New strategies for drug discovery: Activation of silent or weakly expressed microbial gene clusters

Genome sequencing of Streptomycesand fungi showed that, although each strain contains genes that encode a plethora of potential secondary metabolites, only a fraction are expressed during fermentation. Interest has therefore grown in the activation of these cryptic pathways. The key issue for the success of this approach is to find ways to induce or enhance the expression of cryptic or poorly expressed pathways to provide material for structure elucidation and biological testing. We review current progress on this topic, describing concepts for activating silent genes as follows.

1) Broad applicability of the rpoBmutations for activation of silent genes.

2) Utilization of lincomycin to activate silent genes.

3) Applicability of “Metabolism-Remodeling” to nonribosomal-peptide antibiotics, in addition to polyketide antibiotics.

4) Mutagenic modulation of intracellular SAM level to activate bacterial silent genes.

 These approaches may solve the early stage discovery problems of: (a) inducing some level of expression of cryptic biosynthetic gen clusters [waking the sleeping genes] and (b) rapidly increasing product yields to obtain enough material to characterize chemically and biologically [early stage yield enhancement].

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