Deciphering the regulatory mechanisms of formicamycin biosynthesis in Streptomyces formicae, a novel antibiotic against MRSA

Derivatives of the secondary metabolites of Streptomyces bacteria account for over half of the antibiotics currently used in the clinic. A crucial part of overcoming antimicrobial resistance (AMR) is in the development of new antibiotics that function with a novel mechanism of action, to avoid the rapid acquisition of microbial resistance. We previously reported the isolation of the new species Streptomyces formicae, from African Tetraponera penzigiplant-ants, shown to have potent activity against several strains on the World Health Organisation’s AMR watch list including MRSA. Genetic analysis of this strain revealed one of its 45 biosynthetic gene clusters, a type 2 polyketide synthase, produced all 13 formicamycins, the natural products responsible for S. formicae’s antimicrobial activity. Several regulators of the formicamycin biosynthetic pathway have been identified, including the major repressor (ForJ). Having purified ForJ, DNA binding assays were performed based on previous cappable-RNA and ChIP sequencing experiments to confirm the interaction of ForJ with different putative promoters in the cluster. By optimising gene-reporter fusion assays in this novel strain, it has been possible to characterise some of the promoters in relation to ForJ to determine the effect of its binding upon activity of the gene cluster. Such work is essential in the progression of novel antimicrobials from the laboratory into a clinic as it must be thoroughly understood how a compound is synthesised and how its biosynthetic pathway is regulated before it can be exploited for overproduction.