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With billions of years of evolution under its belt, Nature has been expanding and optimizing its biosynthetic capabilities. Chemically complex secondary metabolites continue to challenge and inspire today''s most talented synthetic chemists. A brief glance at these natural products, especially the substantial structural variation within a class of compounds, clearly demonstrates that Nature has long played the role of medicinal chemist. The recent explosion in genome sequencing has expanded our appreciation of natural product space and the vastness of uncharted territory that remains. One small corner of natural product chemical space is occupied by the recently dubbed thiazole/oxazole-modified microcins (TOMMs), which are ribosomally produced peptides with posttranslationally installed heterocycles derived from cysteine, serine and threonine residues. As with other classes of natural products, the genetic capacity to synthesize TOMMs has been widely disseminated among bacteria. Over the evolutionary timescale, Nature has tested countless random mutations and selected for gain of function in TOMM biosynthetic gene clusters, yielding several privileged molecular scaffolds. Today, this burgeoning class of natural products encompasses a structurally and functionally diverse set of molecules (i.e. microcin B17, cyanobactins, and thiopeptides). TOMMs presumably provide their producers with an ecological advantage. This advantage can include chemical weapons wielded in the battle for nutrients, disease-promoting virulence factors, or compounds presumably beneficial for symbiosis. Despite this plethora of functions, many TOMMs await experimental interrogation. This review will focus on the biosynthesis and natural combinatorial diversity of the TOMM family. [Copyright &y& Elsevier]

The hygrolides, a family of 16-member-ring-containing plecomacrolides produced by Actinobacteria, exhibit numerous reported bioactivities. Using HR-MS/MS, nucleophilic 1,4-addition-based labeling, NMR, and bioinformatic analysis, we identified Streptomyces varsoviensis as a novel producer of JBIR-100, a fumarate-containing hygrolide, and elucidated the previously unknown stereochemistry of the natural product. We investigated the antimicrobial activity of JBIR-100, with preliminary insight into mode of action indicating that it perturbs the membrane of Bacillus subtilis . S. varsoviensis is known to produce compounds from multiple hygrolide sub-families, namely hygrobafilomycins (JBIR-100 and hygrobafilomycin) and bafilomycins (bafilomycin C 1 and D). In light of this, we identified the biosynthetic gene cluster for JBIR-100, which, to our knowledge, represents the first reported for a hygrobafilomycin. Finally, we performed a bioinformatic analysis of the hygrolide family, describing clusters from known and predicted producers. Our results indicate that potential remains for the Actinobacteria to yield novel hygrolide congeners, perhaps with differing biological activities. [ABSTRACT FROM AUTHOR]