Rzhepishevska Olena, Hakobyan Shoghik, Ekstrand-Hammarström Barbro, Nygren Yvonne, Karlsson Torbjörn, Bucht Anders, Elofsson Mikael, Boily Jean-François, Ramstedt Madeleine
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
J Inorg Biochem. 2014 Sep;138:1-8. doi: 10.1016/j.jinorgbio.2014.04.009. Epub 2014 Apr 23.
Bacterial biofilms cause a range of problems in many areas and especially in health care. Biofilms are difficult to eradicate with traditional antibiotics and consequently there is a need for alternative ways to prevent and/or remove bacterial biofilms. Furthermore, the emergence of antibiotic resistance in bacteria creates a challenge to find new types of antibiotics with a lower evolutionary pressure for resistance development. One route to develop such drugs is to target the so called virulence factors, i.e. bacterial systems used when bacteria infect a host cell. This study investigates synergy effects between Ga(III) ions, previously reported to suppress biofilm formation and growth in bacteria, and salicylidene acylhydrazides (hydrazones) that have been proposed as antivirulence drugs targeting the type three secretion system used by several Gram-negative pathogens, including Pseudomonas aerugionosa, during bacterial infection of host cells. A library of hydrazones was screened for: Fe(III) binding, enhanced anti-biofilm effect with Ga(III) on P. aeruginosa, and low cytotoxicity to mammalian cells. The metal coordination for the most promising ligand, 2-Oxo-2-[N-(2,4,6-trihydroxy-benzylidene)-hydrazino]-acetamide (ME0163) with Ga(III) was investigated using extended X-ray absorption fine structure spectroscopy as well as density functional theory. The results showed that Ga(III) chelates the hydrazone with 5- and 6-membered chelating rings, and that the Ga(III)-ME0163 complex enhanced the antibiofilm effect of Ga(III) while suppressing the type three secretion system in P. aeruginosa. The latter effect was not observed for the hydrazone alone and was similar for Ga(III)-citrate and Ga(III)-ME0163 complexes, indicating that the inhibition of virulence was caused by Ga(III).
细菌生物膜在许多领域尤其是医疗保健领域引发了一系列问题。生物膜难以用传统抗生素根除，因此需要有替代方法来预防和/或去除细菌生物膜。此外，细菌中抗生素耐药性的出现对寻找新型抗生素构成了挑战，这类新型抗生素产生耐药性进化压力较低。开发此类药物的一条途径是靶向所谓的毒力因子，即细菌感染宿主细胞时所使用的细菌系统。本研究调查了先前报道可抑制细菌生物膜形成和生长的Ga(III)离子与水杨醛酰肼（腙）之间的协同效应，水杨醛酰肼已被提议作为抗毒力药物，靶向包括铜绿假单胞菌在内的几种革兰氏阴性病原体在宿主细胞细菌感染期间所使用的三型分泌系统。对一系列腙进行了筛选，以检测其对Fe(III)的结合能力、与Ga(III)共同作用对铜绿假单胞菌增强的抗生物膜效果以及对哺乳动物细胞的低细胞毒性。使用扩展X射线吸收精细结构光谱以及密度泛函理论研究了最有前景的配体2-氧代-2-[N-(2,4,6-三羟基苄叉基)-肼基]-乙酰胺（ME0163）与Ga(III)的金属配位情况。结果表明，Ga(III)与腙形成了五元环和六元环螯合环，并且Ga(III)-ME0163复合物增强了Ga(III)的抗生物膜效果，同时抑制了铜绿假单胞菌的三型分泌系统。单独的腙未观察到后一种效果，并且Ga(III)-柠檬酸盐和Ga(III)-ME0163复合物的情况相似，这表明毒力的抑制是由Ga(III)引起的。
