In Vitro Studies with Ambruticin, a New Antifungal Antibiotic

Abstract

With the choice of antifungal chemotherapeutic agents suitable for use in treatment of the mycoses still severely limited, it is essential to examine all potential additions to the clinical armamentarium. Ambruticin (W7783) is a recently described antifungal antibiotic isolated from Polyangium cellulosum var. fulvum (6a, 7) that has such potential.A cyclopropyl pyran, ambruticin already has been shown to have antifungal activity in vitro against a variety of filamentous fungal pathogens (7) and also to be both protective and curative in vivo in mice experimentally infected with Coccidioides immitis (5, 6). The following study was undertaken to further define the in vitro spectrum of ambruticin and to compare the in vitro antifungal activity of this new compound with the various drugs of choice used in treatment of the several different groups of human mycotic infections ( Inocula. One hundred and ninety pathogenic fungi were tested (Table 1). These consisted of clinical isolates recovered and identified in our laboratory or cultures from the Center for Disease Control proficiency testing program in Medical Mycology. For the filamentous and dimorphic fungi, inocula were prepared from mycelial-phase cultures grown for 1 month on modified Sabouraud agar slants (Difco) at 250C. Mature, sporulating cultures were washed with 5 ml of sterile physiological saline, and the resulting suspensions were adjusted so as to contain from 104 to 105 colony-forming units per ml as confirmed by viable plate counts. For the monomorphic yeasts (Candida and Torulopsis spp.), cultures were grown on potato dextrose agar (Difco) slants at 25°C for 48 h and were harvested as above except that final inocula were adjusted by nephelometry to contain 10e cells per ml.Media. Selection of media for susceptibility testing was predicated by known requirements of the comparison drugs. With the filamentous and dimorphic fungi, all drugs were incorporated in casein-yeast extract-glucose (CYG) agar (13). For the monomorphic yeasts, ambruticin and miconazole were tested using CYG agar, while 5-FC was tested using solidified, modified yeast nitrogen base agar (8) and amphotericin B was tested using solidified antibiotic medium-3 (Difco; 12). Susceptibility testing. A modification of the standardized ICS agar dilution technique was employed (1). Drugs were diluted in the specified agar media over a final concentration range of 0.063 to 128 ytg/ml.

In Vivo Studies with Ambruticin in Murine Histoplasmosis

“…Ambruticin (W7883) has been shown to be a relatively broad-spectrum antifungal agent active in vitro against a variety of filamentous and dimorphic fungal pathogens (4)(5)(6). It already has been shown to be active in vivo in mice experimentally infected with Coccidioides immitis and, moreover, capable both of protecting experimental animals against infection with this organism and of producing biological cures (1,2).…”

Ambruticins: tetrahydropyran ring formation and total synthesis

“…2,3 Ambruticin S exhibits potent antifungal activity against a variety of fungal pathogens including Coccidioides immitis, Histoplasma capsulatum and Blastomyces dermatitidis. [4][5][6] The antimycotic activity originates from interaction with the high-osmolarity glycerol (HOG) protein kinase signalling pathway, and no toxicity was observed in mice dosed with ambruticin S. 7,8 Due to this promising antifungal activity, and fascinating structure, ambruticin S has been a target for several total syntheses. [9][10][11][12][13] In 2006, Reeves proposed a biosynthetic pathway to the ambruticins, based on results from analysis of the biosynthetic gene cluster alongside gene knockout experiments.…”

Investigating Amine Derivatives of Ambruticin VS‐5 and VS‐4

“…5 The ambruticins have in vitro antifungal activities that are similar to amphotericin (with minimum inhibitory concentrations (MICs) in the μg mL −1 range) 5. 6 The mechanism of action of the ambruticins was first proposed by Knauth and Reichenbach to be similar to that of the phenylpyrroles,7 that is, through induction of the high osmolarity glycerol (HOG) signaling pathway 8. More recently, Vetcher et al.…”