5UWV

Crystal structure of Mycobacterium abscessus L,D-transpeptidase 2

Summary for 5UWV

• Entry DOI: 10.2210/pdb5uwv/pdb
• Descriptor: L,D-TRANSPEPTIDASE 2 (2 entities in total)
• Functional Keywords: l, d-transpeptidase, peptidoglycan synthesis enzyme, cell wall enzyme, ldtmab2, mycobacterium abscessus, transferase
• Biological source: Mycobacterium abscessus (strain ATCC 19977 / DSM 44196 / CIP 104536 / JCM 13569 / NCTC 13031 / TMC 1543)
• Total number of polymer chains: 6
• Total formula weight: 237132.35

Authors

Kumar, P.,Ginell, S.L.,Lamichhane, G. (deposition date: 2017-02-21, release date: 2017-08-16, Last modification date: 2023-10-04)

Primary citation

Kumar, P.,Chauhan, V.,Silva, J.R.A.,Lameira, J.,d'Andrea, F.B.,Li, S.G.,Ginell, S.L.,Freundlich, J.S.,Alves, C.N.,Bailey, S.,Cohen, K.A.,Lamichhane, G.
Mycobacterium abscessus l,d-Transpeptidases Are Susceptible to Inactivation by Carbapenems and Cephalosporins but Not Penicillins.
Antimicrob. Agents Chemother., 61:-, 2017

PubMed Abstract: As a growing number of clinical isolates of are resistant to most antibiotics, new treatment options that are effective against these drug-resistant strains are desperately needed. The majority of the linkages in the cell wall peptidoglycan of are synthesized by nonclassical transpeptidases, namely, the l,d-transpeptidases. Emerging evidence suggests that these enzymes represent a new molecular vulnerability in this pathogen. Recent studies have demonstrated that inhibition of these enzymes by the carbapenem class of β-lactams determines their activity against Here, we studied the interactions of β-lactams with two l,d-transpeptidases in , namely, Ldt and Ldt, and found that both the carbapenem and cephalosporin, but not penicillin, subclasses of β-lactams inhibit these enzymes. Contrary to the commonly held belief that combination therapy with β-lactams is redundant, doripenem and cefdinir exhibit synergy against both pansusceptible and clinical isolates that are resistant to most antibiotics, which suggests that dual-β-lactam therapy has potential for the treatment of Finally, we solved the first crystal structure of an l,d-transpeptidase, Ldt, and using substitutions of critical amino acids in the catalytic site and computational simulations, we describe the key molecular interactions between this enzyme and β-lactams, which provide an insight into the molecular basis for the relative efficacy of different β-lactams against .

PubMed: 28760902
DOI: 10.1128/AAC.00866-17

Experimental method

X-RAY DIFFRACTION (2.98 Å)