beta-Lactamase Inhibitors: The Story so Far

Antimicrobial resistance constitutes one of the major threats regarding pathogenic microorganisms. Gram-negative pathogens, such as Enterobacteriaceae (specially those producing extended-spectrum beta-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. beta-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 beta-lactam antibiotic were reported, thus, emphasizing the facility of pathogenic microorganisms to develop beta-lactam resistance. In Gram-negative pathogens, beta-lactamase production is the main mechanism involved in acquired beta-lactam resistance. Four classes of beta-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 beta-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-beta-lactamases (MBLs). To overcome beta-lactamase-mediated resistance, a combination of beta-lactam and a beta-lactamase inhibitor, which protects the beta-lactam antibiotic from the activity of the beta-lactamase, has been widely used in the treatment of human infections. Although there are some very successful combinations of beta-lactams and beta-lactamase inhibitors, most of the inhibitors act against class A beta-lactamases and remain ineffective against class B, C, and D beta-lactamases. This review constitutes an update of the current status and knowledge regarding class A to D beta-lactamase inhibitors, as well as a summary of the drug discovery strategy currently used to identify new beta-lactamase inhibitors, mainly based on the knowledge of crystal structure of beta-lactamase enzymes.