Structural insight into the inactivation of Mycobacterium tuberculosis non-classical transpeptidase LdtMt2 by biapenem and tebipenem |
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Authors: | Mario A. Bianchet Ying H. Pan Leighanne A. Brammer Basta Harry Saavedra Evan P. Lloyd Pankaj Kumar Rohini Mattoo Craig A. Townsend Gyanu Lamichhane |
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Affiliation: | 1.Department of Neurology,Johns Hopkins University School of Medicine,Baltimore,USA;2.Department of Biophysics and Biophysical Chemistry, Structural Enzymology and Thermodynamics Group,Johns Hopkins University School of Medicine,Baltimore,USA;3.Chemistry Department,United States Naval Academy,Annapolis,USA;4.Department of Chemistry,Johns Hopkins University,Baltimore,USA;5.Division of Infectious Diseases, Center for Tuberculosis Research, Taskforce to study Resistance Emergence & Antimicrobial development Technology (TREAT),Johns Hopkins University School of Medicine,Baltimore,USA;6.Division of Infectious Diseases, Taskforce to study Resistance Emergence & Antimicrobial development Technology (TREAT),Johns Hopkins University School of Medicine,Baltimore,USA |
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Abstract: | BackgroundThe carbapenem subclass of β-lactams is among the most potent antibiotics available today. Emerging evidence shows that, unlike other subclasses of β-lactams, carbapenems bind to and inhibit non-classical transpeptidases (L,D-transpeptidases) that generate 3 → 3 linkages in bacterial peptidoglycan. The carbapenems biapenem and tebipenem exhibit therapeutically valuable potencies against Mycobacterium tuberculosis (Mtb).ResultsHere, we report the X-ray crystal structures of Mtb L,D-transpeptidase-2 (LdtMt2) complexed with biapenem or tebipenem. Despite significant variations in carbapenem sulfur side chains, biapenem and tebipenem ultimately form an identical adduct that docks to the outer cavity of LdtMt2. We propose that this common adduct is an enzyme catalyzed decomposition of the carbapenem adduct by a mechanism similar to S-conjugate elimination by β-lyases.ConclusionThe results presented here demonstrate biapenem and tebipenem bind to the outer cavity of LdtMt2, covalently inactivate the enzyme, and subsequently degrade via an S-conjugate elimination mechanism. We discuss structure based drug design based on the findings and propose that the S-conjugate elimination can be leveraged to design novel agents to deliver and locally release antimicrobial factors to act synergistically with the carbapenem carrier. |
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