L,D-transpeptidase 2 (LdtMt2) (LdtMt2)

LdtMt2 is a non-classical transpeptidase in Mycobacterium tuberculosis that catalyzes the formation of 3-3 peptidoglycan cross-links, which are essential for the structural integrity of the bacterial cell wall [1, 4, 5]. While most bacteria rely on 4-3 cross-links formed by D,D-transpeptidases (penicillin-binding proteins), Mtb utilizes LdtMt2 to generate up to 80% of its cross-links during the stationary phase [1, 7]. This enzymatic activity is critical for the pathogen's persistence, virulence, and adaptation to the host environment [1, 2, 10]. The enzyme is characterized by a catalytic triad featuring a nucleophilic cysteine (Cys354), which distinguishes it from the serine-based PBPs targeted by most beta-lactams [2, 3, 5]. This unique architecture renders Mtb inherently resistant to many traditional penicillins and cephalosporins [1, 5, 10]. However, LdtMt2 is susceptible to carbapenems, such as meropenem and imipenem, which act as suicide substrates by covalently acylating the catalytic cysteine [2, 3, 5]. Inhibition of LdtMt2, particularly when combined with beta-lactamase inhibitors like clavulanate, is a validated strategy for treating multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis [1, 3, 10]. Research into LdtMt2 also focuses on developing non-beta-lactam inhibitors, such as ebselen, to overcome existing resistance mechanisms [2, 3, 9]. The enzyme's role in maintaining the cell wall of dormant persister bacilli makes it a high-priority target for shortening TB treatment duration [1, 5, 10].

Other names

LdtBMT2594Rv2518cLDT 2L,D-transpeptidase B

Irreversible inhibition via covalent acylation of the catalytic cysteine residue (Cys354), forming a stable acyl-enzyme complex that prevents peptidoglycan cross-linking [2, 3, 4, 5, 9].