Inhibition of Mycobacterium tuberculosis L,D‐Transpeptidase 5 by Carbapenems: MD and QM/MM Mechanistic Studies

Mycobacterium tuberculosis (Mtb) is the bacteria that currently claims the most number of human lives each year. The final step of peptidoglycan synthesis involves the generation of 4→3 and 3→3 transpeptide crosslinks catalyzed by D,D‐transpeptidase and L,D‐transpeptidase (Ldt) enzymes, respectively. Unlike in most other bacteria, for Mtb, the majority of the cross‐links are generated by L,D‐transpeptidases. LdtMt5 knock‐out strains of Mtb displayed aberrant growth, and are susceptibility to crystal violet, osmotic shock, and selected carbapenem antibiotics. Here, we used molecular dynamics (MD) and Quantum Mechanical (QM) simulations to probe the molecular interactions of LdtMt5 with carbapenems. LdtMt5 complexes with three carbapenems, ertapenem (ERT), imipenem (IMI) and meropenem (MERO) were simulated. The binding free energies of these complexes were calculated from the MD trajectories using the MM/GBSA approach, the theoretical results revealed higher ▵Gbind for ERT—LdtMt5 and IMI—LdtMt5 than MERO—LdtMt5. To further understand the catalytic reaction mechanism of LdtMt5 with the selected carbapenems, the possible reaction pathway was investigated. The high free energies of activation (▵G) for imipenem and meropenem, explain the reason behind inefficient binding of these carbapenems to LdtMt5. These results provide a better understanding of how the antibacterial agents function and will potentially contribute to the discovery of more potent LdtMt5 inhibitors. This manuscript presents for the first time, a theoretical approach to the inhibition of L,D‐transpeptidase 5 by carbapenems using molecular dynamics and hybrid quantum mechanics/molecular mechanics methods.