9C9O

M. tuberculosis PKS13 acyltransferase (AT) domain in complex with SuFEx inhibitor CMX410 - reaction product

This is a non-PDB format compatible entry.

Summary for 9C9O

• Entry DOI: 10.2210/pdb9c9o/pdb
• Related: 9C0P 9C1C 9C1D 9C1V 9C2R
• Related PRD ID: PRD_900003
• Descriptor: Polyketide synthase Pks13, beta-D-fructofuranose-(2-1)-alpha-D-glucopyranose, SULFATE ION, ... (7 entities in total)
• Functional Keywords: polyketide synthase, acyltransferase domain, inhibitor, mycobacteria, structural genomics, tb structural genomics consortium, tbsgc, transferase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); More
• Total number of polymer chains: 3
• Total formula weight: 170353.64

Authors

Krieger, I.V.,Tang, S.,Sacchetini, J.C.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2024-06-14, release date: 2025-05-07, Last modification date: 2025-10-01)

Primary citation

Krieger, I.V.,Sukheja, P.,Yang, B.,Tang, S.,Selle, D.,Woods, A.,Engelhart, C.,Kumar, P.,Harbut, M.B.,Liu, D.,Tsuda, B.,Qin, B.,Bare, G.A.L.,Li, G.,Chi, V.,Gambacurta, J.,Hvizdos, J.,Reagan, M.,Jones, I.L.,Massoudi, L.M.,Woolhiser, L.K.,Cascioferro, A.,Kundrick, E.,Singh, P.,Reiley, W.,Ioerger, T.R.,Kandula, D.R.,McCabe, J.W.,Guo, T.,Alland, D.,Boshoff, H.I.,Schnappinger, D.,Robertson, G.T.,Mdluli, K.,Lee, K.J.,Dong, J.,Li, S.,Schultz, P.G.,Joseph, S.B.,Love, M.S.,Sharpless, K.B.,Petrassi, H.M.,Chatterjee, A.K.,Sacchettini, J.C.,McNamara, C.W.
SuFEx-based antitubercular compound irreversibly inhibits Pks13.
Nature, 645:755-763, 2025

PubMed Abstract: Mycobacterium tuberculosis (Mtb) remains the world's deadliest bacterial pathogen. There is an urgent medical need to develop new drugs that shorten the treatment duration to combat widespread multi-drug-resistant and extensive-drug-resistant Mtb. Here, we present a preclinical covalent compound, CMX410, that contains an aryl fluorosulfate (SuFEx) warhead and uniquely targets the acyltransferase domain of Pks13, an essential enzyme in cell-wall biosynthesis. CMX410 is equipotent against drug-sensitive and drug-resistant strains of Mtb and efficacious in multiple mouse models of infection. Inhibition by CMX410 is irreversible through a previously undescribed mechanism: CMX410 reacts with the catalytic serine of the AT domain of Pks13, rapidly and irreversibly disabling the active site by forming a β-lactam. CMX410 is highly selective for its target and thus demonstrates excellent pharmacological and safety profiles, including no adverse effects in a 14-day rat toxicity study up to 1,000 mg kg per day. The distinctive mode of action from current drugs, high potency across all tested clinical isolates, oral bioavailability, favourable performance in drug combination testing and superior pharmacological and safety characteristics make CMX410 a promising first-in-class candidate to replace outdated cell-wall biosynthesis inhibitors, such as isoniazid and ethambutol, in tuberculosis regimens.

PubMed: 40739353
DOI: 10.1038/s41586-025-09286-3

Experimental method

X-RAY DIFFRACTION (2.02 Å)