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Discovery of Novel UDP-N-Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa.
Ryan, M Dominic; Parkes, Alastair L; Corbett, David; Dickie, Anthony P; Southey, Michelle; Andersen, Ole A; Stein, Daniel B; Barbeau, Olivier R; Sanzone, Angelo; Thommes, Pia; Barker, John; Cain, Ricky; Compper, Christel; Dejob, Magali; Dorali, Alain; Etheridge, Donnya; Evans, Sian; Faulkner, Adele; Gadouleau, Elise; Gorman, Timothy; Haase, Denes; Holbrow-Wilshaw, Maisie; Krulle, Thomas; Li, Xianfu; Lumley, Christopher; Mertins, Barbara; Napier, Spencer; Odedra, Rajesh; Papadopoulos, Kostas; Roumpelakis, Vasileios; Spear, Kate; Trimby, Emily; Williams, Jennifer; Zahn, Michael; Keefe, Anthony D; Zhang, Ying; Soutter, Holly T; Centrella, Paolo A; Clark, Matthew A; Cuozzo, John W; Dumelin, Christoph E; Deng, Boer; Hunt, Avery; Sigel, Eric A; Troast, Dawn M; DeJonge, Boudewijn L M.
Afiliación
  • Ryan MD; X-Biotix Therapeutics, 465 Waverly Oaks Road, Waltham, Massachusetts 02452, United States.
  • Parkes AL; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Corbett D; Evotec UK, Anti-infectives, Block 23F, Alderley Park, Cheshire SK10 4TG, U.K.
  • Dickie AP; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Southey M; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Andersen OA; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Stein DB; Evotec SE, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
  • Barbeau OR; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Sanzone A; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Thommes P; Evotec UK, Anti-infectives, Block 23F, Alderley Park, Cheshire SK10 4TG, U.K.
  • Barker J; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Cain R; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Compper C; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Dejob M; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Dorali A; Evotec UK, Anti-infectives, Block 23F, Alderley Park, Cheshire SK10 4TG, U.K.
  • Etheridge D; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Evans S; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Faulkner A; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Gadouleau E; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Gorman T; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Haase D; Evotec SE, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
  • Holbrow-Wilshaw M; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Krulle T; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Li X; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Lumley C; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Mertins B; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Napier S; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Odedra R; Evotec UK, Anti-infectives, Block 23F, Alderley Park, Cheshire SK10 4TG, U.K.
  • Papadopoulos K; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Roumpelakis V; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Spear K; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Trimby E; Evotec UK, Anti-infectives, Block 23F, Alderley Park, Cheshire SK10 4TG, U.K.
  • Williams J; Evotec UK, Anti-infectives, Block 23F, Alderley Park, Cheshire SK10 4TG, U.K.
  • Zahn M; Evotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Keefe AD; X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Zhang Y; X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Soutter HT; X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Centrella PA; X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Clark MA; X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Cuozzo JW; X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Dumelin CE; X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Deng B; X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Hunt A; X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Sigel EA; X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Troast DM; X-Chem, 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • DeJonge BLM; X-Biotix Therapeutics, 465 Waverly Oaks Road, Waltham, Massachusetts 02452, United States.
J Med Chem ; 64(19): 14377-14425, 2021 10 14.
Article en En | MEDLINE | ID: mdl-34569791
This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 µg/mL). Lack of activity against E. coli was maintained (IC50 > 20 µM and MIC > 128 µg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pseudomonas aeruginosa / Aciltransferasas / Inhibidores Enzimáticos / Descubrimiento de Drogas / Antibacterianos 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
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pseudomonas aeruginosa / Aciltransferasas / Inhibidores Enzimáticos / Descubrimiento de Drogas / Antibacterianos 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