2. Academic Validation
  3. GaMF1.39's antibiotic efficacy and its enhanced antitubercular activity in combination with clofazimine, Telacebec, ND-011992, or TBAJ-876

GaMF1.39's antibiotic efficacy and its enhanced antitubercular activity in combination with clofazimine, Telacebec, ND-011992, or TBAJ-876

  • Microbiol Spectr. 2023 Nov 20:e0228223. doi: 10.1128/spectrum.02282-23.
Priya Ragunathan 1,  Pearly Shuyi Ng 2,  Samsher Singh 3,  Wee Han Poh 4,  Dennis Litty 5,  Nitin Pal Kalia 6,  Simon Larsson 3,  Amaravadhi Harikishore 1 7,  Scott A Rice 1 4,  Philip W Ingham 3,  Volker Müller 5,  Garrett Moraski 8,  Marvin J Miller 9,  Thomas Dick 10 11 12,  Kevin Pethe 1 3 13,  Gerhard Grüber 1
Affiliations

Affiliations

  • 1 School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
  • 2 Experimental Drug Development Centre, Agency for Science, Technology and Research, Singapore, Singapore.
  • 3 Lee Kong Chian School of Medicine, Nanyang Technological University, Experimental Medicine Building, Singapore, Singapore.
  • 4 Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore.
  • 5 Molecular Microbiology and Bioenergetics, Institute for Molecular Biosciences, Johann Wolfgang Goethe University Frankfurt/Main, Frankfurt, Germany.
  • 6 Department of Biological Sciences (Pharmacology & Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India.
  • 7 School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore.
  • 8 Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana, USA.
  • 9 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
  • 10 Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA.
  • 11 Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA.
  • 12 Department of Microbiology and Immunology, Georgetown University, Washington, DC, USA.
  • 13 National Centre for Infectious Diseases (NCID), Jalan Tan Tock Seng, Singapore, Singapore.
PMID: 37982630 DOI: 10.1128/spectrum.02282-23
Abstract

New drugs are needed to combat multidrug-resistant tuberculosis. The electron transport chain (ETC) maintains the electrochemical potential across the cytoplasmic membrane and allows the production of ATP, the energy currency of any living cell. The mycobacterial engine F-ATP synthase catalyzes the formation of ATP and has come into focus as an attractive and rich drug target. Recent deep insights into these mycobacterial F1FO-ATP synthase elements opened the door for a renaissance of structure-based target identification and inhibitor design. In this study, we present the GaMF1.39 antimycobacterial compound, targeting the rotary subunit γ of the biological engine. The compound is bactericidal, inhibits Infection ex vivo, and displays enhanced anti-tuberculosis activity in combination with ETC inhibitors, which promises new strategies to shorten tuberculosis chemotherapy.

Keywords

F-ATP synthase; Mycobacterium tuberculosis; anti-TB compound; bioenergetics; oxidative phosphorylation; tuberculosis.

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