Institute of Biosciences and Bioresources, CNR, via Pietro Castellino 111, 80131 Napoli, Italy.
Proteomics & Mass Spectrometry Laboratory, ISPAAM, CNR, via Argine 1085, 80147 Napoli, Italy.
Int J Mol Sci. 2021 Jan 8;22(2):571. doi: 10.3390/ijms22020571.
Carbonic anhydrases (CAs) are essential metalloenzymes in nature, catalyzing the carbon dioxide reversible hydration into bicarbonate and proton. In humans, breathing and many other critical physiological processes depend on this enzymatic activity. The CA superfamily function and inhibition in pathogenic bacteria has recently been the object of significant advances, being demonstrated to affect microbial survival/virulence. Targeting bacterial CAs may thus be a valid alternative to expand the pharmacological arsenal against the emergence of widespread antibiotic resistance. Here, we report an extensive study on the inhibition profile of the recently discovered ι-CA class present in some bacteria, including , namely BteCAι, using substituted benzene-sulfonamides and clinically licensed sulfonamide-, sulfamate- and sulfamide-type drugs. The BteCAι inhibition profile showed: (i) several benzene-sulfonamides with an inhibition constant lower than 100 nM; (ii) a different behavior with respect to other α, β and γ-CAs; (iii) clinically used drugs having a micromolar affinity. This prototype study contributes to the initial recognition of compounds which efficiently and selectively inhibit a bacterial member of the ι-CA class, for which such a selective inhibition with respect to other protein isoforms present in the host is highly desired and may contribute to the development of novel antimicrobials.
碳酸酐酶（CA）是自然界中必需的金属酶，催化二氧化碳可逆水合为碳酸氢根和质子。在人类中，呼吸和许多其他关键生理过程都依赖于这种酶活性。CA 超家族在致病细菌中的功能和抑制作用最近取得了重大进展，证明其会影响微生物的存活/毒力。因此，靶向细菌 CA 可能是扩大对抗广泛抗生素耐药性出现的药物库的有效替代方法。在这里，我们报告了对最近在一些细菌中发现的 ι-CA 类的抑制特性进行的广泛研究，包括 ，即 BteCAι，使用取代的苯磺酰胺和临床许可的磺酰胺、磺酸盐和磺酰胺类药物。BteCAι 的抑制特性显示：（i）几种苯磺酰胺的抑制常数低于 100 nM；（ii）与其他 α、β 和 γ-CAs 不同的行为；（iii）具有微摩尔亲和力的临床使用药物。该原型研究有助于初步识别能够有效和选择性抑制 ι-CA 类细菌成员的化合物，对于宿主中存在的其他蛋白质同工型，这种选择性抑制是高度需要的，并且可能有助于开发新的抗菌药物。
