Cysticidal Activity of Antifungals against Different Genotypes of Acanthamoeba

Iovieno, Alfonso; Miller, Darlene; Ledee, Dolena R.; Alfonso, Eduardo C.

doi:10.1128/aac.02635-14

Cited by 31 publications

(22 citation statements)

References 18 publications

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“…Indeed, our recent discovery shows there is an essential requirement for hormonal levels of ergosterol to “spark” (signal) cell proliferation of T. brucei bloodstream forms (Figure 1A) which cannot be satisfied solely by cholesterol salvaged from the host (Haubrich et al, 2015). These studies, plus the demonstration that inhibitors shown to block enzymes in the post-squalene segment of ergosterol biosynthesis pathway prevent growth of many protozoan parasites without effect on cultured animal cells (Gigante et al, 2009; Gros et al, 2006; Gunatilleke et al, 2012; Lepesheva et al, 2007; Lepesheva and Waterman, 2011; Lorente et al, 2004; Lovieno et al, 2014; Porta et al, 2014; Rahman and Pascal., 1990; Zhou et al, 2007) confirms our idea. Consequently, there is an effort underway to probe ergosterol biosynthesis targets with the aim to identify new drugs to treat specific neglected tropical diseases considered ergosterol-dependent.…”

Section: Introductionmentioning

confidence: 99%

Fluorinated Sterols Are Suicide Inhibitors of Ergosterol Biosynthesis and Growth in Trypanosoma brucei

Leaver

Patkar

Singha

et al. 2015

Chemistry & Biology

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SUMMARY Trypanosoma brucei, the causal agent for sleeping sickness, depends on ergosterol for growth. Herein, we describe the effects of a mechanism-based inhibitor, 26-fluorolanosterol (26FL), which converts in vivo to a fluorinated substrate of the sterol C24-methyltransferase essential for sterol methylation and function of ergosterol and missing from the human host. 26FL showed potent inhibition of ergosterol biosynthesis and growth of procyclic and bloodstream forms while it has no effect on cholesterol biosynthesis or growth of human epithelial kidney cells. During exposure of cloned TbSMT to 26-fluorocholesta-5,7,24-trienol, the enzyme is gradually killed as a consequence of the covalent binding of the intermediate C25 cation to the active site (kcat/kinact = 0.26 min-1/0.24 min-1; partition ratio of 1.08) whereas 26FL is non-productively bound. These results demonstrate that poisoning of ergosterol biosynthesis by a 26-fluorinated Δ24-sterol is a promising strategy for developing new treatment for trypanosomiasis.

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Section: Introductionmentioning

confidence: 99%

Fluorinated Sterols Are Suicide Inhibitors of Ergosterol Biosynthesis and Growth in Trypanosoma brucei

Leaver

Patkar

Singha

et al. 2015

Chemistry & Biology

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“…Voriconazole, an antifungal agent, has been proved to have good cysticidal effect against Acanthamoeba through in vitro study. [ 7 ] Although the activity of topical voriconazole and chlorhexidine against AK were similar in the other study, they believe topical voriconazole has better corneal and anterior chamber penetration and lower cellular toxicity on cornea than topical chlorhexidine. [ 8 ] Successful treatment of chlorhexidine- and polyhexamethylene biquanide (PHMB)-resistant AK with voriconazole 1% as an adjuvant has been reported.…”

Section: Discussionmentioning

confidence: 77%

Rapid resolution of stromal keratitis with the assistance of oral voriconazole in resistant acanthamoeba keratitis

Hou

Chen

Hsu

2017

Taiwan J Ophthalmol

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Acanthamoeba keratitis (AK) is an unusual infectious disease of the cornea which sometimes leads to blindness. We report the experience of adding oral voriconazole in conjunction with topical antiacanthamoebic drops to treat refractory AK. A 20-year-old girl experienced a deep stromal keratitis with large epithelial defect in the left eye, suspected as AK. The initial best-corrected visual acuity (BCVA) of the eye was counting finger. She received topical chlorhexidine 0.02% and voriconazole 1% during the first 14 days but in vain. Oral voriconazole was administered and resulted in a rapid regression of the lesion. A total resolution was achieved after 2 weeks of triple combination therapy. The BCVA of the left eye finally achieved 20/20 at 6-month follow-up. Although oral voriconazole was seldom used in treating acute AK, the additional use of oral voriconazole combined with topical antiacanthamoebic drugs may help to achieve a successful treatment effect in refractory stromal AK.

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“…Recently, an in vitro study shows that voriconazole, an antifungal agent, has good cysticidal effect against Acanthamoeba . [6] Another study even believes that topical voriconazole has better corneal and anterior chamber penetration and lower cellular toxicity on the cornea than topical chlorhexidine. [7] It may be the first drug of choice of atypical AK that presents like fungal keratitis when the culture result cannot be reached.…”

Section: Discussionmentioning

confidence: 99%

Dendrite-like anterior stromal keratitis coinfected with Acanthamoeba and Pseudomonas in an orthokeratology contact lens wearer

Hsu

2019

Taiwan J Ophthalmol

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Acanthamoeba species can cause a keratitis misdiagnosed as herpes keratitis or fungal keratitis. We report an unusual dendrite-like anterior stromal keratitis coinfected with Acanthamoeba and Pseudomonas aeruginosa in an orthokeratology contact lens wearer in Taiwan. Topical 1% voriconazole and 0.5% levofloxacin were prescribed because besides Acanthamoeba keratitis, fungal keratitis was also highly suspected initially. Topical 0.02% chlorhexidine was added after the culture of the scraped cornea showed positive results of Acanthamoeba and P. aeruginosa . The lesion subsided using this triple combination therapy for 1 week. Both Acanthamoeba and P. aeruginosa are potentially devastating causes of infectious keratitis. Our case highlights the importance of considering the possibility of a concurrent infection and atypical presentation in cases with contact lens-related keratitis. The use of topical levofloxacin combined with voriconazole should be considered as the first-line treatment in such patients.

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Cysticidal Activity of Antifungals against Different Genotypes of Acanthamoeba

Cited by 31 publications

References 18 publications

Fluorinated Sterols Are Suicide Inhibitors of Ergosterol Biosynthesis and Growth in Trypanosoma brucei

Fluorinated Sterols Are Suicide Inhibitors of Ergosterol Biosynthesis and Growth in Trypanosoma brucei

Rapid resolution of stromal keratitis with the assistance of oral voriconazole in resistant acanthamoeba keratitis

Dendrite-like anterior stromal keratitis coinfected with Acanthamoeba and Pseudomonas in an orthokeratology contact lens wearer

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