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Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.
Lapointe, Guillaume; Skepper, Colin K; Holder, Lauren M; Armstrong, Duncan; Bellamacina, Cornelia; Blais, Johanne; Bussiere, Dirksen; Bian, Jianwei; Cepura, Cody; Chan, Helen; Dean, Charles R; De Pascale, Gianfranco; Dhumale, Bhavesh; Fisher, L Mark; Fulsunder, Mangesh; Kantariya, Bhavin; Kim, Julie; King, Sean; Kossy, Lauren; Kulkarni, Upendra; Lakshman, Jay; Leeds, Jennifer A; Ling, Xiaolan; Lvov, Anatoli; Ma, Sylvia; Malekar, Swapnil; McKenney, David; Mergo, Wosenu; Metzger, Louis; Mhaske, Keshav; Moser, Heinz E; Mostafavi, Mina; Namballa, Sunil; Noeske, Jonas; Osborne, Colin; Patel, Ashish; Patel, Darshit; Patel, Tushar; Piechon, Philippe; Polyakov, Valery; Prajapati, Krunal; Prosen, Katherine R; Reck, Folkert; Richie, Daryl L; Sanderson, Mark R; Satasia, Shailesh; Savani, Bhautik; Selvarajah, Jogitha; Sethuraman, Vijay; Shu, Wei.
Afiliación
  • Lapointe G; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Skepper CK; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Holder LM; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Armstrong D; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
  • Bellamacina C; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Blais J; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Bussiere D; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Bian J; Novartis Global Drug Development, Pudong, Shanghai 201203, China.
  • Cepura C; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Chan H; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Dean CR; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • De Pascale G; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Dhumale B; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
  • Fisher LM; Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, U.K.
  • Fulsunder M; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
  • Kantariya B; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
  • Kim J; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • King S; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Kossy L; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Kulkarni U; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Lakshman J; Novartis Global Drug Development, East Hanover, New Jersey 07936, United States.
  • Leeds JA; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Ling X; Novartis Global Drug Development, Pudong, Shanghai 201203, China.
  • Lvov A; Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
  • Ma S; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Malekar S; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • McKenney D; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Mergo W; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Metzger L; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Mhaske K; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
  • Moser HE; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Mostafavi M; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Namballa S; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
  • Noeske J; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Osborne C; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Patel A; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
  • Patel D; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
  • Patel T; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
  • Piechon P; Novartis Institutes for BioMedical Research, Basel 4002, Switzerland.
  • Polyakov V; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Prajapati K; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
  • Prosen KR; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Reck F; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Richie DL; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Sanderson MR; Randall Centre for Cell and Molecular Biophysics, King's College, Guy's Campus, London Bridge, London SE1 1UL, U.K.
  • Satasia S; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
  • Savani B; Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.
  • Selvarajah J; Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, U.K.
  • Sethuraman V; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • Shu W; Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
J Med Chem ; 64(9): 6329-6357, 2021 05 13.
Article en En | MEDLINE | ID: mdl-33929852
Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV via binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound 25, which has potent activity against Gram-positive bacteria, a favorable in vitro safety profile, and excellent in vivo pharmacokinetic properties. Compound 25 was found to be efficacious against fluoroquinolone-sensitive Staphylococcus aureus infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from Klebsiella pneumoniae, compound 25, and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of 25 compared to fluoroquinolones.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Staphylococcus aureus / Diseño de Fármacos / Fluoroquinolonas / Girasa de ADN / Topoisomerasa de ADN IV / Inhibidores de Topoisomerasa II / Antibacterianos Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Staphylococcus aureus / Diseño de Fármacos / Fluoroquinolonas / Girasa de ADN / Topoisomerasa de ADN IV / Inhibidores de Topoisomerasa II / Antibacterianos Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos