The increasing rise of antibiotic resistant pathogens necessitates the discovery of novel antibiotics and targets. Natural products present a fruitful source for antibiotics, and the onslaught of genomic sequencing provides the ability for a streamlined gene-guided approach to discover novel natural products. Thiazole/oxazole-modified microcins (TOMMs) represent a burgeoning class of ribosomal natural products decorated with thiazoles and oxazoles derived from cysteines, serines, and threonines. Select cysteine, serine or threonine residues of a ribosomally produced precursor peptide are first cyclized by an ATP-dependent cyclodehydratase to the thiazole or (methyl)oxazoline heterocycle, which can then be oxidized by a FMN-dependent dehydrogenase to the thiazole or (methyl)oxazole. Ancillary processing and leader peptide cleavage complete TOMM biosynthesis.Through genome mining efforts, a number of distinct TOMM gene clusters have been found in the Bacillus genus. Investigation of a particular cluster from Bacillus sp. Al Hakam (Balh) has provided insight into the finer details of substrate processing. Using substrate analogs and tandem mass spectrometry, the Balh TOMM biosynthetic enzymes were shown to be both chemoselective and site-selective. To expand our understanding of TOMMs in the Bacillus genus, a number of genetic, chemical, and mass spectrometry tools have been utilized for the discovery of novel TOMMs. Ultimately, understanding the biosynthesis and function of unexplored TOMMs may help solve the current antibiotic crisis.

Investigations of the thiazole/oxazole-modified microcins of <i>?Bacillus</i>

248th National Meeting (2014)

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Investigations of the thiazole/oxazole-modified microcins of ?Bacillus