Straniero Valentina, Sebastián-Pérez Victor, Suigo Lorenzo, Margolin William, Casiraghi Andrea, Hrast Martina, Zanotto Carlo, Zdovc Irena, Radaelli Antonia, Valoti Ermanno
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Luigi Mangiagalli, 25, 20133 Milano, Italy.
Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain.
Antibiotics (Basel). 2021 Apr 15;10(4):442. doi: 10.3390/antibiotics10040442.
Multidrug resistant is a severe threat, responsible for most of the nosocomial infections globally. This resistant strain is associated with a 64% increase in death compared to the antibiotic-susceptible strain. The prokaryotic protein FtsZ and the cell division cycle have been validated as potential targets to exploit in the general battle against antibiotic resistance. Despite the discovery and development of several anti-FtsZ compounds, no FtsZ inhibitors are currently used in therapy. This work further develops benzodioxane-benzamide FtsZ inhibitors. We seek to find more potent compounds using computational studies, with encouraging predicted drug-like profiles. We report the synthesis and the characterization of novel promising derivatives that exhibit very low MICs towards both methicillin-susceptible and -resistant , as well as another Gram positive species, while possessing good predicted physical-chemical properties in terms of solubility, permeability, and chemical and physical stability. In addition, we demonstrate by fluorescence microscopy that Z ring formation and FtsZ localization are strongly perturbed by our derivatives, thus validating the target.
多重耐药是一个严重威胁，导致了全球大多数医院感染。与抗生素敏感菌株相比，这种耐药菌株的死亡风险增加了64%。原核生物蛋白FtsZ和细胞分裂周期已被确认为在对抗抗生素耐药性的总体战斗中可利用的潜在靶点。尽管已经发现并开发了几种抗FtsZ化合物，但目前尚无FtsZ抑制剂用于治疗。这项工作进一步开发了苯并二恶烷-苯甲酰胺类FtsZ抑制剂。我们试图通过计算研究找到更有效的化合物，其预测的类药性质令人鼓舞。我们报告了新型有前景衍生物的合成与表征，这些衍生物对甲氧西林敏感和耐药菌株以及另一种革兰氏阳性菌表现出极低的最低抑菌浓度（MIC），同时在溶解度、渗透性以及化学和物理稳定性方面具有良好的预测物理化学性质。此外，我们通过荧光显微镜证明，我们的衍生物强烈干扰了Z环形成和FtsZ定位，从而验证了该靶点。
