Over the past decade, thiazines, thiadiazoles, and thiohydrazides have attracted increasing attention due to their sedative, antimicrobial, antiviral, antifungal, and antitumor activities. The clinical efficacy of such drugs, as well as the possibility of developing resistance to antimicrobials, will depend on addressing a number of fundamental problems, including the role of membrane lipids during their interaction with plasma membranes. The effects of the eight 1,3- thiazine-, 1,2,3,4- dithiadiazole-, and thiohydrazide-related compounds on the physical properties of model lipid membranes and the effects on reconstituted ion channels induced by the polyene macrolide antimycotic nystatin and antifungal cyclic lipopeptides syringomycin E and fengycin were observed. We found that among the tested agents, the fluorine-containing compound N′-(3,5-difluorophenyl)-benzenecarbothiohydrazide (C6) was the most effective at increasing the electric barrier for anion permeation into the hydrophobic region of the membrane and reducing the conductance of anion-permeable syringomycin pores. A decrease in the membrane boundary potential with C6 adsorption also facilitated the immersion of positively charged syringomycin molecules into the lipid bilayer and increases the pore-forming ability of the lipopeptide. Using differential scanning microcalorimetry, we showed that C6 led to disordering of membrane lipids, possibly by potentiating positive curvature stress. Therefore, we used C6 as an agonist of antifungals forming the pores that are sensitive to membrane curvature stress and lipid packing, i.e., nystatin and fengycin. The dramatic increase in transmembrane current induced by syringomycin E, nystatin, and fengycin upon C6 treatment suggests its potential in combination therapy for treating invasive fungal infections.

在过去的十年中，噻嗪，噻二唑和硫代肼由于其镇静，抗微生物，抗病毒，抗真菌和抗肿瘤活性而受到越来越多的关注。这类药物的临床疗效以及对抗菌素产生耐药性的可能性，将取决于解决许多基本问题，包括膜脂质在与质膜相互作用期间的作用。八种1,3-噻嗪，1,2,3,4-二噻二唑和硫酰肼相关化合物对模型脂质膜物理特性的影响以及对多烯大环内酯类抗霉菌素抑制素诱导的重构离子通道的影响观察到抗真菌环状脂肽丁香霉素E和丰霉素。我们发现在测试的试剂中，含氟化合物ñ'-（3,5-二氟苯基）-苯碳硫酰肼（C6）在增加阴离子渗透进入膜的疏水区域的电势垒并降低阴离子可渗透性丁香霉素孔的电导率方面最有效。C6吸附引起的膜边界电位的降低也促进了带正电荷的丁香霉素分子浸入脂质双层并增加了脂肽的成孔能力。使用差示扫描量热法，我们显示C6可能通过增强正曲率应力导致膜脂紊乱。因此，我们使用C6作为抗真菌剂的激动剂，形成对膜曲率应力和脂质堆积敏感的孔，即制霉菌素和丰霉素。