Alberto Deplano
| Selective activation of bacterial carbonic anhydrases as a strategy to modulate the gut microbiota |
| Alberto Deplano1, Davide Moi1, Simone Carradori2, Marialucia Gallorini 2, Andrea Angeli 3, Damiano Iacovozzi 2, Valentina Onnis 1, Clemente Capasso 4, Claudiu Trandafir Supuran 3. 1 Department of Life and Environmental Sciences, University of Cagliari, University Campus, S.P. 8 CA, 09042 Monserrato, Italy 2 Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy 3 NEUROFARBA Department, Sezione di Scienze Farmaceutiche, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy 4 Department of Biology, Agriculture and Food Sciences, National Research Council, Institute of Biosciences & Bioresources, Naples, 80131, Italy |
| Abstract The gut microbiota is a community of microorganisms that live in the digestive tracts of humans and animals [1]. It plays an important role in many physiological functions, including protection against pathogens, digestion, enhancement of the immune system, and the regulation of epithelial cell proliferation and differentiation. The alteration of the microbial composition, known as dysbiosis, can lead to the colonization of resistant pathogens and the overgrowth of opportunistic species and is associated with the development of several diseases. The most commonly employed approach to restore the microbiota is the administration of probiotics, which can inhibit the colonization of pathogenic bacteria, being Bifidobacteria and Lactobacilli the most extensively used. In this context, the development of small molecules capable of modulating the activity of key bacterial enzymes may represent an effective strategy for the treatment of dysbiosis. A promising strategy may involve enhancing their enzymatic activity through the selective activation of carbonic anhydrases in these probiotic strains. This hypothesis remains largely unexplored due to the limited scientific literature currently available in this field. In contrast, while structure-activity relationships for the development of carbonic anhydrase inhibitors have been extensively studied and are well established, the selective activation of these enzymes remains considerably more challenging and significantly less explored [2]. Herein we describe the design, synthesis, and evaluation of a novel class of bacterial carbonic anhydrase activators based on biogenic amines, amino acids, and short peptides, all of which are established carbonic anhydrase activators. The synthesized compounds were found to activate bacterial carbonic anhydrases with Ka values in the low micromolar range. Importantly, they showed no detectable activity against human carbonic anhydrases, indicating a high degree of selectivity. The most promising derivatives were selected for further biological evaluation. |
| References [1] Quigley, E. M., Gut bacteria in health and disease. Gastroenterol Hepatol (N Y) 2013, 9, 560-9, [2] Bonardi, A.; Carradori, S.; Paoletti, N.; Angeli, A.; Ferraroni, M.; Iacovozzi, D.; Gallorini, M.; D’Agostino, I.; De Luca, V.; Gratteri, P.; Cataldi, A.; Supuran, C. T.; Capasso, C., Production, crystallographic studies, and functional profiling of gamma-carbonic anhydrase from the probiotic Limosilactobacillus reuteri: In vitro and cell-based insights. Eur J Med Chem 2026, 302, 118291, 10.1016/j.ejmech.2025.118291. |