Molecular characterization and elucidation of regulatory network involved in Echinocandin B production

Abstract

Worldwide, nearly a billion peoples affected by fungal infections among these 150 million are at high risk with a mortality rate of 1.5 million each year. During past decades, fungal infections emerged as a serious hospital-acquired threat, particularly among patients in the intensive care unit (ICU) across the world; most of them are due to Candida spp. C. albicans is the most infectious opportunistic fungal pathogen that contributes almost 80-90% of all IFIs. The elevated mortality may be due to development of resistance, delayed diagnosis and treatment. Echinocandin B (ECB), a cyclic hexa-lipopeptide is considered to be a first line antifungal that inhibits and#946;-(1,3)-glucan synthase function, leading to damage fungal cell walls. It shows fungicidal effect against most Candida spp. and fungi-static against Aspergillus spp. This potent antifungal secondary metabolite (SMs) is naturally isolated from a fungus called Emericella rugulosa NRRL 11440. It is well documented that genes encoded for fungal SMs synthesis are present in the cluster and often located at sub-telomere region. The regulation of SMs synthesis in fungi can be accomplished at different level including pathway-specific (in- clustered transcription factor), global regulatory proteins and chromatin remodelling proteins. The transcription factor (TF) encoding gene located in gene cluster is considered to be a crucial regulatory circuit for SMs biosynthetic pathway. In a recent study, Cacho et al., identified two ECB biosynthetic gene cluster termed as ecd and hty in E. rugulosa NRRL 11440. The ecd gene cluster comprises of 12 genes (ecdA-L), which encodes for non-ribosomal peptide synthatases (NRPS), TF, transporters and various oxidases which were predicted to have a role in ECB synthesis. On other hand, hty gene cluster synthesizes the L-homotyrosine (a bricks of ECB). The function and regulatory action of most of these genes are not known so far. In present study, we targeted our study to explore the regulatory network involved in ECB biosynthesis,