High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis

ACS Chemical Biology
Todd J SullivanPeter J Tonge

Abstract

Novel chemotherapeutics for treating multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) are required to combat the spread of tuberculosis, a disease that kills more than 2 million people annually. Using structure-based drug design, we have developed a series of alkyl diphenyl ethers that are uncompetitive inhibitors of InhA, the enoyl reductase enzyme in the MTB fatty acid biosynthesis pathway. The most potent compound has a Ki' value of 1 nM for InhA and MIC99 values of 2-3 microg mL(-1) (6-10 microM) for both drug-sensitive and drug-resistant strains of MTB. Overexpression of InhA in MTB results in a 9-12-fold increase in MIC99, consistent with the belief that these compounds target InhA within the cell. In addition, transcriptional response studies reveal that the alkyl diphenyl ethers fail to upregulate a putative efflux pump and aromatic dioxygenase, detoxification mechanisms that are triggered by the lead compound triclosan. These diphenyl ether-based InhA inhibitors do not require activation by the mycobacterial KatG enzyme, thereby circumventing the normal mechanism of resistance to the front line drug isoniazid (INH) and thus accounting for their activity against INH-resistant strains of MTB.

References

Aug 21, 1992·Science·B R Bloom, C J Murray
Sep 22, 1995·The Journal of Biological Chemistry·J A MarcinkevicieneJ S Blanchard
Jun 11, 1998·Emerging Infectious Diseases·A RattanN Ahmad
Aug 26, 1998·Nature·L M McMurryS B Levy
Nov 7, 1998·The Journal of Biological Chemistry·R J HeathC O Rock
Feb 27, 1999·Antimicrobial Agents and Chemotherapy·L M McMurryS B Levy
Apr 10, 1999·The Journal of Biological Chemistry·R J HeathC O Rock
Jul 10, 1999·Journal of Molecular Biology·M J StewartC Kisker
Oct 27, 1999·Proceedings of the National Academy of Sciences of the United States of America·M WilsonG K Schoolnik
Oct 10, 2001·Progress in Lipid Research·R J HeathC O Rock
Sep 18, 2002·Antimicrobial Agents and Chemotherapy·David J PayneWilliam F Huffman
Jan 17, 2003·Journal of Biomolecular Structure & Dynamics·Jayaraman MuralidharanNamita Surolia
Feb 28, 2003·The Journal of Biological Chemistry·Mack R KuoDavid A Fidock
Mar 26, 2003·Antimicrobial Agents and Chemotherapy·Srinivas V RamaswamyEdward A Graviss
Mar 26, 2003·The Journal of Biological Chemistry·Laurent KremerGurdyal S Besra
Nov 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Richa RawatPeter J Tonge
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

❮ Previous
Next ❯

Citations

Sep 26, 2009·Journal of Molecular Modeling·Ashutosh Kumar, Mohammad Imran Siddiqi
Sep 11, 2013·European Journal of Medicinal Chemistry·Christophe MenendezMichel Baltas
Jan 16, 2008·Accounts of Chemical Research·Hao Lu, Peter J Tonge
Dec 15, 2007·Nature Reviews. Microbiology·James C SacchettiniJoel S Freundlich
Oct 30, 2012·Bioinformatics·Benjamin MergetChristoph A Sotriffer
Sep 8, 2009·The Journal of Antimicrobial Chemotherapy·Kathleen EnglandRichard A Slayden
Mar 12, 2011·The Journal of Antimicrobial Chemotherapy·Nina LiuPeter J Tonge
Mar 1, 2007·Acta Crystallographica. Section D, Biological Crystallography·Stephen P MuenchDavid W Rice
Nov 9, 2011·Acta Crystallographica. Section E, Structure Reports Online·G JagadeesanS Aravindhan
May 17, 2012·Acta Crystallographica. Section E, Structure Reports Online·G SureshS Aravindhan
Feb 21, 2013·Acta Crystallographica. Section E, Structure Reports Online·G SureshS Aravindhan
Jun 2, 2011·Antimicrobial Agents and Chemotherapy·Catherine VilchèzeWilliam R Jacobs
Aug 15, 2009·Drugs·Xian-Zhi Li, Hiroshi Nikaido
Jun 29, 2011·Future Microbiology·Claudia Sala, Ruben C Hartkoorn
Aug 28, 2012·Indian Journal of Pharmaceutical Sciences·O PrakashC Sharma
Sep 19, 2012·EMBO Molecular Medicine·Ruben C HartkoornStewart T Cole
Jul 24, 2014·European Journal of Medicinal Chemistry·K Mohan KrishnaG S Vijaykumar
Dec 3, 2013·Nature Chemical Biology·Ruben C HartkoornStewart T Cole
Apr 10, 2013·Expert Review of Anti-infective Therapy·Juan M Belardinelli, Héctor R Morbidoni
Oct 13, 2015·International Journal of Molecular Sciences·Camilo Henrique da Silva LimaMagaly Girão Albuquerque
Nov 11, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Ondrej HolasMartin Dolezal
Apr 10, 2012·European Journal of Medicinal Chemistry·Christophe MenendezMichel Baltas
Jan 31, 2015·Journal of Chemical Information and Modeling·Alexander L PerrymanArthur J Olson
Sep 20, 2015·Journal of Molecular Graphics & Modelling·Sanchaita RajkhowaRamesh Chandra Deka
Oct 24, 2008·Bioorganic & Medicinal Chemistry·Guiping OuyangSong Zeng
May 7, 2008·Bioorganic & Medicinal Chemistry Letters·Christopher W am EndePeter J Tonge
Aug 29, 2007·Bioorganic & Medicinal Chemistry·Xin HePaul R Ortiz de Montellano
Jun 15, 2007·Bioorganic & Medicinal Chemistry·Gabriel Navarrete-VázquezSalvador Said-Fernández
Feb 13, 2007·Bioorganic & Medicinal Chemistry·Yves L Janin

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antitubercular Agents (ASM)

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antitubercular Agents

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.