Beta-lactamase, the enzyme that catalyzes the chemical degradation of beta-lactam antibiotics, is a leading cause of the fading efficacy of beta-lactam antibiotics, particularly in problematic Gram-negative organisms.  Co-administration of beta-lactam antibiotics with beta-lactamase inhibitors (BLIs) has been a time honored strategy to restore clinical efficacy. Beta-lactamases are categorized into four classes: Classes A, C and D are serine-based hydrolases; Class B comprises zinc�metallo hydrolases. Unfortunately, the currently marketed beta-lactamase inhibitors are only effective on a subset of beta-lactamases. Thus there is an important medical need to develop new beta-lactamase inhibitors to combat the growing threat of antibiotic resistance.  To this end, MK-4698 was discovered as a potent extended-spectrum BLI clinical candidate with excellent preclinical efficacy.  Compared with marketed inhibitors, it offers much greater coverage for beta-lactamase panels of resistant bacterial strains.  In animal models of resistant infection, it potentiated existing beta-lactam antibiotic therapies effectively.

Discovery of MK-4698 as a candidate for broad-spectrum beta-lactamase inhibitor

247th National Meeting (2014)

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