A d-Phenylalanine-Benzoxazole Derivative Reveals the Role of the Essential Enzyme Rv3603c in the Pantothenate Biosynthetic Pathway of Mycobacterium tuberculosis

Abstract

New drugs and new targets are urgently needed to treat tuberculosis. We discovered the Dphenylalanine-benzoxazole Q112 displays potent antibacterial activity against Mycobacterium tuberculosis (Mtb) in multiple media and in macrophage infections. Metabolomic profiling indicates that Q112 has a unique mechanism of action. Q112 perturbs the essential pantothenate/CoA biosynthetic pathway, depleting pantoate while increasing ketopantoate, as would be expected if ketopantoate reductase (KPR) were inhibited. We searched for alternative KPRs since the enzyme annotated as PanE KPR is not essential in Mtb. The ketolacid reductoisomerase IlvC catalyzes the KPR reaction in the close Mtb relative Corynebacterium glutamicum, but Mtb IlvC does not display KPR activity. We identified the essential protein Rv3603c as an ortholog of PanG KPR, and demonstrated that purified recombinant Rv3603c has KPR activity. Q112 inhibits Rv3603c, explaining the metabolomic changes. Surprisingly, pantothenate does not rescue Q112-treated bacteria, indicating that Q112 has an additional target(s). Q112-resistant strains contain loss-of-function mutations in the twin arginine translocaseTatABC, further underscoring Q112's unique mechanism of action. Loss of TatABC causes a severe fitness deficit attributed to changes in nutrient uptake, suggesting that Q112 resistance may derive from a decrease in uptake.

Ethnopharmacology study of medicinal plants utilization for antidiarrheal remedies by Tengger tribe in Tosari District, Indonesia

“…Peonidin is known to have antibacterial (Jeyaraj et al, 2023), antiinflammation, and antioxidant activity (Bonetti et al, 2017). Dphenylalanine-benzoxazole showed antibacterial activity against Mycobacterium tuberculosis (Pepi et al, 2022(Pepi et al, , 2023. 6-shogaol had antimicrobial, antioxidant (Ghasemzadeh et al, 2018), antiinflammation (Deb et al, 2019), antibiofilm, and antivirulence activity (Lee et al, 2018).…”

Ethnopharmacology of medicinal plants used by the Tenggerese community in Bromo Tengger Semeru National Park, Indonesia

“…Peonidin, D-phenylalaninebenzoxazole, 6-Shogaol, and Piperine each exhibit diverse pharmacological potential, positioning them as promising candidates for therapeutic applications. Of noteworthy mention, D-phenylalanine-benzoxazole, as underscored by recent studies by Pepi et al (2022Pepi et al ( , 2023, has garnered attention for its robust antitubercular properties.…”