Synergistic antifungal indolecarbazoles from Streptomyces sp. CNS-42 associated with traditional Chinese medicine Alisma orientale

Abstract

Multi-drug resistance of pathogenic microorganisms is a serious threat to human health. In particular, Candida albicans, the most common opportunistic clinical fungal pathogen is one of the major causes of systemic infections, resulting in an estimated 30% of severe fungal infections, with mortality rate reaching nearly 40%.1, 2 Widespread and repeated use of current drugs, particularly azoles, have contributed to the rapid occurrence of antifungal drug resistance,3, 4 and most screening approaches for new drugs which target essential genes and fungal pathogens are likely to generate resistance over time. Given the high mortality rate resulting from fungal infections in immunocompromised patients and the limited number of highly effective, yet safe treatment agents, the development of new antifungal therapeutics is critical.1, 2, 5 A strategy limiting the pressure on drug targets would increase the lifespan of antifungal agents and reduce the frequency of treatment failures.3, 6 For instance, using synergistic drugs aimed at more than one target and slowing down the emergence of drug-resistant pathogens will be one of the key approaches to antifungal therapy. Our research group demonstrated that beauvericin (BEA) showed strong synergism with ketoconazole against diverse fungal pathogens both in vitro and in vivo,5 and that this synergetic effect was not caused by their pharmacokinetic interaction.7