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Antibiotics 2014, 3(3), 285-316; doi:10.3390/antibiotics3030285
Review

Evolution of Metallo-β-lactamases: Trends Revealed by Natural Diversity and in vitro Evolution

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Received: 11 April 2014; in revised form: 15 June 2014 / Accepted: 18 June 2014 / Published: 1 July 2014
(This article belongs to the Special Issue Mechanisms of Antibiotic Resistance)
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Abstract: The production of β-lactamase enzymes is one of the most distributed resistance mechanisms towards β-lactam antibiotics. Metallo-β-lactamases constitute a worrisome group of these kinds of enzymes, since they present a broad spectrum profile, being able to hydrolyze not only penicillins, but also the latest generation of cephalosporins and carbapenems, which constitute at present the last resource antibiotics. The VIM, IMP, and NDM enzymes comprise the main groups of clinically relevant metallo-β-lactamases. Here we present an update of the features of the natural variants that have emerged and of the ones that have been engineered in the laboratory, in an effort to find sequence and structural determinants of substrate preferences. This knowledge is of upmost importance in novel drug design efforts. We also discuss the advances in knowledge achieved by means of in vitro directed evolution experiments, and the potential of this approach to predict natural evolution of metallo-β-lactamases.The production of β-lactamase enzymes is one of the most distributed resistance mechanisms towards β-lactam antibiotics. Metallo-β-lactamases constitute a worrisome group of these kinds of enzymes, since they present a broad spectrum profile, being able to hydrolyze not only penicillins, but also the latest generation of cephalosporins and carbapenems, which constitute at present the last resource antibiotics. The VIM, IMP, and NDM enzymes comprise the main groups of clinically relevant metallo-β-lactamases. Here we present an update of the features of the natural variants that have emerged and of the ones that have been engineered in the laboratory, in an effort to find sequence and structural determinants of substrate preferences. This knowledge is of upmost importance in novel drug design efforts. We also discuss the advances in knowledge achieved by means of in vitro directed evolution experiments, and the potential of this approach to predict natural evolution of metallo-β-lactamases.
Keywords: resistance; metallo-β-lactamases; evolution resistance; metallo-β-lactamases; evolution
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Meini, M.-R.; Llarrull, L.I.; Vila, A.J. Evolution of Metallo-β-lactamases: Trends Revealed by Natural Diversity and in vitro Evolution. Antibiotics 2014, 3, 285-316.

AMA Style

Meini M-R, Llarrull LI, Vila AJ. Evolution of Metallo-β-lactamases: Trends Revealed by Natural Diversity and in vitro Evolution. Antibiotics. 2014; 3(3):285-316.

Chicago/Turabian Style

Meini, María-Rocío; Llarrull, Leticia I.; Vila, Alejandro J. 2014. "Evolution of Metallo-β-lactamases: Trends Revealed by Natural Diversity and in vitro Evolution." Antibiotics 3, no. 3: 285-316.

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