Next generation lactamase inhibitors

The 3-lactamase enzymes degrade 3-lactam antibiotics, exemplified by penicillin. As such, the families of metallo- and serine 3-lactamase enzymes are responsible for a major antimicrobial resistance mechanism in many clinically relevant species of Gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. To preserve the antimicrobial activity of 3-lactam antibiotics, inhibitors of 3-lactamases can be used in combination with a 3-lactam antibiotic during treatment of an antimicrobial resistant infection. However, these inhibitors often have a narrow spectrum of activity against 3-lactamases, and other bacterial mechanisms of resistance against them. This project aims to investigate the structure-activity relationships of various serine 3-lactamases with different commercially available and in-house developed 3-lactamase substrates and 3-lactamase inhibitors. In particular, this project will use time-resolved serial crystallography techniques, as well as other spectroscopic and spectrometric techniques. Data derived from these studies will be used for the rational design of novel 3-lactamase inhibitors. UKRI-BBSRC priority areas addressed: Combatting antimicrobial resistance