Didehydroroflamycoin pentaene macrolide family from Streptomyces durmitorensis MS405^T : production optimization and antimicrobial activity

Abstract

Aims: The aim of this study was to improve production of pentaene 32,33-didehydroroflamycoin (DDHR) in Streptomyces durmitorensis MS405 strain to obtain quantities sufficient for in depth analysis of antimicrobial properties. Methods and Results: Through classical medium optimization conditions for stable growth, DDHR production within 7 days of incubation was established. Yields of 215 mg l À1 were achieved in shake flask experiments in complex medium with mannitol as the primary carbon source. DDHR had poor antibacterial activity with minimal inhibitory concentrations (MIC) of 400 lg ml À1 for Staphylococcus aureus and Bacillus subtilis, while MIC of 70 lg ml À1 was determined for Candida albicans. Using flow cytometry and fluorescent microscopy, it was demonstrated that DDHR induced membrane damage in C. albicans followed by cell death. Combination studies with known antifungal nystatin showed that DDHR is a promising agent for the development of novel antimycotic treatments potentially less toxic for human cells. Conclusions: Pentaene didehydroroflamycoin has no antibacterial activity but can be further developed for the application in antifungal therapy. Significance and Impact of the Study: This study is the first report on the stable and production in high yields of a novel pentaene family that acts on Candida cell membranes and can be used in combination with known antifungals. Polyenes are still antifungal antibiotics of choice, and therefore, isolation and production of new lead structures are highly significant.

Streptomyces sp. BV410 isolate from chamomile rhizosphere soil efficiently produces staurosporine with antifungal and antiangiogenic properties

“…Both of these media were optimized from our previous work with Streptomyces spp. and have been described earlier (Stankovic et al, ).…”

Disease control efficacy of 32,33-didehydroroflamycoin produced by Streptomyces rectiviolaceus strain DY46 against gray mold of tomato fruit

“…DDHR, a new member of the polyene macrolide family, was recently isolated from a culture of S. durmitorensis strain MS405, and its structure was identified by Stodůlková et al . Antitumor and antifungal activities of DDHR against various cancer cell lines and pathogenic fungi have also been reported 15,35,36 . Recently, it was identified that the mechanism of action of DDHR is related to membrane disruption through pore formation in the fungal cell membrane 37 .…”

“…The use of postharvest fungicide should be considered with caution because the period between treatment and consumption is short. At two days after treatment, the DDHR residue in tomato fruit was significantly reduced by 47.3% of the amount recovered at 0 h. Additionally, recent studies on nystatin and DDHR have shown that DDHR has low toxicity to human cells 35 . These results suggest that DDHR would be relatively safe for use as a postharvest fungicide, especially for freshly cut fruit that is stored at low temperatures and that is vulnerable to gray mold.…”

Control of human and plant fungal pathogens using pentaene macrolide 32, 33-didehydroroflamycoin

“…Cultures were grown in the dark at 30°C on a rotary shaker (200 rev min −1 ) for 7 days and crude ethyl acetate extract containing DDHR was purified using dry flash chromatography, as previously described (Stankovic et al . ). Unless otherwise stated, all media components were purchased either from Oxoid (Cambridge, UK), Becton Dickinson (Sparks, MD) or Sigma Aldrich (Munich, Germany).…”