Identification of a series containing a pentafluorophenyl moiety that targets Pks13 to inhibit growth of Mycobacterium tuberculosis

TY - JOUR

T1 - Identification of a series containing a pentafluorophenyl moiety that targets Pks13 to inhibit growth of Mycobacterium tuberculosis

AU - Green, Simon

AU - Harrison, Justin

AU - Thompson, Stephen

AU - Murugesan, Dinakaran

AU - Libardo, M. Daben J.

AU - Engelhart, Curtis A.

AU - Meshanni, Jaclynn

AU - Fletcher, Daniel A.

AU - Scullion, Paul

AU - Edwards, Darren

AU - Epemolu, Ola

AU - Mutter, Nicole

AU - Shishikura, Yoko

AU - Riley, Jennifer

AU - Ioerger, Thomas R.

AU - Roca Guillén, José Juan

AU - Guijarro-Lopez, Laura

AU - Read, Kevin D.

AU - Barry, Clifton E

AU - Schnappinger, Dirk

AU - Wyatt, Paul G.

AU - Boshoff, Helena I. M.

AU - Cleghorn, Laura A. T.

N1 - Publisher Copyright: © 2025 The Authors. Published by American Chemical Society.

PY - 2025/3/14

Y1 - 2025/3/14

N2 - 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.

AB - 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.

KW - Pks13

KW - metabolic instability

KW - pentafluorophenyl

KW - tuberculosis

UR - https://www.scopus.com/pages/publications/86000163594

U2 - 10.1021/acsinfecdis.4c00808

DO - 10.1021/acsinfecdis.4c00808

M3 - Article

C2 - 40014668

SN - 2373-8227

VL - 11

SP - 715

EP - 726

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 3

ER -