Abstract
The development and spread of multidrug resistant pathogens have reinforced the urgency to find novel natural products with antibiotic activity. In bacteria, orphan biosynthetic gene clusters (BGCs) far outnumber the BGCs for which chemistry is known, possibly because they are transcriptionally silent under laboratory conditions. A strategy to trigger the production of this biosynthetic potential is to challenge the microorganism with low concentrations of antibiotics, and by using a Burkholderia genetic reporter strain (Seyedsayamdost, Proc Natl Acad Sci 111:7266–7271), we found BGC unsilencing activity for the antimicrobial andrimid, produced by the marine bacterium Vibrio coralliilyticus. Next, we challenged another marine Vibrionaceae, Photobacterium galatheae, carrier of seven orphan BGCs with sub-inhibitory concentrations of andrimid. A combined approach of transcriptional and chemical measurements of andrimid-treated P. galatheae cultures revealed a 10-fold upregulation of an orphan BGC and, amongst others, a 1.6–2.2-fold upregulation of the gene encoding the core enzyme for biosynthesis of holomycin. Also, addition of andrimid caused an increase, based on UV-Vis peak area, of 4-fold in production of the antibiotic holomycin. Transcriptional measurements of stress response related genes in P. galatheae showed a co-occurrence of increased transcript levels of rpoS (general stress response) and andrimid induced holomycin overproduction, while in trimethoprim treated cultures attenuation of holomycin production coincided with a transcriptional increase of recA (SOS stress response). This study shows that using antimicrobial compounds as activators of secondary metabolism can be a useful strategy in eliciting biosynthetic gene clusters and facilitate natural product discovery. Potentially, such interactions could also have ecological relevant implications.
Highlights
Microbial natural products have provided humankind with a broad range of medically useful molecules (Patridge et al, 2016)
Five antibiotic producing marine bacterial strains were tested for their capability to activate the silent mal biosynthetic gene clusters (BGCs) in B. thailandensis
Andrimid was fractionated and purified from V. coralliilyticus cultures to test in subminimal inhibitory concentrations (sub-MIC) (MIC of andrimid for B. thailandensis malL-lacZ was 32 μM) in the reporter strain
Summary
Microbial natural products have provided humankind with a broad range of medically useful molecules (Patridge et al, 2016). Genes encoding for the enzymes necessary to biosynthesize a natural product are almost exclusively clustered together on so-called biosynthetic gene clusters (BGCs) (Walsh and Fischbach, 2010). This genetic organization makes it possible to query the potential for production of secondary metabolites in genome-sequenced bacteria using specialized bioinformatics tools (Medema et al, 2011). Revealing the chemical products from orphan BGCs is an important point at the agenda of discovering novel natural products and potential novel drugs
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