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.