The bacterial redox signaller pyocyanin as an antiplasmodial agent: comparisons with its thioanalog methylene blue
The bacterial redox signaller pyocyanin as an antiplasmodial agent: comparisons with its thioanalog methylene blue
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DOI：
10.1179/174329211x13049558293678
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发表时间：
2011-07-01
期刊：
影响因子：
3.8
通讯作者：
Becker, Katja
中科院分区：
文献类型：
--
作者：
Kasozi, D. M.;Gromer, S.;Becker, Katja
绿脓菌素（PYO）是铜绿假单胞菌（Pseudomonasaeruginosa）感染的一种重要的群体感应分子和信号分子。与吩噻嗪类药物的比较表明，抗疟化合物亚甲蓝（MB）可被视为PYO的硫类似物。这一工作假设将解释为什么合成药物MB表现为生物进化中形成的化合物。在这里，我们报告氧化还原相关的生物和生化特性的PYO直接比较其合成类似物MB。我们定量描述了这两种化合物对细胞还原剂的反应性，其还原的无色形式对O（2）的反应性，以及它们与含FAD的二硫键还原酶的相互作用。此外，PYO与人谷胱甘肽还原酶的相互作用进行了研究，通过X-射线晶体学的结构细节，显示一个单一的PYO分子结合到酶的亚基间腔。与MB一样，还发现PYO在体外对恶性疟原虫的血液寄生虫具有活性。此外，这两种化合物对疾病传播配子体形式的寄生虫，这是系统地在体外研究。如对小鼠所示，PYO毒性太大，不能用作药物。然而，它可能在许多伴有假单胞菌感染的人类患者中具有抗疟活性。与PYO相比，MB耐受性良好，是一种基于MB的抗疟疾联合疗法的有前景的药物。当前和未来的临床研究可以通过本文报告的MB和PYO之间的比较来指导。此外，研究囊性纤维化或严重伤口感染患者的疟疾保护是否以及在多大程度上是基于假单胞菌属产生的PYO是有意义的。
The quorum sensor and signalling molecule pyocyanin (PYO) contributes significantly to the pathophysiology of Pseudomonas aeruginosa infections. Comparison to phenothiazine drugs suggests that the antimalarial compound methylene blue (MB) can be regarded as a sulfur analog of PYO. This working hypothesis would explain why the synthetic drug MB behaves as a compound shaped in biological evolution. Here we report on redox-associated biological and biochemical properties of PYO in direct comparison to its synthetic analog MB. We quantitatively describe the reactivity of both compounds toward cellular reductants, the reactivity of their reduced leuco-forms towards O(2), and their interactions with FAD-containing disulfide reductases. Furthermore, the interaction of PYO with human glutathione reductase was studied in structural detail by x-ray crystallography, showing that a single PYO molecule binds to the intersubunit cavity of the enzyme. Like MB, also PYO was also found to be active against blood schizonts of the malaria parasite P. falciparum in vitro. Furthermore, both compounds were active against the disease transmitting gametocyte forms of the parasites, which was systematically studied in vitro. As shown for mice, PYO is too toxic to be used as a drug. It may, however, have antimalarial activity in numerous human patients with concomitant Pseudomonas infections. MB, in contrast to PYO, is well tolerated and represents a promising agent for MB-based combination therapies against malaria. Current and future clinical studies can be guided by the comparisons between MB and PYO reported here. Additionally, it is of interest to study if and to what extent the protection from malaria in patients with cystic fibrosis or with severe wound infections is based on PYO produced by Pseudomonas species.