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β-Lactamase Inhibitors: The Story so Far

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Antimicrobial resistance constitutes one of the major threats regarding pathogenic microorganisms. Gramnegative pathogens, such as Enterobacteriaceae (specially those producing extended-spectrum β-lactamases), Pseudomonas aeruginosa, and Acinetobacter baumannii, have acquired an important role in hospital infections, which is of particular concern because of the associated broad spectrum of antibiotic resistance.

β-Lactam antibiotics are considered the most successful antimicrobial agents since the beginning of the antibiotic era. Soon after the introduction of penicillin, microorganisms able to destroy this β-lactam antibiotic were reported, thus, emphasizing the facility of pathogenic microorganisms to develop β-lactam resistance. In Gram-negative pathogens, β- lactamase production is the main mechanism involved in acquired β-lactam resistance. Four classes of β-lactamases have been described: A, B, C, and D. Classes A, C, and D are enzymes with a serine moiety in the active centre that catalyzes hydrolysis of the β -lactam ring through an acyl-intermediate of serine, whereas the class B enzymes require a metal cofactor (e.g. zinc in the natural form) to function, and for this reason, they are also referred to as metallo- β-lactamases (MBLs).

To overcome β-lactamase-mediated resistance, a combination of β-lactam and a β-lactamase inhibitor, which protects the β-lactam antibiotic from the activity of the β-lactamase, has been widely used in the treatment of human infections. Although there are some very successful combinations of β-lactams and ??-lactamase inhibitors, most of the inhibitors act against class A β-lactamases and remain ineffective against class B, C, and D β-lactamases.

This review constitutes an update of the current status and knowledge regarding class A to D β-lactamase inhibitors, as well as a summary of the drug discovery strategy currently used to identify new ??-lactamase inhibitors, mainly based on the knowledge of crystal structure of β-lactamase enzymes.

Keywords: Antibiotic resistance; antimicrobial design; drug discovery

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986709789104957

Affiliations: Laboratorio de Microbiologia, CH Universitario A Coruna-INIBIC, Xubias de Arriba, s/n, 15006, A Coruna Spain.

Publication date: October 1, 2009

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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