Cruentaren, a New Antifungal Salicylate-Type Macrolide from Byssovorax cruenta (Myxobacteria) with Inhibitory Effect on Mitochondrial ATPase Activity

Abstract

The novel macrolide cruentaren A was produced at levels up to 3.2 mg/liter by cultures of the myxobacterium Byssovorax cruenta. The new compound strongly inhibited the growth of yeasts and filamentous fungi and showed high cytotoxicity against L929 mouse fibroblast cells. A minor co-metabolite of cruentaren A, named cruentaren B, and identified as a six-membered lactone isomer of cruentaren A, showed only marginal cytotoxicity and no antifungal activity. Cruentaren A inhibited F 0 F 1 mitochondrial ATP-hydrolysis in submitochondrial particles of yeasts and beef heart.

Inhibitors of V-ATPases: old and new players

“…Because of its structural relationship to the benzolactone enamides, with apicularen as the closest relative, it was initially assumed that cruentaren may also be a specific VATPase inhibitor. But surprisingly cruentaren had no effect on VATPases; instead it inhibited the evolutionarily related mitochondrial F-ATPases at nanomolar concentrations (Kunze et al, 2006;Kunze et al, 2007). Beyond that the interaction site of cruentaren resides in the F 1 complex whereas the benzolactone enamides, as mentioned above, operate via the membrane bound V O complex.…”

“…3), Petri et al (Petri et al, 2005). V-ATPase inhibitors which exhibits a high cytotoxity for mammalian and fungal cells (Kunze et al, 2006). Because of its structural relationship to the benzolactone enamides, with apicularen as the closest relative, it was initially assumed that cruentaren may also be a specific VATPase inhibitor.…”

“…The aim of this current review is to illustrate recent advances in the field, to present an update on the old players in the inhibition game, the plecomacrolides bafilomycin and concanamycin, and to introduce some of the new players, the macrolactone archazolid (Sasse et al, 2003), the benzolactone enamides salicylihalamide, lobatamide, apicularen, oximidine and cruentaren (Erickson et al, 1997;Galinis et al, 1997;Kim et al, 1999;Kunze et al, 1998;Kunze et al, 2006), and the indolyls (Gagliardi et al, 1998b;Nadler et al, 1998). Obviously this cast is not complete and, therefore, the specific V-ATPase inhibitors, which are not the focus of this review, are briefly mentioned here.…”

Myxobacterial secondary metabolites: bioactivities and modes-of-action

“…Although a close structural relative of apicularen, cruentaren 56 133 does not affect V-ATPases. Instead, its extremely high cytotoxicity (IC 50 of 1.2 ng/mL against mouse fibroblast cell line L929) arises from inhibition of the evolutionarily-related F o F 1 ATPases, through interaction with the F 1 complex.…”

V-ATPase Inhibitors in Cancer Treatment and Their Implication in Multidrug Resistance in Oral Squamous Cell Carcinoma

“…New molecules capable of inhibiting V-ATPase to a greater or lesser extent via different mechanisms of action were later discovered. Such molecules include benzolactone enamides salicylihalamide (Erickson et al 1997), lobatamide A and B (Galinis et al 1997), apicularen (Kunze B., Janse R., Sasse F., Höfle G. and Reichenbach H. 1998), indolyls , oximidine (Kim et al 1999), macrolactone archazolid (Sasse et al 2003), lobatamide C (Shen et al 2003), and cruentaren (Kunze et al 2006). The latest generation of inhibitors include NiK12192 (Saroussi, Nelson 2008, Petrangolini et al 2006, FR202126 (Niikura 2007), and PPI SB 242784 (Hesselink et al 2008).…”