The fall of the mycobacterial cell wall: interrogating peptidoglycan synthesis for novel anti-TB agents

Tuberculosis (TB) caused by Mycobacterium tuberculosis has been a threat to human health for thousands of years and still leads to millions of deaths each year. TB is a disease that is refractory to treatment, partially due to its capacity for in-host persistence. The cell wall of mycobacteria, rich in mycolic acid, is broadly associated with bacterial persistence together with antimicrobial and immunological resistance. Enzymes for the biosynthesis of bacterial peptidoglycan, an essential component of the cell wall, have been addressed and considered as appealing drug targets in pathogens. Significant effort has been dedicated to finding inhibitors that hinder peptidoglycan biosynthesis, many with demonstrated enzymatic inhibition in vitro being published. One family of critical biosynthetic enzymes are the Mur enzymes, with many enzyme specific inhibitors having been reported. However, a lesser developed strategy which may have positive clinical implications is to take advantage of the common structural and catalytic characteristics among Mur enzymes and to allow simultaneous, multiple Mur inhibition, and avert the development of drug resistance. M. tuberculosis relies on these essential Mur enzymes, with the best-known subset being Mur ligases, but also utilizes unique functions of atypical transpeptidases resulting in peptidoglycan peptide cross-linking beneficial to the bacteria's capacity for chronic persistence in humans. A systematic review is now needed, with an emphasis on M. tuberculosis. The urgent development of novel anti-TB agents to counter rapidly developing drug resistance requires a revisit of the literature, past successes and failures, in an attempt to reveal liabilities in critical cellular functions and drive innovation.