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Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs.
Lavin, Richard C; Johnson, Calvin; Ahn, Yong-Mo; Kremiller, Kyle M; Sherwood, Matthew; Patel, Jimmy S; Pan, Yan; Russo, Riccardo; MacGilvary, Nathan J; Giacalone, David; Kevorkian, Yuzo L; Zimmerman, Matthew D; Glickman, J Fraser; Freundlich, Joel S; Tan, Shumin.
Afiliação
  • Lavin RC; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
  • Johnson C; Graduate Program in Molecular Microbiology, Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, United States of America.
  • Ahn YM; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
  • Kremiller KM; Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey, United States of America.
  • Sherwood M; Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey, United States of America.
  • Patel JS; Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey, United States of America.
  • Pan Y; Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey, United States of America.
  • Russo R; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, United States of America.
  • MacGilvary NJ; Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenco Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University-New Jersey Medical School, Newark, New Jersey, United States of America.
  • Giacalone D; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
  • Kevorkian YL; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
  • Zimmerman MD; Graduate Program in Molecular Microbiology, Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, United States of America.
  • Glickman JF; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
  • Freundlich JS; Graduate Program in Molecular Microbiology, Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts, United States of America.
  • Tan S; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, United States of America.
PLoS Biol ; 19(7): e3001355, 2021 07.
Article em En | MEDLINE | ID: mdl-34319985
ABSTRACT
Sensing and response to environmental cues, such as pH and chloride (Cl-), is critical in enabling Mycobacterium tuberculosis (Mtb) colonization of its host. Utilizing a fluorescent reporter Mtb strain in a chemical screen, we have identified compounds that dysregulate Mtb response to high Cl- levels, with a subset of the hits also inhibiting Mtb growth in host macrophages. Structure-activity relationship studies on the hit compound "C6," or 2-(4-((2-(ethylthio)pyrimidin-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole, demonstrated a correlation between compound perturbation of Mtb Cl- response and inhibition of bacterial growth in macrophages. C6 accumulated in both bacterial and host cells, and inhibited Mtb growth in cholesterol media, but not in rich media. Subsequent examination of the Cl- response of Mtb revealed an intriguing link with bacterial growth in cholesterol, with increased transcription of several Cl--responsive genes in the simultaneous presence of cholesterol and high external Cl- concentration, versus transcript levels observed during exposure to high external Cl- concentration alone. Strikingly, oral administration of C6 was able to inhibit Mtb growth in vivo in a C3HeB/FeJ murine infection model. Our work illustrates how Mtb response to environmental cues can intersect with its metabolism and be exploited in antitubercular drug discovery.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Desenvolvimento de Medicamentos / Mycobacterium tuberculosis / Antituberculosos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: PLoS Biol Assunto da revista: BIOLOGIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Desenvolvimento de Medicamentos / Mycobacterium tuberculosis / Antituberculosos Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: PLoS Biol Assunto da revista: BIOLOGIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos