The Reducing Milieu of Parasitized Cells as a Target of Antimalarial Agents: Methylene Blue as an Ethical Drug

Meißner, Peter; Adler, Heike; Kasozi, Denis M; Fritz‐Wolf, Karin; Schirmer, R. Heiner

doi:10.1002/9783527633883.ch7

Cited by 1 publication

(1 citation statement)

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“…It has been intensely studied and its numerous favorable properties have been described, including the differential staining of cell biological structures and protein crystals, its medicinal applications, and its unique physicochemical and photochemical characteristics. [17][18][19][20][21] Like PYO, MB exhibits a remarkable reactivity toward cellular reductants and interacts with signaling proteins, flavoenzymes, haem proteins, or transmembrane transporters. 19,20 Thus, MB behaves almost as a molecule shaped in biological evolution and indeed it has striking structural and functional similarities with PYO ( Fig.…”

Section: Introductionmentioning

confidence: 99%

The bacterial redox signaller pyocyanin as an antiplasmodial agent: comparisons with its thioanalog methylene blue

Kasozi¹,

Gromer²,

Adler³

et al. 2011

Redox Report

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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 O2, 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.

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