Discovery of elfamycin-class inhibitors combating carbapenem-resistant Acinetobacter baumannii from the Antarctic-derived Streptomyces sp. A3-7

Abstract

Carbapenem-resistant Acinetobacter baumannii (CRAB) poses a critical global health threat. An activity-guided screen of eight Antarctic Streptomyces strains identified the active isolate Streptomyces sp. A3-7, from which four new elfamycin-class polyketides (1–4) and one known analogue (5) were obtained. The structures of these compounds were elucidated through extensive MS and NMR spectroscopic analysis, and their biosynthesis is directed by the krn gene cluster. Anti-CRAB evaluation revealed that 5 was the most potent, with an MIC of 0.4 μg/mL, whereas 1 was inactive up to 50 μg/mL, indicating that the tetrahydrofuran ring in the kirromycin-type scaffold (1) significantly reduces anti-A. baumannii activity, whereas the linear “open” ethylene glycol scaffold of the kirrothricin-type analogues (2–5) provides a more effective antibacterial framework. A gradual decrease in potency was observed for 2–4 (MICs 1.6–12.5 μg/mL), suggesting the pyridone ring is a key functional group for activity within the kirrothricin series. Notably, all compounds demonstrated low cytotoxicity toward normal hepatocytes AC2F (CC₅₀ > 20 μM). This promising safety profile, combined with their potent activity, highlights the potential of kirrothricin-type compounds as promising drug candidates for combating CRAB.