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Structure of mycobacterial CIII2CIV2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203).

<div class='caption-title'>Structure of the Mycobacteriumsmegmatis CIII2CIV2 respiratory complex.</div>
<div class='caption-title'>Electron cryomicroscopy (CryoEM) map validation.</div>
<div class='caption-title'>Three-dimensional (3D) variability analysis of LpqE and the cyt. cc domain.</div>
Yanofsky DJ, Di Trani JM, Król S, Abdelaziz R, Bueler SA, Imming P, Brzezinski P, Rubinstein JL
OpenAccess logo Elife 10 (2021)
Related entries: 7rh5, 7rh7

Cited: 11 times
EuropePMC logo PMID: 34590581

Abstract

The imidazopyridine telacebec, also known as Q203, is one of only a few new classes of compounds in more than 50 years with demonstrated antituberculosis activity in humans. Telacebec inhibits the mycobacterial respiratory supercomplex composed of complexes III and IV (CIII2CIV2). In mycobacterial electron transport chains, CIII2CIV2 replaces canonical CIII and CIV, transferring electrons from the intermediate carrier menaquinol to the final acceptor, molecular oxygen, while simultaneously transferring protons across the inner membrane to power ATP synthesis. We show that telacebec inhibits the menaquinol:oxygen oxidoreductase activity of purified Mycobacterium smegmatis CIII2CIV2 at concentrations similar to those needed to inhibit electron transfer in mycobacterial membranes and Mycobacterium tuberculosis growth in culture. We then used electron cryomicroscopy (cryoEM) to determine structures of CIII2CIV2 both in the presence and absence of telacebec. The structures suggest that telacebec prevents menaquinol oxidation by blocking two different menaquinol binding modes to prevent CIII2CIV2 activity.

Reviews citing this publication (3)

  1. Quinone binding sites of cyt bc complexes analysed by X-ray crystallography and cryogenic electron microscopy. Kao WC, Hunte C. Biochem Soc Trans 50 877-893 (2022)
  2. Uncovering interactions between mycobacterial respiratory complexes to target drug-resistant Mycobacterium tuberculosis. McNeil MB, Cheung CY, Waller NJE, Adolph C, Chapman CL, Seeto NEJ, Jowsey W, Li Z, Hameed HMA, Zhang T, Cook GM. Front Cell Infect Microbiol 12 980844 (2022)
  3. A Review of Antibacterial Candidates with New Modes of Action. Butler MS, Vollmer W, Goodall ECA, Capon RJ, Henderson IR, Blaskovich MAT. ACS Infect Dis 10 3440-3474 (2024)

Articles citing this publication (8)

  1. Structure of mycobacterial CIII2CIV2 respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203). Yanofsky DJ, Di Trani JM, Król S, Abdelaziz R, Bueler SA, Imming P, Brzezinski P, Rubinstein JL. Elife 10 e71959 (2021)
  2. Structure of mycobacterial respiratory complex I. Liang Y, Plourde A, Bueler SA, Liu J, Brzezinski P, Vahidi S, Rubinstein JL. Proc Natl Acad Sci U S A 120 e2214949120 (2023)
  3. Cryo-Electron Microscopy Structure of the Mycobacterium tuberculosis Cytochrome bcc:aa3 Supercomplex and a Novel Inhibitor Targeting Subunit Cytochrome cI. Mathiyazakan V, Wong CF, Harikishore A, Pethe K, Grüber G. Antimicrob Agents Chemother 67 e0153122 (2023)
  4. A simple assay for inhibitors of mycobacterial oxidative phosphorylation. Harden SA, Courbon GM, Liang Y, Kim AS, Rubinstein JL. J Biol Chem 300 105483 (2024)
  5. Electron transfer in the respiratory chain at low salinity. Lobez AP, Wu F, Di Trani JM, Rubinstein JL, Oliveberg M, Brzezinski P, Moe A. Nat Commun 15 8241 (2024)
  6. Imidazopyridine Amides: Synthesis, Mycobacterium smegmatis CIII2CIV2 Supercomplex Binding, and In Vitro Antimycobacterial Activity. Abdelaziz R, Di Trani JM, Sahile H, Mann L, Richter A, Liu Z, Bueler SA, Cowen LE, Rubinstein JL, Imming P. ACS Omega 8 19081-19098 (2023)
  7. Long-range charge transfer mechanism of the III2IV2 mycobacterial supercomplex. Riepl D, Gamiz-Hernandez AP, Kovalova T, Król SM, Mader SL, Sjöstrand D, Högbom M, Brzezinski P, Kaila VRI. Nat Commun 15 5276 (2024)
  8. Telacebec Interferes with Virulence Lipid Biosynthesis Protein Expression and Sensitizes to Other Antibiotics. Zhou Z, Wattiez R, Constant P, Marrakchi H, Soetaert K, Mathys V, Fontaine V, Zeng S. Microorganisms 11 2469 (2023)


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