little impact. However, research last few decades has produced several examples where play important roles. These include optimizing expression enhancing translation initiation accelerating decelerating elongation via usage...

Quinolones inhibit bacterial type II DNA topoisomerases (e.g. gyrase) and are among the most important antibiotics in current use. However, their efficacy is now being threatened by various plasmid-mediated resistance determinants. Of these, pentapeptide repeat-containing (PRP) Qnr proteins believed to act as mimics particularly prevalent Gram-negative bacteria. Predicted Qnr-like also present numerous environmental Here, we demonstrate that one such, Aeromonas hydrophila AhQnr, soluble,...

In light of the biomedical significance metallo-β-lactamases (MβLs), ten new mercaptoacetic acid thioester amino derivatives were synthesized and characterized. Biological activity assays indicated that all these compounds are very potent inhibitors L1, exhibiting an IC50 value range 0.018-2.9 μM a K i 0.11-0.95 using cefazolin as substrate. Partial thioesters also showed effective inhibitory activities against NDM-1 ImiS with 12-96 3.6-65 μM, respectively. Also, increased susceptibility E....

Abstract The emergence and spread of antibiotic‐resistant pathogens is a global public health problem. Metallo‐β‐lactamases (MβLs) such as New Delhi MβL‐1 (NDM‐1) are principle contributors to the resistance because their ability hydrolyze almost all known β‐lactam antibiotics including penicillins, cephalosporins, carbapenems. A clinical inhibitor MBLs has not yet been found. In this study we developed eighteen new diaryl‐substituted azolylthioacetamides found them be inhibitors MβL L1 from...

The metallo-β-lactamases (MβLs) cleave the β-lactam ring of antibiotics, conferring resistance against these drugs to bacteria. Twenty-four triazolylthioacetamides were prepared and evaluated as inhibitors representatives three subclasses MβLs. All compounds exhibited specific inhibitory activity NDM-1 with an IC50 value range 0.15-1.90 μM, but no CcrA, ImiS, L1 at inhibitor concentrations up 10 μM. Compounds 4d 6c are partially mixed K i values 0.49 0.63 μM using cefazolin substrate....

A new scaffold, azolylthioacetamide, was constructed and assayed against metallo-β-lactamases (MβLs). The obtained molecules specifically inhibited MβL ImiS, 1c found to be the most potent inhibitor, with a Ki = 1.2 μM using imipenem as substrate. Structure–activity relationships reveal that aromatic carboxyl improves inhibitory activity of inhibitors, but aliphatic does not. Compounds 1c–d 1h–i showed best antibacterial activities E. coli BL21(DE3) cells producing CcrA or resulting in 32-...

ADVERTISEMENT RETURN TO ISSUEPREVPerspectiveNEXTEvolving Carbapenemases: Can Medicinal Chemists Advance One Step Ahead of the Coming Storm?Peter Oelschlaeger*†, Ni Ai‡, Kevin T. DuPrez†, William J. Welsh‡, and Jeffrey H. Toney§View Author Information† Chemistry Department Center for Macromolecular Modeling Materials Design, California State Polytechnic University, Pomona, California‡ Pharmacology, Robert Wood Johnson Medical School Informatics Institute, University Medicine Dentistry New...

ABSTRACT Metallo-β-lactamases (MBLs) are enzymes that hydrolyze β-lactam antibiotics, resulting in bacterial resistance to these drugs. These proteins have caused concerns due their facile transference, broad substrate spectra, and the absence of clinically useful inhibitors. To facilitate classification, nomenclature, analysis MBLs, an automated database system was developed, Metallo-β-Lactamase Engineering Database (MBLED) ( http://www.mbled.uni-stuttgart.de ). It contains information on...

A series of rhodanines was constructed, their Z-configuration confirmed by small molecule X-ray crystal structures, and activity against metallo-β-lactamases (MβLs) measured. The obtained 26 molecules a thioenolate specifically inhibited the MβL L1 with an IC50 range 0.02–1.7 μM, compounds 2h–m exhibited broad-spectrum inhibition MβLs NDM-1, VIM-2, ImiS, values <16 μM. All inhibitors increased antimicrobial effect cefazolin E. coli cells expressing L1, resulting in 2–8-fold reduction MIC....

Extremely drug-resistant (XDR) Acinetobacter baumannii is a notorious and frequently encountered pathogen demanding novel therapeutic interventions. An initial monoclonal antibody (MAb), C8, raised against A. capsule, proved highly effective treatment minority of clinical isolates. To overcome this limitation, we broadened coverage by developing second for use in combination regimen. We sought to develop an additional anti-A. MAb through hybridoma technology immunizing mice with sublethal...

Metallo-β-lactamases can hydrolyze a broad spectrum of β-lactam antibiotics and thus confer resistance to bacteria. For the Pseudomonas aeruginosa enzyme IMP-1, several variants have been reported. IMP-6 IMP-1 differ by single residue (glycine serine at position 196, respectively), but significantly different substrate spectra; while catalytic efficiency toward two cephalosporins cephalothin cefotaxime is similar for both variants, up 10-fold more efficient than cephaloridine ceftazidime....

The control of the catalytic power and fidelity DNA polymerases involves complex combined effect protein residues, Mg2+ ions, interaction between bases. In an attempt to advance understanding control, we analyze taking human polymerase beta as a model system. Specifically, examine ability different theoretical models reproduce ionized residues on transition state (TS) binding energy corresponding k(pol)/KD. We also explore role ions in catalysis processes. application microscopic linear...

Metallo-beta-lactamases have raised concerns due to their ability hydrolyze a broad spectrum of beta-lactam antibiotics. The G262S point mutation distinguishing the metallo-beta-lactamase IMP-1 from IMP-6 has no effect on hydrolysis drugs cephalothin and cefotaxime, but significantly improves catalytic efficiency toward cephaloridine, ceftazidime, benzylpenicillin, ampicillin, imipenem. This change in specificity occurs even though residue 262 is remote active site. We investigated substrate...

Two models, a purely nonbonded model and cationic dummy atom approach, were examined for the modeling of binuclear zinc‐containing IMP‐1 metallo‐β‐lactamase in complex with mercaptocarboxylate inhibitor. The approach had substantial advantages as it maintained initial, experimentally determined geometry metal‐containing active site during molecular dynamics simulations water. method was extended to free enzyme cephalosporin substrate docked an intermediate structure. For all three systems,...

The "superbug" infection caused by New Delhi metallo-β-lactamase (NDM-1) has become an emerging threat. Monitoring NDM-1 proven challenging due to its shuttling between pathogenic bacteria. Here, we report isothermal titration calorimetry (ITC) method that can monitor activity and inhibition of in live bacterial cells real time. This been exemplified monitoring the target enzyme evaluating breakdown antibiotics bacteria expressing β-lactamases. Cell-based studies demonstrate expressed was...

The global rise of metallo-β-lactamases (MBLs) is problematic due to their ability inactivate most β-lactam antibiotics. MBL inhibitors that could be coadministered with and restore the efficacy β-lactams are highly sought after. In this study, we employ virtual screening candidate without thiols or carboxylates avoid off-target effects using Avalanche software package, followed by experimental validation selected compounds. As target enzymes, chose clinically relevant B1 MBLs NDM-1, IMP-1,...

Computational protein design methods were used to predict five variants of monofunctional Escherichia coli chorismate mutase expected maintain catalytic activity. The tested experimentally and three active site mutants exhibited activity similar or greater than the wild-type enzyme. One mutant, Ala32Ser, showed increased efficiency.

Metallo-β-lactamases are important determinants of antibacterial resistance. In this study, we investigate the sequence-activity relationship between closely related enzymes IMP-1, IMP-6, and IMP-25. While IMP-1 is more efficient enzyme across overall spectrum tested β-lactam agents, IMP-6 IMP-25 seem to have evolved specifically inactivate newer carbapenem meropenem. Molecular modeling indicates that G235S mutation distinguishing from may affect activity via Asn233.

ABSTRACT Antibiotic resistance in bacteria is ever changing and adapting, as once-novel β-lactam antibiotics are losing their efficacy, primarily due to the production of β-lactamases. Metallo-β-lactamases (MBLs) efficiently inactivate a broad range antibiotics, including carbapenems, often coexpressed with other antibacterial factors. The rapid dissemination MBLs lack novel antibacterials pose an imminent threat global health. In effort better counter these resistance-conferring...

Metallo-β-lactamases (MBLs), also known as class B β-lactamases (BBLs), are Zn(II)-containing enzymes able to inactivate a broad range of β-lactams, the most commonly used antibiotics, including life-saving carbapenems. They have been for about six decades, yet they only gained much attention clinical problem three decades. The naming conventions these changed over time and followed various strategies, sometimes leading confusion. We summarizing strategies currently MBLs. These quite diverse...