Redox control of antibiotic biosynthesis

Streptomyces bacteria make diverse specialized metabolites that form the basis of ~55% of clinically used antibiotics. Despite this, only 3% of their encoded specialized metabolites have been matched to molecules, and understanding how their biosynthesis is controlled is essential to fully exploit their potential. Here, we use Streptomyces formicae and the formicamycin biosynthetic pathway as a model to understand the complex regulation of specialized metabolism. We analyzed all three pathway-specific regulators and found that biosynthesis is subject to negative feedback and redox control via two MarR-family proteins, while activation of the pathway is dependent on a cytoplasmic two-component system. Like many Streptomyces antibiotics, formicamycins are only produced in solid culture, and biosynthesis is switched off in aerated liquid cultures. Here, we demonstrate that a redox-sensitive repressor named ForJ senses oxygen via a single cysteine residue that is required to repress formicamycin biosynthesis in liquid cultures.IMPORTANCEAntimicrobial resistance presents a significant threat to human health. Streptomyces bacteria are a promising source of novel antimicrobials; however, encouraging production of these molecules under laboratory conditions remains a challenge because we have limited understanding of the signals that control their production. Here, we use the formicamycin producer, Streptomyces formicae, as a model to further understand how antibiotic production is regulated in response to various signals. We show that three regulatory elements work together to coordinate formicamycin biosynthesis in response to intracellular signals, redox stress, and formicamycin accumulation. We also show that by making the regulators "blind" to these signals, we can induce high-level production of formicamycins in industrially relevant conditions, which facilitates their development as new antimicrobials.