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Non-classical transpeptidases yield insight into new antibacterials

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.

Nat Chem Biol. 2017 Jan;13(1):54-61.
doi: 10.1038/nchembio.2237. Epub 2016 Nov 7.

 

© Copyright 2017 Macmillan Publishers Limited

  Kumar P, Kaushik A, Lloyd EP, Li SG, Mattoo R, Ammerman NC, Bell DT, Perryman AL, Zandi TA, Ekins S, Ginell SL, Townsend CA, Freundlich JS, Lamichhane G.

Further Back:

EsxB, a secreted protein from Bacillus anthracis forms two distinct helical bundles
Structural Basis for Ligand Binding to the Guanidine-I Riboswitch

 

Structure. 2017 Jan 3;25(1):195-202.
doi: 10.1016/j.str.2016.11.020.
Epub 2016 Dec 22.

NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors
NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors

 

Elife. 2016 Oct 26;5. pii: e18790.
doi: 10.7554/eLife.18790.

Phosphorylation of spore coat proteins by a family of atypical protein kinases
Bile salt receptor complex activates a pathogenic type III secretion system

 

Elife. 2016 Jul 5;5. pii: e15718.
doi: 10.7554/eLife.15718.

Crystal Structure of the FERM-SH2 Module of Human Jak2

Crystal Structure of the FERM-SH2 Module of Human Jak2.

 

PLoS One. 2016 May 26;11(5):e0156218.
doi: 10.1371/journal.pone.0156218.
eCollection 2016.

EsxB, a secreted protein from Bacillus anthracis forms two distinct helical bundles
Structural Studies of Medicago truncatula Histidinol Phosphate Phosphatase from Inositol Monophosphatase Superfamily...

 

J Biol Chem. 2016 May 6;291(19):9960-73.
doi: 10.1074/jbc.M115.708727.
Epub 2016 Mar 18.

Crystal structure of the human sterol transporter ABCG5/ABCG8
Crystal structure of the human sterol transporter ABCG5/ABCG8

 

 

Nature. 2016 May 4;533(7604):561-4.
doi: 10.1038/nature17666.

Structural basis of cohesin cleavage by separase
Structural basis of cohesin cleavage by separase

 

Nature. 2016 Apr 7;532(7597):131-4.
doi: 10.1038/nature17402. Epub 2016 Mar 30.

Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana
Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana

 

Nature. 2016 Mar 10;531(7593):196-201.
doi: 10.1038/nature16446.
Epub 2015 Dec 21..

 

EsxB, a secreted protein from Bacillus anthracis forms two distinct helical bundles
Crystal structures of the human elongation factor eEFSec suggest a non-canonical mechanism for selenocysteine incorporation

 

Nat Commun. 2016 Oct 6;7:12941.
doi: 10.1038/ncomms12941.

EsxB, a secreted protein from Bacillus anthracis forms two distinct helical bundles
Structure and function of human Naa60 (NatF), a Golgi-localized bi-functional acetyltransferase

 

Sci Rep. 2016 Aug 23;6:31425.
doi: 10.1038/srep31425.

EsxB, a secreted protein from Bacillus anthracis forms two distinct helical bundles
Phosphorylation of spore coat proteins by a family of atypical protein kinases

 

Proc Natl Acad Sci U S A. 2016 Jun 21;113(25):E3482-91.
doi: 10.1073/pnas.1605917113. Epub 2016 May 16.

The mechanism of RNA 5′ capping with NAD+, NADH and desphospho-CoA

The mechanism of RNA 5′ capping with NAD+, NADH and desphospho-CoA

 

Nature. 2016 Jul 21;535(7612):444-7.

The Vaccinia Virus H3 Envelope Protein, a Major Target of Neutralizing Antibodies, Exhibits a Glycosyltransferase Fold and Binds UDP-Glucose
The Vaccinia Virus H3 Envelope Protein, a Major Target of Neutralizing Antibodies, Exhibits a Glycosyltransferase Fold and Binds UDP-Glucose

 

J Virol. 2016 Apr 29;90(10):5020-30.
doi: 10.1128/JVI.02933-15.
Print 2016 May 15.

Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway
Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway

 

Nat Chem Biol. 2016 Apr;12(4):282-9. doi: 10.1038/nchembio.2036. Epub 2016 Feb 22.

Molecular mechanism of respiratory syncytial virus fusion inhibitors
Molecular mechanism of respiratory syncytial virus fusion inhibitors

 

Nat Chem Biol. 2016 Feb;12(2):87-93.
doi: 10.1038/nchembio.1982.
Epub 2015 Dec 7.

Structural and molecular basis for Ebola virus neutralization by protective human antibodies
Structural and molecular basis for Ebola virus neutralization by protective human antibodies

 

Science. 2016 Mar 18;351(6279):1343-6.
doi: 10.1126/science.aad6117.
Epub 2016 Feb 25.

And Even Further Back:

Structural Basis of Latrophilin-FLRT-UNC5 Interaction in Cell Adhesion
2015

 

A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

 

Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2

 

A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism

 

EsxB, a secreted protein from Bacillus anthracis forms two distinct helical bundles

 

Functional Diversity of Haloacid Dehalogenase Superfamily Phosphatases from Saccharomyces cerevisiae

 

An Intrinsically Disordered Peptide from Ebola Virus VP35 Controls Viral RNA Synthesis by Modulating Nucleoprotein-RNA Interactions

 

Crystal structures of alkylperoxo and anhydride intermediates in an intradiol ring-cleaving dioxygenase

 

EsxB, a secreted protein from Bacillus anthracis forms two distinct helical bundles
2015

 

Crystal Structure of the Zorbamycin-Binding Protein ZbmA, the Primary Self-Resistance Element in Streptomyces flavoviridis ATCC21892

 

Structural Basis of Latrophilin-FLRT-UNC5 Interaction in Cell Adhesion

 

Sperm Lysozyme-Like Protein 1 (SLLP1), an intra-acrosomal oolemmal-binding sperm protein, reveals filamentous organization in protein crystal form

 

Structural integration in hypoxia-inducible factors

 

New aminopeptidase from microbial dark matter archaeon

 

A Novel Cofactor-binding Mode in Bacterial IMP Dehydrogenases Explains Inhibitor Selectivity

 

Ebola Virus VP24 Targets a Unique NLS Binding Site on Karyopherin Alpha 5 to Selectively Compete with Nuclear Import of Phos. STAT1