Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis.

ChemMedChem
Joel S FreundlichJ C Sacchettini

Abstract

Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, the inhibition of which leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted triclosan derivatives was developed. Two groups of derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC(50) value of 21 nM, which was 50-fold more potent than triclosan. X-ray crystal structures of InhA in complex with four triclosan derivatives revealed the structural basis for the inhibitory activity. Six selected triclosan derivatives were tested against isoniazid-sensitive and resistant strains of M. tuberculosis. Among those, the best inhibitor had an MIC value of 4.7 microg mL(-1) (13 microM), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogues was more potent than isoniazid against two isoniazid-resistant M. tuberculosis strains, demonstrating the significant potential for structure-based design in the development of next generation antituberc...Continue Reading

References

Feb 1, 1997·Genitourinary Medicine·R Coker
Aug 26, 1998·Nature·L M McMurryS B Levy
Nov 7, 1998·The Journal of Biological Chemistry·R J HeathC O Rock
Apr 14, 1999·Nature·C W LevyJ B Rafferty
Dec 28, 1999·Journal of Molecular Biology·A RoujeinikovaD W Rice
Aug 16, 2000·Proceedings of the National Academy of Sciences of the United States of America·A E DeBarberC E Barry
Sep 29, 2000·The Journal of Biological Chemistry·R J HeathC O Rock
Feb 28, 2003·The Journal of Biological Chemistry·Mack R KuoDavid A Fidock
Nov 26, 2003·Antimicrobial Agents and Chemotherapy·Glenn P MorlockRobert C Cooksey
Jul 23, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Li-Quan WangMargaret O James
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Jul 28, 2006·Antimicrobial Agents and Chemotherapy·Manzour Hernando HazbónDavid Alland
Aug 15, 2006·Nature Medicine·Catherine VilchèzeWilliam R Jacobs
Jan 18, 2007·The Journal of Experimental Medicine·Feng WangJames C Sacchettini
Nov 24, 2007·Annual Review of Microbiology·Catherine Vilchèze, William R Jacobs
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

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Citations

Feb 5, 2011·Journal of Chemical Information and Modeling·Sarah L KinningsPhilip E Bourne
Oct 27, 2011·Chemical Reviews·Cyrille Y BottéChristophe Biot
Oct 30, 2012·Bioinformatics·Benjamin MergetChristoph A Sotriffer
Jun 2, 2011·Antimicrobial Agents and Chemotherapy·Catherine VilchèzeWilliam R Jacobs
Nov 23, 2012·BMC Bioinformatics·Rodrigo C BarrosOsmar Norberto de Souza
Sep 19, 2012·EMBO Molecular Medicine·Ruben C HartkoornStewart T Cole
Aug 7, 2014·The Journal of Antibiotics·Giovanna Riccardi, Maria Rosalia Pasca
Jun 19, 2013·Nature Chemical Biology·Regina WilsonDavid Alland
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 31, 2012·Expert Review of Anti-infective Therapy·Lorenza Favrot, Donald R Ronning
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
Jan 27, 2016·Chemical Reviews·Gabriella CavalloGiancarlo Terraneo
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
Dec 15, 2010·Molecular Microbiology·Virginie MolleLaurent Kremer
Sep 22, 2016·International Journal of Mycobacteriology·Joseph Mwanzia NgutaPhyllis G A Addo
Jun 10, 2011·Expert Opinion on Therapeutic Patents·Xiaoyun LuQidong You
Dec 12, 2013·Expert Opinion on Therapeutic Targets·Geetha Vani Rayasam
Aug 24, 2010·Bioorganic & Medicinal Chemistry·Muhammad MuddassarAe Nim Pae
Jan 1, 2014·Chemistry & Biology·Hedia MarrakchiMamadou Daffé
Jan 7, 2014·Bioorganic & Medicinal Chemistry Letters·Barbora ServusováJan Zitko
Jan 9, 2015·Science Translational Medicine·Ujjini H ManjunathaThierry T Diagana
Sep 18, 2014·FEMS Microbiology Letters·Xiangke DuanJianping Xie
May 22, 2016·Journal of Biomolecular Structure & Dynamics·Vivek Kumar, M Elizabeth Sobhia

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