Overview Metallo-β-lactamase inhibitors: Promise for the future?
نویسندگان
چکیده
Carbapenem resistance continues to erode the effectiveness of antibiotics such as imipenem and meropenem in the clinic. Resistance mechanisms can include interplay between porin loss (membrane permeability), mutation of penicillin binding proteins necessary for cell division, and expression of class A, B and D β-lactamases. Bacterial resistance to β-lactams such as penicillin or amoxicillin has been overcome in the clinic using several strategies, including development of antibiotics not susceptible to hydrolysis by βlactamases, or co-administration of the antibiotic with β-lactamase inhibitors. This overview will focus on progress since 2000 in identifying inhibitors of class B, or metallo-β-lactamases with the aim of reversing carbapenem resistance.
منابع مشابه
Quantum Mechanical Approach for the Catalytic Mechanism of Dinuclear Zinc Metallo-β-lactamase by Penicillin and Cephalexin: Kinetic and Thermodynamic Points of View
Metallo-β-lactamases (MβL) catalyzing the hydrolytic cleavage of the four-membered β-lactam ring in broad spectrum of antibiotics and therefore inactivating the drug; However, the mechanism of these enzymes is still not well understood. Electronic structure and electronic energy of metallo-β-lactamase active center, two inhibitors of this enzyme including penicillin and cephalexin, and differen...
متن کاملCombined Support-Vector-Machine-Based Virtual Screening and Docking Method for the Discovery of IMP-1 Metallo-β-Lactamase Inhibitors
Metallo-β-lactamases can hydrolyze a broad range of β-lactam antibiotics and no effective inhibitors could be used in the clinic. Therefore, the discovery of metallo-β-lactamase inhibitors has attracted much attention in recent years. In this study, a support vector machine (SVM) that separates compounds into positives and negatives, combined with docking method was employed for virtual screeni...
متن کاملSolution structures of the Bacillus cereus metallo-β-lactamase BcII and its complex with the broad spectrum inhibitor R-thiomandelic acid
Metallo-β-lactamases, enzymes which inactivate β-lactam antibiotics, are of increasing biological and clinical significance as a source of antibiotic resistance in pathogenic bacteria. In the present study we describe the high-resolution solution NMR structures of the Bacillus cereus metallo-β-lactamase BcII and of its complex with R-thiomandelic acid, a broad-spectrum inhibitor of metallo-β-la...
متن کاملComplete 1H, 15N and 13C resonance assignments of Bacillus cereus metallo-β-lactamase and its complex with the inhibitor R-thiomandelic acid
β-Lactamases inactivate β-lactam antibiotics by hydrolysis of their endocyclic β-lactam bond and are a major cause of antibiotic resistance in pathogenic bacteria. The zinc dependent metallo-β-lactamase enzymes are of particular concern since they are located on highly transmissible plasmids and have a broad spectrum of activity against almost all β-lactam antibiotics. We present here essential...
متن کاملIdentification of 76 novel B1 metallo-β-lactamases through large-scale screening of genomic and metagenomic data
BACKGROUND Metallo-β-lactamases are bacterial enzymes that provide resistance to carbapenems, the most potent class of antibiotics. These enzymes are commonly encoded on mobile genetic elements, which, together with their broad substrate spectrum and lack of clinically useful inhibitors, make them a particularly problematic class of antibiotic resistance determinants. We hypothesized that there...
متن کامل