Discovery of novel antibacterial agents: Recent developments in D-alanyl-D-alanine ligase inhibitors

Bacterial infections can cause serious problems that threaten public health over a long period of time. Moreover, the continuous emergence of drug-resistant bacteria necessitates the development of novel antibacterial agents. D-alanyl-D-alanine ligase (Ddl) is an indispensable adenosine triphosphate-dependent bacterial enzyme involved in the biosynthesis of peptidoglycan precursor, which catalyzes the ligation of two D-alanine molecules into one D-alanyl-D-alanine dipeptide. This dipeptide is an essential component of the intracellular peptidoglycan precursor, uridine diphospho-N-acetylmuramic acid (UDP-MurNAc)-pentapeptide, that maintains the integrity of the bacterial cell wall by cross-linking the peptidoglycan chain, and is crucial for the survival of pathogens. Consequently, Ddl is expected to be a promising target for the development of antibacterial agents. In this review, we present a brief introduction regarding the structure and function of Ddl, as well as an overview of the various Ddl inhibitors currently being used as antibacterial agents, specifically highlighting their inhibitory activities, structure-activity relationships and mechanisms of action.