Structural and biochemical analyses of the LdtMt2-panipenem adduct provide new insights into the effect of the 1-β-methyl group on carbapenems

Abstract

Tuberculosis has attracted increased attention worldwide due to its high morality and its resistance to treatment with traditional antibacterial drugs. The l,d-transpeptidase Ldt_Mt2 confers resistance to traditional β-lactams and is considered a target for anti-Tuberculosis treatment. Carbapenems are proposed to inhibit Mycobacterium tuberculosis by repressing the activity of Ldt_Mt2. The interaction mechanisms between Ldt_Mt2 and carbapenems have been revealed by Ldt_Mt2-carbapenem adduct structures along with various biochemical assays. Interestingly, the lack of the 1-β-methyl group in imipenem may be related to its high binding ability to Ldt_Mt2. However, there is limited evidence on the interaction mode of Ldt_Mt2 and panipenem, another carbapenem lacking the 1-β-methyl group. Herein, we identified the biochemical features of panipenem binding to Ldt_Mt2. We further suggest that the presence of the 1-β-methyl group in carbapenems is indeed related to the ligand affinity of Ldt_Mt2 and that the presence of the Y308 and Y318 residues in Ldt_Mt2 stabilized the conformation of the Ldt_Mt2-carbepenem adduct. Our research provides a structural basis for the development of novel carbapenems against L,D-transpeptidases.

Keywords: Carbapenems; Ldt(Mt2); Panipenem; Tuberculosis; l,d-transpeptidase.