Antimicrobial resistance (AMR) is a growing concern around the globe and is expected to become a leading cause of death worldwide by 2050. Tuberculosis (TB) is a mycobacterial infection caused by Mycobacterium tuberculosis (Mtb), and the disease comes in different forms including multidrug-resistant-TB (MDR-TB) and extensively drug-resistant-TB (XDR-TB). The growing predicament AMR infections pose to public health combined with recent decades’ decrease in new antibiotic products demands our attention. Almost all bacteria possess a peptidoglycan (PG) layer which is essential for their survival. This PG layer is formed from cross linkages of amino acids between stem peptides. In most bacteria, these are 4→3 cross linkages which are catalyzed by D, D-transpeptidases (Ddts, more commonly referred to as penicillin-binding proteins, PBPs). However in most mycobacteria, like that which causes TB, the PG are predominantly 3→3 cross linked, and these linkages are catalyzed by L, D-transpeptidases (Ldts). PBPs and Ldts are nonhomologous, and thus β-lactam antibiotics, which represent 60% of all clinically administered antibiotics, that target PBPs are largely ineffective in treating mycobacterial infections. That said, the β-lactam subclass of antibiotics called carbapenems has demonstrated activity against Ldt enzymes. Carbapenems inhibit Ldt function via acylation, and this reaction can be monitored with tryptophan fluorescence. Here, we present our work in investigating a novel atypical β-lactam compound, 10a, and its ability to acylate mycobacterial Ldt enzymes in comparison to commercial carbapenems. We anticipate these results will guide rational drug design strategies toward generating more effective antibiotics to treat mycobacterial infections.

Characterization of mycobacterial L,D-transpeptidase inactivation by commercial and atypical β-lactams.

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.