2. Academic Validation
  3. Identification of a Series Containing a Pentafluorophenyl Moiety That Targets Pks13 to Inhibit Growth of Mycobacterium tuberculosis

Identification of a Series Containing a Pentafluorophenyl Moiety That Targets Pks13 to Inhibit Growth of Mycobacterium tuberculosis

  • ACS Infect Dis. 2025 Mar 14;11(3):715-726. doi: 10.1021/acsinfecdis.4c00808.
Simon R Green 1,  Justin R Harrison 1,  Stephen Thompson 1,  Dinakaran Murugesan 1,  M Daben J Libardo 2,  Curtis A Engelhart 3,  Jaclynn Meshanni 3,  Daniel Fletcher 1,  Paul Scullion 1,  Darren Edwards 1,  Ola Epemolu 1,  Nicole Mutter 1,  Yoko Shishikura 1,  Jennifer Riley 1,  Thomas R Ioerger 4,  Jose Juan Roca Guillén 5,  Laura Guijarro López 5,  Kevin D Read 1,  Clifton E Barry 3rd 2,  Dirk Schnappinger 4,  Paul G Wyatt 1,  Helena I M Boshoff 2,  Laura A T Cleghorn 1
Affiliations

Affiliations

  • 1 Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.
  • 2 Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Rockville Pike, Bethesda, Maryland 9000, United States.
  • 3 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, United States.
  • 4 Department of Computer Science and Engineering, Texas A&M University, College Station, Texas 77843, United States.
  • 5 Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain.
PMID: 40014668 DOI: 10.1021/acsinfecdis.4c00808
Abstract

Although not currently in the infectious disease spotlight, there is still a pressing need for new agents to treat tuberculosis caused by Mycobacterium tuberculosis. As there is an ever-increasing amount of clinical resistance to the current drugs, ideally new drugs would be found against novel targets to circumvent pre-existing resistance. A phenotypic growth screen identified a novel singleton, 1, as an inhibitor of M. tuberculosis growth. Mechanism-of-action studies determined that 1 targeted Pks13, an essential Enzyme in cell wall biosynthesis that, as of yet, has not been targeted by agents in the clinic. The reactive nature of the pentafluorophenyl warhead meant that the molecule was inherently metabolically unstable. A medicinal chemistry optimization program is described that resulted in the identification of a compound that was reactive enough to still inhibit Pks13 and M. tuberculosis growth while being metabolically stable enough to explore in vivo.

Keywords

Pks13; metabolic instability; pentafluorophenyl; tuberculosis.

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