Structural and biochemical analyses of the LdtMt2-panipenem adduct provide new insights into the effect of the 1-ß-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 LdtMt2 confers resistance to traditional ß-lactams and is considered a target for anti-Tuberculosis treatment. Carbapenems are proposed to inhibit Mycobacterium tuberculosis by repressing the activity of LdtMt2. The interaction mechanisms between LdtMt2 and carbapenems have been revealed by LdtMt2-carbapenem adduct structures along with various biochemical assays. Interestingly, the lack of the 1-ß-methyl group in imipenem may be related to its high binding ability to LdtMt2. However, there is limited evidence on the interaction mode of LdtMt2 and panipenem, another carbapenem lacking the 1-ß-methyl group. Herein, we identified the biochemical features of panipenem binding to LdtMt2. We further suggest that the presence of the 1-ß-methyl group in carbapenems is indeed related to the ligand affinity of LdtMt2 and that the presence of the Y308 and Y318 residues in LdtMt2 stabilized the conformation of the LdtMt2-carbepenem adduct. Our research provides a structural basis for the development of novel carbapenems against L,D-transpeptidases.