Synergistic Lethality of a Binary Inhibitor of Mycobacterium tuberculosis KasA

  • Pradeep Kumar, Glenn C. Capodagli, Divya Awasthi, Riju Shrestha, Karishma Maharaja, Paridhi Sukheja, Shao-Gang Li, Daigo Inoyama, Matthew Zimmerman, Hsin Pin Ho Liang, Jansy Sarathy, Marizel Mina, George Rasic, Riccardo Russo, Alexander L. Perryman, Todd Richmann, Aditi Gupta, Eric Singleton, Sheetal Verma, Seema Husain, Patricia Soteropoulos, Zhe Wang, Roxanne Morris, Gene Porter, Gautam Agnihotri, Padmini Salgame, Sean Ekins, Kyu Y. Rhee, Nancy Connell, Véronique Dartois, Matthew B. Neiditch, Joel S. Freundlich, David Alland
  • mBio, December 2018, ASM Journals
  • DOI: 10.1128/mbio.02101-17

An inhibitor for Mtb KasA that binds the active site twice

What is it about?

We report GSK3011724A (DG167) as a binary inhibitor of -ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis. We show synergy in vitro and in vivo and provide various crystal structures and biochemical data.

Why is it important?

We show that two molecules of DG167 bind in two different sites simultaneously which contradicts the work of GSK published earlier.

Perspectives

Dr Sean Ekins
Collaborations in Chemistry

This was a multi- year project. This work was virtually completed when the GSK paper came out which showed only one molecule of DG167 in the binding pocket. What followed was the classic story of publishing a paper when you have just been beaten to the punch. It bounced around a few journals, reviewers also asked for extensive revisions which took close to a year to complete. As far as we know GSK have not issued a correction of their structure.

Read Publication

http://dx.doi.org/10.1128/mbio.02101-17

The following have contributed to this page: Dr Sean Ekins