Abstract:
P. aeruginosa ranks among the top five organisms causing nosocomial infections. Among the many novel strategies for developing new therapeutics against infection, targeting iron uptake mechanism seems promising as P. aeruginosa needs iron for its growth and survival. To scavenge iron, the bacterium produces siderophores possessing a very high affinity towards Fe(III) ions such as pyoverdines. In this work, we decided to study two pyoverdine analogs, aPvd2 and aPvd3, structurally close to the endogen pyoverdine. The pFe constants calculated with the values of formation showed a high affinity of aPvd3 towards Fe(III). Molecular dynamics calculations demonstrated that aPvd3-Fe forms with Fe(III) stable 1:1 complexes in water, whereas aPvd2 does not. Only aPvd3 is able to increase the bacterial growth and represents thus an alternative to pyoverdine for iron acquisition by the bacterium. The aPvd2-3 interaction studies with a lipid membrane indicated that they were unable to interact and to cross the plasma membrane of bacteria by passive diffusion. Consequently, the penetration of aPvd3 is ruled by a transport membrane protein. These results showed that aPvd3 may be used to inhibit pyoverdine uptake or to promote the accumulation and release of antibiotics into the cell following a Trojan horse strategy.
摘要:
铜绿假单胞菌是引起医院感染的前五名生物之一。在开发抗感染新疗法的许多新策略中,靶向铁摄取机制似乎很有希望,因为铜绿假单胞菌需要铁来维持其生长和生存。为了清除铁,该细菌产生对Fe(III)离子具有非常高亲和力的铁载体,例如pyoverdine。在这项工作中,我们决定研究两种Pyoverdine类似物,aPvd2和aPvd3,在结构上接近内生素pyoverdine。用形成值计算的pFe常数显示aPvd3对Fe(III)的高亲和力。分子动力学计算表明,aPvd3-Fe与Fe(III)在水中形成稳定的1:1配合物,而aPvd2没有。只有aPvd3能够增加细菌生长,因此代表了pyoverdine的替代品,用于细菌获取铁。aPvd2-3与脂质膜的相互作用研究表明,它们无法通过被动扩散相互作用并穿过细菌的质膜。因此,aPvd3的渗透受转运膜蛋白支配。这些结果表明,aPvd3可用于抑制pyoverdine的摄取或促进特洛伊木马策略后抗生素向细胞中的积累和释放。