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Abstract
Tuberculosis is an infectious disease of global concern. Members of the diazaquinomycin (DAQ) class of natural products have shown potent and selective activity against drug-resistant Mycobacterium tuberculosis. However, poor solubility has prevented further development of this compound class. Understanding DAQ biosynthesis may provide a viable route for the generation of derivatives with improved properties. We have sequenced the genomes of two actinomycete bacteria that produce distinct DAQ derivatives. While software tools for automated biosynthetic gene cluster (BGC) prediction failed to detect DAQ BGCs, comparative genomics using MAUVE alignment led to the identification of putative BGCs in the marine Streptomyces sp. F001 and in the freshwater Micromonospora sp. B006. Deletion of the identified daq BGC in strain B006 using CRISPR-Cas9 genome editing abolished DAQ production, providing experimental evidence for BGC assignment. A complete model for DAQ biosynthesis is proposed based on the genes identified. Insufficient knowledge of natural product biosynthesis is one of the major challenges of productive genome mining approaches. The results reported here fill a gap in knowledge regarding the genetic basis for the biosynthesis of DAQ antibiotics. Moreover, identification of the daq BGC shall enable future generations of improved derivatives using biosynthetic methods.
Highlights
Tuberculosis is an infectious disease of global concern
Automated genome mining techniques, such as antiSMASH 4.0, failed to identify putative daq biosynthetic gene cluster (BGC) in strains F001 or B006, suggesting that biosynthesis of DAQs does not conform to generally known biosynthetic pathways for secondary metabolites or that their biosynthesis resembles primary metabolism
We identified homologous daq BGCs in Streptomyces sp
Summary
Tuberculosis (TB) is a global health threat. In 2016, the World Health Organization reported 10.4 million new TB cases and approximately 1.7 million deaths worldwide, with over 95% of them occurring in low- and middle-income countries. Approximately 20% of the. Deoxynybomycin [11], originally described as a degradation product of 10,10 was later found to be produced by a soil Streptomyces hyalinum strain and to have more potent activity than 10.16, SCH 538415 [12] was isolated in 2003 from an unidentified bacterial microbe during a mechanism-based drug discovery campaign aimed at identifying inhibitors of bacterial acyl carrier protein synthetase, and again three years later from a riverbank soil-derived Streptomyces sp.. SCSIO 01299.19, Deoxynyboquinone [13] has been shown to be reductively activated by the enzyme NAD(P)H:quinone oxidoreductase 1, and to undergo redox cycling that induces cancer cell death through a reactive oxygen species (ROS)-based mechanism., DAQs suffer from poor water solubility, presumably due to their planar structures leading to intermolecular pi-stacking interactions, and the hydrophobicity of the aliphatic side chains, as has been reported for 13 and 10.10, 13 This has prevented extensive animal studies far. Based on the genes identified we propose a model for diazaquinomycin biosynthesis
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