Structure-Guided Discovery of Neuroprotective Kromycin-Type Macrolides from Streptomyces narbonensis sp.

Six new kromycin-type macrolides, kromycins B-G (1-6), and with the known kromycin A (7), were isolated from Streptomyces narbonensis sp. CPCC 206470 guided by the Global Natural Products Social Molecular Networking (GNPS) analysis. Their structures were comprehensively established by extensive spectroscopic analyses, time-dependent density functional theory electronic circular dichroism (TDDFT-ECD) comparison, and single-crystal X-ray diffraction analysis. These compounds represent a structurally distinct subclass of 14-membered macrolides. Compound 7 exhibited substantial neuroprotective activity by inhibiting Aβ42 aggregation and ameliorating oxidative stress and neuroinflammation in N2a neuronal cells. It enhanced antioxidant enzyme activities (SOD and CAT) and suppressed nitric oxide production. Genomic analysis identified a pikromycin-related biosynthetic gene cluster in the producing strain. This study expands the chemical diversity of kromycin-type natural products and highlights their potential as multitarget therapeutic agents for neurodegenerative diseases.