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Investigation into the Mechanism of Action of the Tuberculosis Drug Candidate SQ109 and Its Metabolites and Analogues in Mycobacteria.
Malwal, Satish R; Mazurek, Ben; Ko, Jihee; Xie, Pujun; Barnes, Chikako; Varvitsiotis, Christine; Zimmerman, Matthew D; Olatunji, Samir; Lee, Jaeyong; Xie, Min; Sarathy, Jansy; Caffrey, Martin; Strynadka, Natalie C J; Dartois, Véronique; Dick, Thomas; Lee, Bom Nae Rin; Russell, David G; Oldfield, Eric.
Afiliación
  • Malwal SR; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
  • Mazurek B; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
  • Ko J; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
  • Xie P; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
  • Barnes C; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
  • Varvitsiotis C; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
  • Zimmerman MD; Center for Discovery and Innovation, 111 Ideation Way, Nutley, New Jersey 07110, United States.
  • Olatunji S; Schools of Medicine and Biochemistry & Immunology, Trinity College, Dublin D02 R590, Ireland.
  • Lee J; Department of Biochemistry and Molecular Biology and Centre for Blood Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
  • Xie M; Center for Discovery and Innovation, 111 Ideation Way, Nutley, New Jersey 07110, United States.
  • Sarathy J; Center for Discovery and Innovation, 111 Ideation Way, Nutley, New Jersey 07110, United States.
  • Caffrey M; Schools of Medicine and Biochemistry & Immunology, Trinity College, Dublin D02 R590, Ireland.
  • Strynadka NCJ; Department of Biochemistry and Molecular Biology and Centre for Blood Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
  • Dartois V; Center for Discovery and Innovation, 111 Ideation Way, Nutley, New Jersey 07110, United States.
  • Dick T; Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, New Jersey 07110, United States.
  • Lee BNR; Center for Discovery and Innovation, 111 Ideation Way, Nutley, New Jersey 07110, United States.
  • Russell DG; Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, New Jersey 07110, United States.
  • Oldfield E; Department of Microbiology and Immunology, Georgetown University, Washington, District of Columbia 20007, United States.
J Med Chem ; 66(11): 7553-7569, 2023 06 08.
Article en En | MEDLINE | ID: mdl-37235809
We tested a series of SQ109 analogues against Mycobacterium tuberculosis and M. smegmatis, in addition to determining their uncoupling activity. We then investigated potential protein targets, involved in quinone and cell wall biosynthesis, using "rescue" experiments. There was little effect of menaquinone on growth inhibition by SQ109, but there were large increases in the IC50 of SQ109 and its analogues (up to 20×) on addition of undecaprenyl phosphate (Up), a homologue of the mycobacterial decaprenyl (C50) diphosphate. Inhibition of an undecaprenyl diphosphate phosphatase, an ortholog of the mycobacterial phosphatase, correlated with cell growth inhibition, and we found that M. smegmatis cell growth inhibition could be well predicted by using uncoupler and Up-rescue results. We also investigated whether SQ109 was metabolized inside Mycobacterium tuberculosis, finding only a single metabolite, previously shown to be inactive. The results are of general interest since they help explain the mechanism of SQ109 in mycobacteria.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tuberculosis / Mycobacterium tuberculosis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2023 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: Tuberculosis / Mycobacterium tuberculosis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos