Development of Corramycin as an antibiotic against Gram-negative bacteria

Corramycin is a linear peptide with a distinct structure, isolated from the myxobacterium Corallococcus coralloides spp., and features novel amino acids like methylated β-hydroxy-D-histidine. This compound exhibits strong antibacterial activity (in the low µM range) against Gram-negative pathogens of the Enterobacteriaceae family, including clinically relevant strains of multidrug resistant E. coli. Recently, we also discovered that it shows promising efficacy against Mycobacterium tuberculosis (Mtb), with sub- to low-µM activity. The unique structure of corramycin, along with its lack of cross-resistance, points to a novel mechanism of action. Although the precise molecular target remains unclear, extensive resistance studies have shown an induction of the SOS response, suggesting an inhibition of DNA synthesis. Furthermore, there is evidence that bacterial gyrase may be involved in its mechanism of action. To confirm the target and assess binding interactions, techniques such as target fishing and biophysical assays will be employed, and specific chemical tools for this purpose are currently being synthesized.

Due to the difficulty of producing corramycin through fermentation or heterologous expression, a complete synthetic route has been optimized. The C-terminal pentapeptide is synthesized using solid-phase peptide synthesis, supported by the Fmoc strategy. The N-terminal pharmacophore, highly functionalized, is created using stereoselective synthetic methods for the non-proteinogenic component and sequential peptide coupling in solution. The final natural product is formed by chemically ligating the two synthetic fragments and performing global deprotection. Moving forward, the aim is to modify the pharmacophore through total synthesis and medicinal-chemistry optimization to create more potent derivatives with enhanced pharmacokinetics, increased activity against Gram-negative and Mtb. These derivatives will then undergo evaluations for antibacterial activity, ADMET profiling, in vivo PK/PD studies, and toxicity testing.