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Abstract

Finding new antimicrobial compounds is vital to combat the growing threat of resistance. Most currently used antibiotics originate from actinomycetes discovered more than half a century ago. We recently reported the new species Streptomyces formicae, isolated from the African fungus-farming plant-ant, Tetraponera penzigi. S. formicae produces a novel family of polyketide antibiotics, the formicamycins, that have potent activity against resistant pathogens including MRSA and vancomycin-resistant Enterococci (VRE). Using CRISPR/Cas9, we have identified and characterised the genes responsible for formicamycin biosynthesis in the native producer. In addition, we used cappable RNA- and ChIP-sequencing to determine the transcriptional organisation of the pathway. We exploited this information to generate multiple mutants of S. formicae that overproduce formicamycins and their biosynthetic intermediates, some of which also have bioactivity. Furthermore, the potential for novel chemistry from S. formicae is not limited to the formicamycin pathway; antiSMASH analysis shows this talented strain contains at least 45 secondary metabolite biosynthetic gene clusters (BGCs). Under standard laboratory conditions, wild-type S. formicae also exhibits antifungal activity against the drug resistant Lamentospora prolificans, and when the formicamycin BGC is deleted, the strain produces even more potent antibacterial activity against MRSA. To identify the biosynthetic pathways for these metabolites, entire BGCs up to 208 kbp were deleted using CRISPR. Overall, this work demonstrates that searching under-explored environments for new species combined with genome editing is a promising route towards finding novel anti-invectives.

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/content/journal/acmi/10.1099/acmi.ac2019.po0067
2019-04-08
2019-10-14
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