Gausemycin Antibiotic Family Acts via Ca2+-Dependent Membrane Targeting

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2024-04, Vol.87 (4), p.664-674
• Main Authors: Kravchenko, Tatyana V., Paramonov, Alexander S., Kudzhaev, Arsen M., Efimova, Svetlana S., Khorev, Alexey S., Kudryakova, Gulnara Kh, Ivanov, Igor A., Chistov, Alexey A., Baranova, Anna A., Krasilnikov, Maxim S., Lapchinskaya, Olda A., Tyurin, Anton P., Ostroumova, Olga S., Smirnov, Ivan V., Terekhov, Stanislav S., Dontsova, Olga A., Shenkarev, Zakhar O., Alferova, Vera A., Korshun, Vladimir A.
• Format: Article
• Language: English
• Subjects: antimicrobial properties; calcium; daptomycin; lipid bilayers; lipid composition; mechanism of action; micelles; phosphates; zwitterions
• ISSN: 0163-3864; 1520-6025; 1520-6025
• DOI: 10.1021/acs.jnatprod.3c00612

We report the molecular mechanism of action of gausemycins and the isolation of new members of the family, gausemycins C (1c), D (1d), E (1e), and F (1f), the minor components of the mixture. To elucidate the mechanism of action of gausemycins, we investigated the antimicrobial activity of the most active compounds, gausemycins A and B, in the presence of Ca2+, other metal ions, and phosphate. Gausemycins require a significantly higher Ca2+ concentration for maximum activity than daptomycin but lower than that required for malacidine and cadasides. Species-specific antimicrobial activity was found upon testing against a wide panel of Gram-positive bacteria. Membranoactivity of gausemycins was demonstrated upon their interactions with model lipid bilayers and micelles. The pore-forming ability was found to be dramatically dependent on the Ca2+ concentration and the membrane lipid composition. An NMR study of gausemycin B in zwitterionic and anionic micelles suggested the putative structure of the gausemycin/membrane complex and revealed the binding of Ca2+ by the macrocyclic domain of the antibiotic.