Section of Pharmaceutical and Nutraceutical Sciences, Department of Neurofarba, University of Florence, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy.
Institute of Biosciences and Bioresources, CNR, Via Pietro Castellino 111, 80131 Napoli, Italy.
Int J Mol Sci. 2021 Apr 21;22(9):4324. doi: 10.3390/ijms22094324.
Carbon dioxide (CO), a vital molecule of the carbon cycle, is a critical component in living organisms' metabolism, performing functions that lead to the building of compounds fundamental for the life cycle. In all living organisms, the CO/bicarbonate (HCO) balancing is governed by a superfamily of enzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1). CAs catalyze the pivotal physiological reaction, consisting of the reversible hydration of the CO to HCO and protons. Opportunistic and pathogenic fungi can sense the environmental CO levels, which influence their virulence or environmental subsistence traits. The fungal CO-sensing is directly stimulated by HCO produced in a CA-dependent manner, which directly activates adenylyl cyclase (AC) involved in the fungal spore formation. The interference with CA activity may impair fungal growth and virulence, making this approach interesting for designing antifungal drugs with a novel mechanism of action: the inhibition of CAs linked to the CO/HCO/pH chemosensing and signaling. This review reports that sulfonamides and their bioisosteres as well as inorganic anions can inhibit in vitro the β- and α-CAs from the fungi, suggesting how CAs may be considered as a novel "pathogen protein" target of many opportunistic, pathogenic fungi.
二氧化碳（CO）是碳循环中的重要分子，也是生物代谢的关键组成部分，其功能导致了对生命周期至关重要的化合物的形成。在所有生物中，CO/碳酸氢盐（HCO）的平衡受碳酸酐酶（CA，EC 4.2.1.1）家族的超家族调控。CA 催化关键的生理反应，包括 CO 的可逆水合作用生成 HCO 和质子。机会性和致病性真菌可以感知环境中的 CO 水平，这些水平会影响它们的毒力或环境生存特征。真菌的 CO 感应直接受到 CA 依赖性产生的 HCO 的刺激，这直接激活了参与真菌孢子形成的腺苷酸环化酶（AC）。干扰 CA 活性可能会损害真菌的生长和毒力，这使得这种方法对于设计具有新型作用机制的抗真菌药物很有意义：抑制与 CO/HCO/pH 化学感应和信号转导相关的 CA。本综述报告称，磺胺类药物及其生物等排体以及无机阴离子可以体外抑制真菌的β-和α-CA，这表明 CA 可能被视为许多机会性、致病性真菌的新型“病原体蛋白”靶标。
