Non-classical transpeptidases yield insight into new antibacterials

نویسندگان

  • Pankaj Kumar
  • Amit Kaushik
  • Evan P Lloyd
  • Shao-Gang Li
  • Rohini Mattoo
  • Nicole C Ammerman
  • Drew T Bell
  • Alexander L Perryman
  • Trevor A Zandi
  • Sean Ekins
  • Stephan L Ginell
  • Craig A Townsend
  • Joel S Freundlich
  • Gyanu Lamichhane
چکیده

Bacterial survival requires an intact peptidoglycan layer, a three-dimensional exoskeleton that encapsulates the cytoplasmic membrane. Historically, the final steps of peptidoglycan synthesis are known to be carried out by D,D-transpeptidases, enzymes that are inhibited by the β-lactams, which constitute >50% of all antibacterials in clinical use. Here, we show that the carbapenem subclass of β-lactams are distinctly effective not only because they inhibit D,D-transpeptidases and are poor substrates for β-lactamases, but primarily because they also inhibit non-classical transpeptidases, namely the L,D-transpeptidases, which generate the majority of linkages in the peptidoglycan of mycobacteria. We have characterized the molecular mechanisms responsible for inhibition of L,D-transpeptidases of Mycobacterium tuberculosis and a range of bacteria including ESKAPE pathogens, and used this information to design, synthesize and test simplified carbapenems with potent antibacterial activity.

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عنوان ژورنال:

دوره 13  شماره 

صفحات  -

تاریخ انتشار 2017