![]() ![]() ![]() Concomitantly, broad use of β-lactams as antibacterials applies a selective pressure that increases the reproductive success of pathogenic strains carrying evolved β-lactamase genes capable of combating our arsenal of β-lactam antibiotics. Since the discovery of penicillin, several classes of naturally occurring and semi-synthetic β-lactams have entered the clinic. Simultaneously, cell wall hydrolases and autolysins continue to break down peptidoglycan crosslinks, resulting in cellular lysis and death. The first β-lactam discovered-penicillin-inhibits the function of the D-Ala-D-Ala transpeptidase that links the peptidoglycan molecules in bacteria. Β-Lactams are the most broadly used antibacterials world-wide due to their effectiveness at irreversibly inhibiting cell wall biosynthetic enzymes required for peptidoglycan recycling, and minimal toxicity in humans. Unfortunately, the integrity of the “big guns” (meropenem, imipenem, doripenem, ertapenem) has become compromised by a number of β-lactamases with extended spectrum activity, that is, the ability to inactivate all classes of β-lactam antibiotics, including carbapenems. One of the last lines of defense against multiple and extensively drug resistant infections is the carbapenem class of β-lactam antibiotics, which was developed to evade β-lactamase mediated resistance posed by aerobic as well as anaerobic pathogens. The crystal structures of NDM-1 presented here reveal an open, enlarged and flexible active site that explains the observed extended spectrum activity of this zinc dependent β-lactamase. Biochemical and structural elucidation of NDM-1 facilitates the thorough mechanistic understanding required for a rational design of small molecule inhibitors specific to NDM-1 for co-administration with β-lactam antibiotics. The imminent threat posed by the recent discovery and dissemination of the plasmid encoded New Delhi Metallo-β-lactamase (NDM-1) gene ( blaNDM-1) harbored by multiple pathogenic microorganisms has prompted the formation of a global scientific corps d'armée. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. Department of Energy, Office of Biological and Environmental Research, under contract DE-AC02-06CH11357. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was supported by National Institutes of Health grant GM094585 (AJ), GM094568 (JS) and by the U. Received: JAccepted: AugPublished: September 8, 2011Ĭopyright: © 2011 Kim et al. PLoS ONE 6(9):Įditor: Adam Driks, Loyola University Medical Center, United States of America (2011) Structure of Apo- and Monometalated Forms of NDM-1-A Highly Potent Carbapenem-Hydrolyzing Metallo-β-Lactamase. ![]() ![]() Loop 1 in particular, shows conformational flexibility, apparently related to the acceptance and positioning of substrates for cleavage by a zinc-activated water molecule.Ĭitation: Kim Y, Tesar C, Mire J, Jedrzejczak R, Binkowski A, Babnigg G, et al. Indeed, five loops contribute “keg” residues in the active site including side chains involved in metal binding. This site is capable of accommodating many β-lactam substrates by having many of the catalytic residues on flexible loops, which explains the observed extended spectrum activity of this zinc dependent β-lactamase. The crystal structures of metal-free apo- and monozinc forms of NDM-1 presented here revealed an enlarged and flexible active site of class B1 metallo-β-lactamase. Biochemical studies revealed that NDM-1 is capable of efficiently hydrolyzing a wide range of β-lactams, including many carbapenems considered as “last resort” antibiotics. The rapid emergence of NDM-1 has been linked to mobile plasmids that move between different strains resulting in world-wide dissemination. The New Delhi Metallo-β-lactamase (NDM-1) gene makes multiple pathogenic microorganisms resistant to all known β-lactam antibiotics. ![]()
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