β-Lactamase Inhibitors: The Story so Far

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.