Metacycloprodigiosin produced by a high-yield Streptomyces spectabilis restores colistin susceptibility in resistant...

The prodiginine family constitutes a distinctive class of tripyrrolic natural products notable for their red pigmentation and diverse bioactivities. While the biological activities of the linear prodiginine prodigiosin have been extensively studied, cyclic prodiginines remain comparatively underexplored despite structural features that may confer distinct membrane-perturbing properties and enhanced antibacterial activity. Here, a high-producing colony variant of Streptomyces spectabilis (ISP-5512) is described that yields the cyclic prodiginine metacycloprodigiosin at up to 300 mg L^-1 isolated yield, representing the highest reported production to date. This high-yield production enabled a comprehensive biological evaluation of metacycloprodigiosin against a diverse panel of colistin-resistant Gram-negative (CRGN) pathogens as a colistin adjuvant, and demonstrates that 5 µM metacycloprodigiosin reduces the colistin minimum inhibitory concentration (MIC) up to 32 768-fold across A. baumannii, K. pneumoniae, P. aeruginosa, and E. coli isolates harboring both chromosomal and plasmid-mediated (mcr-1) resistance. Initial investigation into the adjuvant action of metacycloprodigiosin reveals that an increase in reactive oxygen species (ROS) could underpin evident colistin potentiation activity in CRGN A. baumannii. These findings establish metacycloprodigiosin as a potent colistin adjuvant, highlight the potential of cyclic prodiginines for combating antimicrobial resistance, and provide insight into structure-activity relationships governing membrane-active antibiotic adjuvants.