Concanamycin A

Concanamycin A, a macrolide antibiotic, is a specific inhibitor of vacuolar-type ATPase (V-ATPase) with an IC₅₀ value of 10nM^[1]. Concanamycin A counteracts the HIV accessory protein Nef, reversing the MHC-I downregulation mediated by Nef, thereby enhancing the clearance of HIV-infected primary lymphocytes by cytotoxic T lymphocytes (CTL)^[2]. Concanamycin A has been widely used to block growth of Neurospora crassa in medium adjusted to pH 7^[3].

In vitro, Concanamycin A (12nM) pretreatment for 4 hours significantly inhibited the production of nitric oxide in mouse peritoneal macrophages induced by Lipopolysaccharide (LPS) (1µg/ml), reduced the expression of TLR4 molecules on the cell surface, and decreased the activation of NF-κB^[4]. Treatment with 2nM Concanamycin A for 48 hours triggered apoptosis in human submandibular gland ductal carcinoma cells, accompanied by nuclear condensation, DNA fragmentation, and a decrease in the level of heat shock protein 27 (HSP27)^[5]. Treatment with 10nM Concanamycin A for 24 hours restrained the growth of RAW 264.7 cells and disrupted the mitochondrial membrane potential^[6]. 3nM Concanamycin A treatment for 24 hours upregulated the tyrosinase activity in FM3 and B16-G4F cells, promoting melanin production^[7].

References:

[1] Huss M, Ingenhorst G, König S, et al. Concanamycin A, the specific inhibitor of V-ATPases, binds to the Vo subunit c[J]. Journal of Biological Chemistry, 2002, 277(43): 40544-40548.

[2] Painter M M, Zimmerman G E, Merlino M S, et al. Concanamycin A counteracts HIV-1 Nef to enhance immune clearance of infected primary cells by cytotoxic T lymphocytes[J]. Proceedings of the National Academy of Sciences, 2020, 117(38): 23835-23846.

[3] Bowman E J, O'Neill F J, Bowman B J. Mutations of pma-1, the gene encoding the plasma membrane H+-ATPase of Neurospora crassa, suppress inhibition of growth by concanamycin A, a specific inhibitor of vacuolar ATPases[J]. Journal of biological chemistry, 1997, 272(23): 14776-14786.

[4] Eswarappa S M, Basu N, Joy O, et al. Folimycin (concanamycin A) inhibits LPS-induced nitric oxide production and reduces surface localization of TLR4 in murine macrophages[J]. Innate Immunity, 2008, 14(1): 13-24.

[5] Aiko K, Tsujisawa T, Koseki T, et al. Involvement of cytochrome c and caspases in apoptotic cell death of human submandibular gland ductal cells induced by concanamycin A[J]. Cellular signalling, 2002, 14(8): 717-722.

[6] Hong J J, Nakano Y, Yokomakura A, et al. Nitric oxide production by the vacuolar-type (H+)-ATPase inhibitors bafilomycin A1 and concanamycin A and its possible role in apoptosis in RAW 264.7 cells[J]. The Journal of pharmacology and experimental therapeutics, 2006, 319(2): 672-681.

[7] Ancans J, Thody A J. Activation of melanogenesis by vacuolar type H+-ATPase inhibitors in amelanotic, tyrosinase positive human and mouse melanoma cells[J]. FEBS letters, 2000, 478(1-2): 57-60.