Enhancement of Heme-Induced Membrane Damage by the Anti-malarial Clotrimazole: the Role of Colloid-Osmotic Forces

Huy, Nguyen Tien; Takano, Ryo; Hara, Saburo; Kamei, Kaeko

doi:10.1248/bpb.27.361

Cited by 22 publications

(7 citation statements)

References 35 publications

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“…We recently demonstrated that CQ and antifungal azoles, which have antimalarial activities, possess abilities for binding heme and enhancing the toxicity of heme (19,20,23). Here, to explore the effect of BPQ on heme-induced membrane destabilization, hemolytic experiments were performed using fresh erythrocytes as described in Materials and Methods.…”

Section: Resultsmentioning

confidence: 99%

2- tert -Butyl-8-Quinolinamines Exhibit Potent Blood Schizontocidal Antimalarial Activity via Inhibition of Heme Crystallization

Huy

Mizunuma

Kaur

et al. 2007

Antimicrob Agents Chemother

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We have recently reported that the attachment of a bulky metabolically stable tert-butyl group at the C-2 position of a quinoline ring in primaquine results in a tremendous improvement in the blood schizontocidal antimalarial activity of 8-quinolinamine. Because free heme released from hemoglobin catabolism in a malarial parasite is highly toxic, the parasite protects itself mainly by crystallization of heme into insoluble nontoxic hemozoin. We now demonstrate the ability of 2-tert-butylprimaquine to inhibit in vitro beta-hematin formation, to form a complex with heme with a stoichiometry of 1:1, and to enhance heme-induced hemolysis. The results described herein indicate that a major improvement in the blood-schizontocidal antimalarial activity of 2-tert-butylprimaquine might be due to a disturbance of heme catabolism pathway in the malarial parasite.

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Section: Resultsmentioning

confidence: 99%

2- tert -Butyl-8-Quinolinamines Exhibit Potent Blood Schizontocidal Antimalarial Activity via Inhibition of Heme Crystallization

Huy

Mizunuma

Kaur

et al. 2007

Antimicrob Agents Chemother

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“…In addition, it is of interest that clotrimazole has been shown to be clinically useful for treating other diseases, such as sickle cell anemia, malaria, beriberi, tinea pedis, Chagas disease, and cancer [50]. Clotrimazole acts as an anti-malarial agent by causing heme-induced membrane damage in the malaria parasite [51]. As a well-known antifungal agent, clotrimazole works by altering the permeability and fluidity of the fungal cell membrane through inhibition of ergosterol synthesis, with ergosterol depleted and replaced with unusual sterols [52].…”

Section: Discussionmentioning

confidence: 99%

Identification of FDA-Approved Drugs with Activity against Stationary Phase Bartonella henselae

Feng

Xiao

et al. 2019

Antibiotics

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Bartonella henselae can cause various infections in humans, ranging from benign and self-limiting diseases to severe and life-threatening diseases as well as persistent infections that are difficult to treat. To develop more effective treatments for persistent Bartonella infections, in this study, we performed a high-throughput screen of an FDA-approved drug library against stationary phase B. henselae using the SYBR Green I/propidium iodide (PI) viability assay. We identified 110 drug candidates that had better activity against stationary phase B. henselae than ciprofloxacin, and among the top 52 drug candidates tested, 41 drugs were confirmed by microscopy to have higher activity than the current frontline antibiotic erythromycin. The identified top drug candidates include pyrvinium pamoate, daptomycin, methylene blue, azole drugs (clotrimazole, miconazole, sulconazole, econazole, oxiconazole, butoconazole, bifonazole), aminoglycosides (gentamicin and streptomycin, amikacin, kanamycin), amifostine (Ethyol), antiviral Lopinavir/ritonavir, colistin, nitroxoline, nitrofurantoin, verteporfin, pentamidine, berberine, aprepitant, olsalazine, clinafloxacin, and clofoctol. Pyrvinium pamoate, daptomycin, methylene blue, clotrimazole, and gentamicin and streptomycin at their respective maximum drug concentration in serum (Cmax) had the capacity to completely eradicate stationary phase B. henselae after 3-day drug exposure in subculture studies. While the currently used drugs for treating bartonellosis, including rifampin, erythromycin, azithromycin, doxycycline, and ciprofloxacin, had very low minimal inhibitory concentration (MIC) against growing B. henselae, they had relatively poor activity against stationary phase B. henselae, except aminoglycosides. The identified FDA-approved agents with activity against stationary phase B. henselae should facilitate development of more effective treatments for persistent Bartonella infections.

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“…The enhancement of heme-induced hemolysis by clotrimazole is due to a colloid osmotic hemolysis mechanism. The hydrophobicity and the large molecular size of the heme-clotrimazole complex might be key factors for induction of hemolysis (Huy et al, 2004). CLT inhibits parasite growth with a IC 50 value approximately 1 μM and the full inhibition is achieved at 2.5 μM (Saliba and Kirk, 1998).…”

Section: Azoles and Its Derivatives: Structure-function Relationshipmentioning

confidence: 99%

Antimalarial drugs inhibiting hemozoin (β-hematin) formation: A mechanistic update

et al. 2007

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Enhancement of Heme-Induced Membrane Damage by the Anti-malarial Clotrimazole: the Role of Colloid-Osmotic Forces

Cited by 22 publications

References 35 publications

2- tert -Butyl-8-Quinolinamines Exhibit Potent Blood Schizontocidal Antimalarial Activity via Inhibition of Heme Crystallization

2- tert -Butyl-8-Quinolinamines Exhibit Potent Blood Schizontocidal Antimalarial Activity via Inhibition of Heme Crystallization

Identification of FDA-Approved Drugs with Activity against Stationary Phase Bartonella henselae

Antimalarial drugs inhibiting hemozoin (β-hematin) formation: A mechanistic update

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