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Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase I Inhibitors.
Tran, Wendy; Kusay, Ali S; Hawkins, Paige M E; Cheung, Chen-Yi; Nagalingam, Gayathri; Pujari, Venugopal; Ford, Daniel J; Stoye, Alexander; Ochoa, Jessica L; Audette, Rebecca E; Hortle, Elinor; Oehlers, Stefan H; Charman, Susan A; Linington, Roger G; Rubin, Eric J; Dowson, Christopher G; Roper, David I; Crick, Dean C; Balle, Thomas; Cook, Gregory M; Britton, Warwick J; Payne, Richard J.
Afiliação
  • Tran W; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
  • Kusay AS; Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
  • Hawkins PME; Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia.
  • Cheung CY; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
  • Nagalingam G; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand.
  • Pujari V; Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
  • Ford DJ; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, United States.
  • Stoye A; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
  • Ochoa JL; School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
  • Audette RE; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California 95064, United States.
  • Hortle E; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, United States.
  • Oehlers SH; Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
  • Charman SA; Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
  • Linington RG; Centre for Drug Candidate Optimisation, Monash University, Parkville, VIC 3052, Australia.
  • Rubin EJ; Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
  • Dowson CG; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, United States.
  • Roper DI; School of Life Sciences, University of Warwick, Coventry CV4 7AL, U.K.
  • Crick DC; School of Life Sciences, University of Warwick, Coventry CV4 7AL, U.K.
  • Balle T; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, United States.
  • Cook GM; Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
  • Britton WJ; Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia.
  • Payne RJ; Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand.
J Med Chem ; 64(23): 17326-17345, 2021 12 09.
Article em En | MEDLINE | ID: mdl-34845906
ABSTRACT
Herein, we report the design and synthesis of inhibitors of Mycobacterium tuberculosis (Mtb) phospho-MurNAc-pentapeptide translocase I (MurX), the first membrane-associated step of peptidoglycan synthesis, leveraging the privileged structure of the sansanmycin family of uridylpeptide natural products. A number of analogues bearing hydrophobic amide modifications to the pseudo-peptidic end of the natural product scaffold were generated that exhibited nanomolar inhibitory activity against Mtb MurX and potent activity against Mtb in vitro. We show that a lead analogue bearing an appended neopentylamide moiety possesses rapid antimycobacterial effects with a profile similar to the frontline tuberculosis drug isoniazid. This molecule was also capable of inhibiting Mtb growth in macrophages where mycobacteria reside in vivo and reduced mycobacterial burden in an in vivo zebrafish model of tuberculosis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Proteínas de Bactérias / Uridina / Transferases (Outros Grupos de Fosfato Substituídos) / Inibidores Enzimáticos / Mycobacterium tuberculosis Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Austrália
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Proteínas de Bactérias / Uridina / Transferases (Outros Grupos de Fosfato Substituídos) / Inibidores Enzimáticos / Mycobacterium tuberculosis Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Austrália