Otitiglycomycins A and B: Glycolipids from the Strain Nocardia otitidiscavarum 20S-13 with Antiviral Activity against Zika Virus

The Zika virus (ZIKV), an emerging orthoflavivirus, presents a significant public health threat due to its rapid dissemination and association with severe neurological complications. The urgent need for effective antiviral agents has driven research into novel bioactive compounds derived from unique natural sources. Microorganisms inhabiting extreme environments are particularly promising for such discoveries due to their potential to produce unique metabolites. In this study, we explored microorganisms from the underexplored French Polynesian microbial mats known as "Kopara" to identify new bioactive natural products. Using a molecular networking-based dereplication strategy, we investigated various culture and extraction techniques of the strain Nocardia otitidiscaviarum 20-S13, leading to the discovery of two novel glycoglycerolipids, otitiglycomycins A and B (1 and 2). Structure elucidation of these compounds was achieved through NMR spectroscopy, X-ray crystallography, and TDDFT-specific rotation prediction. We found that otitiglycomycin A (1), but not otitiglycomycin B (2), suppresses ZIKV infection at non cytotoxic concentrations without effects on cell viability. Time-of-drug addition assays along with virus inactivation and binding assays demonstrated that 1 neutralizes ZIKV infectivity by preventing the virus from attaching to the host cell membrane.