In Vitro and In Vivo Assessment of the Efficacy of Bromoageliferin, an Alkaloid Isolated from the Sponge Agelas dilatata, against Pseudomonas aeruginosa

[Abstract] The pyrrole-imidazoles, a group of alkaloids commonly found in marine sponges belonging to the genus Agelas, display a wide range of biological activities. Herein, we report the first chemical study of the secondary metabolites of the sponge A. dilatata from the coastal area of the Yucatan Peninsula (Mexico). In this study, we isolated eight known alkaloids from an organic extract of the sponge. We used NMR and MS analysis and comparison with existing databases to characterize the alkaloids: ageliferin (1), bromoageliferin (2), dibromoageliferin (3), sceptrin (4), nakamuric acid (5), 4-bromo-1H-pyrrole-2-carboxylic acid (6), 4,5-dibromopyrrole-2-carboxylic acid (7) and 3,7-dimethylisoguanine (8). We also evaluated, for the first time, the activity of these alkaloids against the most problematic multidrug-resistant (MDR) pathogens, i.e., the Gram-negative bacteria Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii. Bromoageliferin (2) displayed significant activity against P. aeruginosa. Comparison of the antibacterial activity of ageliferins 1–3 (of similar structure) against P. aeruginosa revealed some relationship between structure and activity. Furthermore, in in vitro assays, 2 inhibited growth and biofilm production in clinical strains of P. aeruginosa. Moreover, 2 increased the survival time in an in vivo Galleria mellonella model of infection. The findings confirm bromoageliferin (2) as a potential lead for designing new antibacterial drugs.This work was supported by Grants RTI2018-093634-B-C22 (AEI/FEDER, EU) from the State Agency for Research (AEI) of Spain, both co-funded by the FEDER Programme from the European Union and BLUEBIOLAB (0474_BLUEBIOLAB_1_E), Programme INTERREG V A of Spain-Portugal (POCTEP). The study was also funded by projects GRC2018/039 and Agrupación Estratégica CICA-INIBIC ED431E 2018/03 (Consellería de Educación, Universidades e Formación Profesional) from the Xunta de Galicia (autonomous government of the region). This work was also funded by Projects PI17/01482 awarded to AB and PI15/00860 to GB, all within in the National Plan for Scientific Research, Development and Technological Innovation 2013-2016 and funded by the ISCIII-General Subdirection of Assessment and Promotion of the Research-European Regional Development Fund (FEDER) “A way of making Europe” and operative program Intelligent Growth 2014-2020. The study was also funded by project IN607A 2016/22 (GAIN- Agencia Gallega de Innovación - Consellería de Economía, Emprego e Industria) awarded to GB. D.P.-P. received a fellowship from the program National Council of Science and Technology (CONACYT) of Mexico and the Secretariat of Research, Innovation and Higher Education (SIIES) of Yucatan. Mexico and the Secretariat of Research, Innovation and Higher Education (SIIES) of Yucatan. JCVU was financially supported by the pFIS Program (FI18/00315), MMG by a Clara Roy grant (SEIMC) and CLM by IN606A-2019/029Xunta de Galicia; GRC2018/039Xunta de Galicia; ED431E 2018/03Xunta de Galicia; IN607A 2016/22Xunta de Galicia; IN606A-2019/02