A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors Animals Antitubercular Agents / chemistry Bacterial Proteins / antagonists & inhibitors Drug Discovery Enzyme Inhibitors / chemistry Female Humans Mice Models, Molecular Mycobacterium tuberculosis / drug effects Tuberculosis / drug therapy
JSF-3285 KasA Mycobacterium tuberculosis antitubercular pharmacokinetics structure-based design

Journal

Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030

Informations de publication

Date de publication:
21 05 2020
Historique:
received: 20 08 2019
revised: 26 01 2020
accepted: 26 02 2020
pubmed: 21 3 2020
medline: 21 5 2021
entrez: 21 3 2020
Statut: ppublish

Résumé

Published Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis.

Identifiants

DOI: 10.1016/j.chembiol.2020.02.007 PMID: 32197094 PMC: PMC7245553
pubmed: 32197094
pii: S2451-9456(20)30071-4
doi: 10.1016/j.chembiol.2020.02.007
pmc: PMC7245553
mid: NIHMS1572786
pii:
doi:

Substances chimiques

Antitubercular Agents 0
Bacterial Proteins 0
Enzyme Inhibitors 0
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase EC 2.3.1.41

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

560-570.e10

Subventions

Organisme : NIAID NIH HHS
ID : U19 AI109713
Pays : United States
Organisme : NIH HHS
ID : S10 OD023524
Pays : United States
Organisme : NIAID NIH HHS
ID : R33 AI111647
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI111647
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI142731
Pays : United States

Informations de copyright

Copyright © 2020 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests D.I., D.Awasthi, G.C.C., D.Alland, M.B.N., P.K., and J.S.F. are listed as inventors on patent filings pertinent to the indole and indazole compounds disclosed in this manuscript as employees of Rutgers University.

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Auteurs

Daigo Inoyama (D)

Department of Pharmacology, Physiology, and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Divya Awasthi (D)

Department of Pharmacology, Physiology, and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Glenn C Capodagli (GC)

Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, USA.

Kholiswa Tsotetsi (K)

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Paridhi Sukheja (P)

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Matthew Zimmerman (M)

Public Health Research Institute, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Shao-Gang Li (SG)

Department of Pharmacology, Physiology, and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Ravindra Jadhav (R)

Department of Pharmacology, Physiology, and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Riccardo Russo (R)

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Xin Wang (X)

Department of Pharmacology, Physiology, and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Courtney Grady (C)

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Todd Richmann (T)

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Riju Shrestha (R)

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Liping Li (L)

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Yong-Mo Ahn (YM)

Department of Pharmacology, Physiology, and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Hsin Pin Ho Liang (HP)

Public Health Research Institute, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Marizel Mina (M)

Public Health Research Institute, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Steven Park (S)

Public Health Research Institute, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

David S Perlin (DS)

Public Health Research Institute, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Nancy Connell (N)

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

Véronique Dartois (V)

Public Health Research Institute, Rutgers University - New Jersey Medical School, Newark, NJ, USA.

David Alland (D)

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA. Electronic address: allandda@njms.rutgers.edu.

Matthew B Neiditch (MB)

Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, USA. Electronic address: neiditmb@njms.rutgers.edu.

Pradeep Kumar (P)

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA. Electronic address: kumarp3@njms.rutgers.edu.

Joel S Freundlich (JS)

Department of Pharmacology, Physiology, and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA; Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA. Electronic address: freundjs@rutgers.edu.

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Acyltransferases › 3-Oxoacyl (acyl carrier protein) synthase › A Preclinical Candidate Targeting...
questionsmedicales.fr › Eucaryotes › Animaux › A Preclinical Candidate Targeting...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antibactériens › Antituberculeux › A Preclinical Candidate Targeting...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines bactériennes › A Preclinical Candidate Targeting...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › A Preclinical Candidate Targeting...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › A Preclinical Candidate Targeting...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A Preclinical Candidate Targeting...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › A Preclinical Candidate Targeting...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › A Preclinical Candidate Targeting...
questionsmedicales.fr › Bactéries › Bactéries à Gram positif › Bâtonnets à Gram positif › Bâtonnets asporogènes à Gram positif › Bâtonnets asporogènes réguliers à Gram positif › Mycobacteriaceae › Mycobacterium › Mycobacterium tuberculosis › A Preclinical Candidate Targeting...
questionsmedicales.fr › Infection › Infections bactériennes et mycoses › Infections bactériennes › Infections bactériennes à Gram positif › Infections à Actinomycetales › Infections à Mycobacterium › Tuberculose › A Preclinical Candidate Targeting...