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TitleStructural and mechanistic study of a novel inhibitor analogue of cytochrome bc:aa.
Journal, issue, pagesNPJ Drug Discov, Vol. 2, Issue 1, Page 6, Year 2025
Publish dateApr 2, 2025
AuthorsAmit K Verma / Robbert Q Kim / Dirk A Lamprecht / Clara Aguilar-Pérez / Sarah Wong / Nicolas Veziris / Alexandra Aubry / José M Bartolomé-Nebreda / Rodrigo J Carbajo / Jennefer Wetzel / Meindert H Lamers /
PubMed AbstractDrug-resistant tuberculosis (TB) continues to challenge treatment options, necessitating the exploration of new compounds of novel targets. The mycobacterial respiratory complex cytochrome bc:aa has ...Drug-resistant tuberculosis (TB) continues to challenge treatment options, necessitating the exploration of new compounds of novel targets. The mycobacterial respiratory complex cytochrome bc:aa has emerged as a promising target, exemplified by the success of first-in-class inhibitor Q203 in phase 2 clinical trials. However, to fully exploit the potential of this target and to identify the best-in-class inhibitor more compounds need evaluation. Here, we introduce JNJ-2901, a novel Q203 analogue, that demonstrates activity against multidrug-resistant clinical strains at sub-nanomolar concentration and 4-log reduction in bacterial burden in a mouse model of TB infection. Inhibitory studies on purified enzymes validate the nanomolar inhibitions observed in mycobacterial cells. Additionally, cryo-EM structure analysis of cytochrome bc:aa bound to JNJ-2901 reveals the binding pocket at the menaquinol oxidation site (Qp), akin to other substate analogue inhibitors like Q203 and TB47. Validation of the binding site is further achieved by generating and isolating the JNJ-2901 resistant mutations in , followed by purification and resistance analysis of the resistant cytochrome bc:aa complex. Our comprehensive work lays the foundation for further clinical validations of JNJ-2901.
External linksNPJ Drug Discov / PubMed:40191462 / PubMed Central
MethodsEM (single particle)
Resolution3.1 Å
Structure data

51689

9gy6

EMDB-51689, PDB-9gy6:
Mycobacterial cytochrome bc1:aa3 with inhibitor
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-FES:
FE2/S2 (INORGANIC) CLUSTER

ChemComp-9YF:
(2R)-2-(hexadecanoyloxy)-3-{[(S)-hydroxy{[(1R,2R,3R,4R,5R,6S)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propyl (9S)-9-methyloctadecanoate

ChemComp-PLM:
PALMITIC ACID

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

ChemComp-CDL:
CARDIOLIPIN / phospholipid*YM

PDB-1ire:
Crystal Structure of Co-type nitrile hydratase from Pseudonocardia thermophila

ChemComp-HEC:
HEME C

ChemComp-MQ9:
MENAQUINONE-9

ChemComp-9Y0:
(2R)-3-(((2-aminoethoxy)(hydroxy)phosphoryl)oxy)-2-(palmitoyloxy)propyl (E)-octadec-9-enoate

ChemComp-CU:
COPPER (II) ION

ChemComp-HEA:
HEME-A

ChemComp-CA:
Unknown entry

ChemComp-MQ7:
MENAQUINONE-7

ChemComp-HOH:
WATER

Source
  • mycolicibacterium smegmatis mc2 155 (bacteria)
KeywordsOXIDOREDUCTASE / membrane protein / inhibitor complex / mycobacterium / cytochrome bc

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