Mycobacterial L,D-transpeptidases (Ldts) are under investigation as potential drug targets. Mycobacterial species, including pathogenic Mycobacterium tuberculosis and opportunistic pathogens like Mycobacterium abscessus, express as many as six Ldts, and their apparent redundancy is not well understood. While Ldts function in maintaining mycobacterial peptidoglycan (PG), these enzymes are not homologous to the well-studied D,D-transpeptidases (Ddts, also known as penicillin binding proteins, PBPs) and are likewise not inhibited by traditional β-lactam antibiotics, including penicillins and cephalosporins. For this reason, coupled with the fact that mycobacterial species express endogenously coded β-lactamases, penicillin and cephalosporin β-lactams have not been historically used to treat mycobacterial infections. As the threat of antibiotic resistance continues to threaten public health, the need to identify new antibiotics increases, and we believe mycobacterial Ldts, which are required to properly maintain the mycobacterial cell wall, should be explored as drug targets. There are six evolutionarily distinct classes of mycobacterial Ldts, and the physiological roles of the different classes are not well understood. In order to effectively target these Ldts, we need to understand the reactions they catalyze. We hypothesize that different Ldt classes have unique substrate preferences. Putative Ldt substrates are difficult to access synthetically, making substrate activity relationship studies challenging. For this reason, we are attempting to enzymatically generate six putative Ldt substrates toward better understanding the physiological roles of these Ldts. Likewise, we are using (carba)penems as probes in specificity studies in order to identify unique inhibitor binding preferences among homologous Ldts. We anticipate our work will help to guide rational drug design strategies as we learn more about mycobacterial Ldts and the reactions they catalyze.

Understanding mycobacterial L,D-transpeptidases in order to design better β-lactam antibiotics

ACS Spring 2022

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