Institute of Biosciences and Bioresources, CNR, Via Pietro Castellino 111, 80131 Napoli, Italy.
Proteomics, Metabolomics & Mass Spectrometry Laboratory, Institute for the Animal Production System in the Mediterranean Environment, CNR, P.le Enrico Fermi 1, 80055 Portici (Napoli), Italy.
Int J Mol Sci. 2021 Nov 22;22(22):12601. doi: 10.3390/ijms222212601.
Fungi are exposed to various environmental variables during their life cycle, including changes in CO concentration. CO has the potential to act as an activator of several cell signaling pathways. In fungi, the sensing of CO triggers cell differentiation and the biosynthesis of proteins involved in the metabolism and pathogenicity of these microorganisms. The molecular machineries involved in CO sensing constitute a promising target for the development of antifungals. Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial enzymes in the CO sensing systems of fungi, because they catalyze the reversible hydration of CO to proton and HCO. Bicarbonate in turn boots a cascade of reactions triggering fungal pathogenicity and metabolism. Accordingly, CAs affect microorganism proliferation and may represent a potential therapeutic target against fungal infection. Here, the inhibition of the unique -CA (MpaCA) encoded in the genome of , a fungus with substantial relevance in veterinary and medical sciences, was investigated using a series of conventional CA inhibitors (CAIs), namely aromatic and heterocyclic sulfonamides. This study aimed to describe novel candidates that can kill this harmful fungus by inhibiting their CA, and thus lead to effective anti-dandruff and anti-seborrheic dermatitis agents. In this context, current antifungal compounds, such as the azoles and their derivatives, have been demonstrated to induce the selection of resistant fungal strains and lose therapeutic efficacy, which might be restored by the concomitant use of alternative compounds, such as the fungal CA inhibitors.
真菌在其生命周期中会暴露于各种环境变量中，包括 CO 浓度的变化。CO 有可能作为几种细胞信号通路的激活剂。在真菌中，CO 的感应触发细胞分化，并合成参与这些微生物代谢和致病性的蛋白质。参与 CO 感应的分子机制构成了开发抗真菌药物的有前途的目标。碳酸酐酶（CA，EC 4.2.1.1）是真菌 CO 感应系统中的关键酶，因为它们催化 CO 的可逆水合作用生成质子和 HCO。碳酸氢盐反过来引发一系列反应，触发真菌的致病性和代谢。因此，CA 影响微生物的增殖，可能代表针对真菌感染的潜在治疗靶点。在这里，使用一系列常规 CA 抑制剂（CAI），即芳基和杂环磺酰胺，研究了在兽医和医学科学中具有重要意义的真菌 中基因组编码的独特 -CA（MpaCA）的抑制作用。本研究旨在描述通过抑制其 CA 可以杀死这种有害真菌的新型候选物，从而导致有效的抗头皮屑和抗脂溢性皮炎药物。在这种情况下，目前的抗真菌化合物，如唑类及其衍生物，已被证明会诱导耐药真菌菌株的选择并失去治疗效果，这可能通过同时使用替代化合物（如真菌 CA 抑制剂）来恢复。
