Non-classical transpeptidases yield insight into new antibacterials.
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.
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Pankaj
P
Kumar
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Amit
A
Kaushik
Department of Chemistry, Johns Hopkins University, Baltimore, Maryland, USA.
Evan P
EP
Lloyd
Departments of Pharmacology &Physiology and Medicine, Rutgers University Medical School, New Jersey, USA.
Shao-Gang
SG
Li
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Rohini
R
Mattoo
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Nicole C
NC
Ammerman
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Drew T
DT
Bell
Departments of Pharmacology &Physiology and Medicine, Rutgers University Medical School, New Jersey, USA.
Alexander L
AL
Perryman
Department of Biophysics, Johns Hopkins University, Baltimore, Maryland, USA.
Trevor A
TA
Zandi
Collaborations in Chemistry, Fuquay-Varina, North Carolina, USA.
Sean
http://orcid.org/0000-0002-5691-5790
S
Ekins
Biosciences Division, Argonne National Laboratory, Argonne, Illinois, USA.
Stephan L
SL
Ginell
Department of Chemistry, Johns Hopkins University, Baltimore, Maryland, USA.
Craig A
CA
Townsend
Departments of Pharmacology &Physiology and Medicine, Rutgers University Medical School, New Jersey, USA.
Joel S
JS
Freundlich
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Gyanu
http://orcid.org/0000-0002-2214-0114
G
Lamichhane
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D010458:Peptidyl Transferases