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Publication Abstract from PubMed

L,D-transpeptidases, widely distributed in bacteria and even in the difficult-to-treat ESKAPE pathogens, can confer antibacterial resistance against the traditional beta-lactam antibiotics through bypass of the 4-->3 transpeptide linkage. LdtMt2, a l,d-transpeptidase in Mycobacteria tuberculosis, is essential for bacterial virulence and is considered as a potential anti-tuberculosis target inhibited by carbapenems. Diverse interaction modes between carbapenems and LdtMt2 have been reported, there are only limited evidences to validate those interaction modes. Herein, we identified the stable binding states of two carbapenems, imipenem and ertapenem, via crystallographic and biochemical studies, discovered that they adopt similar binding conformations. We further demonstrate the absence of the 1-beta-methyl group in imipenem and the presence of both Y308 and Y318 residues in LdtMt2 synergistically resulted in one order of magnitude higher affinity for imipenem than ertapenem. Our study provides a structural basis for the rational drug design and evolvement of novel carbapenems against bacterial L,D-transpeptidases.

The 1-beta-methyl group confers a lower affinity of l,d-transpeptidase LdtMt2 for ertapenem than for imipenem.,Zhao F, Hou YJ, Zhang Y, Wang DC, Li DF Biochem Biophys Res Commun. 2019 Mar 5;510(2):254-260. doi:, 10.1016/j.bbrc.2019.01.082. Epub 2019 Jan 25. PMID:30686533^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.