Novel drugs with unique and targeted mode of action are very much need of the hour to treat and manage severe multidrug infections and other life-threatening complications. Though natural molecules have proved to be effective and environmentally safe, the relative paucity of discovery of new drugs has forced us to lean towards synthetic chemistry for developing novel drug molecules. Plants and microbes are the major resources that we rely upon in our pursuit towards discovery of novel compounds of pharmacological importance with less toxicity. Endophytes, an eclectic group of microbes having the potential to chemically bridge the gap between plants and microbes, have attracted the most attention due to their relatively high metabolic versatility. Since continuous large scale supply of major metabolites from microfungi and especially endophytes is severely impeded by the phenomenon of attenuation in axenic cultures, the major challenge is to understand the regulatory mechanisms in operation that drive the expression of metabolic gene clusters of pharmaceutical importance. This review is focused on the major regulatory elements that operate in filamentous fungi and various combinatorial multi-disciplinary approaches involving bioinformatics, molecular biology, and metabolomics that could aid in large scale synthesis of important lead molecules.

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