Mechanistic studies of beta-lactamases and transpeptidases to combat bacterial resistance to beta-lactam antibiotics

β-Lactams, the most widely used class of antibiotic, act by targeting transpeptidases involved in bacterial cell wall biosynthesis. However, bacteria have developed resistance mechanisms against β-lactam antibiotics, most importantly through the production of β-lactamase enzymes. This seminar describes mechanistic studies on both β-lactamases and transpeptidases, focusing on how they interact with and/or degrade β-lactams. NMR approaches were used to study the carbamylation of class D serine β-lactamases, a post-translational modification required for activity. These NMR studies led to the identification of a new enzymatic mechanism through which the clinically important carbapenem β-lactam antibiotics are degraded. Additional work has investigated the role of the nucleophilic residue (serine or cysteine) in the mechanisms of β-lactamases and transpeptidases, revealing that alternative fragmentation pathways are viable for the acyl-enzyme complexes derived from cysteine. These studies provide a better understanding of the activity and mechanism of serine β-lactamases and transpeptidases, and open perspectives for the development of new β-lactam antibiotics and serine β-lactamase inhibitors.