Microbiological profiling and mode of action studies of polyketomycin

Multi-drug resistant bacteria are becoming increasingly common, emphasizing the urgent need for new antimicrobially active compounds. The discovery and investigation of natural products as antibacterial agents is a promising approach towards identifying new substances and new modes of action (MoA). Because of their chemical diversity and potency, natural products form a great resource for discovering new bacterial targets and mechanisms to treat even multi‑resistant pathogens. Polyketomycin is an antibacterial tetracyclic quinone glycoside produced by Streptomyces diastatochromogenes Tü 6028 (Paululat et al., 1999) whose MoA is unknown. In production screening to find a reliable cultivation medium, we could detect polyketomycin in various settings and purify it, as confirmed by HPLC-MS. In addition, we improved a previously reported purification procedure (Paululat et al., 1999). Microbiological and cytotoxic profiling confirmed strong activity against a broad range of Gram-positive bacteria while eukaryotic cell lines were somewhat less susceptible. Moreover, we could show that polyketomycin is bactericidal and remarkably fast-acting. Exploring the mechanism further, we discovered that it apparently affects the cell envelope of Gram-positive bacteria in a concentration-dependent manner, causing pore formation and lysis at high concentrations and cell wall impairment already at low concentrations. Detailed mode of action studies are in progress to clarify the effects on the molecular level.

References:

Paululat, T., Zeeck, A., Gutterer, J. M., & Fiedler, H. P. (1999). Biosynthesis of polyketomycin produced by Streptomyces diastatochromogenes Tü 6028. The Journal of antibiotics, 52(2), 96–101. https://doi.org/10.7164/antibiotics.52.96