Differential cytotoxicity of phospholipid analogues to pathogenic Acanthamoeba species and mammalian cells

McBride, James; Mullen, Alexander B.; Carter, K. Christine; Roberts, Craig W.

doi:10.1093/jac/dkm245

Cited by 21 publications

(6 citation statements)

References 17 publications

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“…Finally, since synthetic PC analogues were recently suggested as promising drugs against Acanthamoeba species [7], [33], the results obtained may help to find more effective antimicrobials to treat Acanthamoeba infections. The goal of our future studies is to assess the biological significance of these fatty acids and their sensitivity/resistance to antiprotozoal agents.…”

Section: Discussionmentioning

confidence: 98%

Identification of Unusual Phospholipid Fatty Acyl Compositions of Acanthamoeba castellanii

et al. 2014

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Acanthamoeba are opportunistic protozoan pathogens that may lead to sight-threatening keratitis and fatal granulomatous encephalitis. The successful prognosis requires early diagnosis and differentiation of pathogenic Acanthamoeba followed by aggressive treatment regimen. The plasma membrane of Acanthamoeba consists of 25% phospholipids (PL). The presence of C20 and, recently reported, 28- and 30-carbon fatty acyl residues is characteristic of amoeba PL. A detailed knowledge about this unusual PL composition could help to differentiate Acanthamoeba from other parasites, e.g. bacteria and develop more efficient treatment strategies. Therefore, the detailed PL composition of Acanthamoeba castellanii was investigated by 31P nuclear magnetic resonance spectroscopy, thin-layer chromatography, gas chromatography, high performance liquid chromatography and liquid chromatography-mass spectrometry. Normal and reversed phase liquid chromatography coupled with mass spectrometric detection was used for detailed characterization of the fatty acyl composition of each detected PL. The most abundant fatty acyl residues in each PL class were octadecanoyl (18∶0), octadecenoyl (18∶1 Δ9) and hexadecanoyl (16∶0). However, some selected PLs contained also very long fatty acyl chains: the presence of 28- and 30-carbon fatty acyl residues was confirmed in phosphatidylethanolamine (PE), phosphatidylserine, phosphatidic acid and cardiolipin. The majority of these fatty acyl residues were also identified in PE that resulted in the following composition: 28∶1/20∶2, 30∶2/18∶1, 28∶0/20∶2, 30∶2/20∶4 and 30∶3/20∶3. The PL of amoebae are significantly different in comparison to other cells: we describe here for the first time unusual, very long chain fatty acids with Δ5-unsaturation (30∶35,21,24) and 30∶221,24 localized exclusively in specific phospholipid classes of A. castellanii protozoa that could serve as specific biomarkers for the presence of these microorganisms.

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Section: Discussionmentioning

confidence: 98%

Identification of Unusual Phospholipid Fatty Acyl Compositions of Acanthamoeba castellanii

et al. 2014

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“…While a wide range of antiparasitic, antimicrobial, and other pharmacologic agents has been tested against Acanthamoeba, these agents have shown limited activity and reports of successful treatment have been few (18)(19)(20)(21)(22). The current drugs of choice in treating Acanthamoeba keratitis are two biguanides and two diamidines.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Efficacy of Corifungin against Acanthamoeba castellanii Trophozoites and Cysts

Debnath

Tunac²,

Silva-Olivares

et al. 2014

Antimicrob Agents Chemother

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cPainful blinding keratitis and fatal granulomatous amebic encephalitis are caused by the free-living amebae Acanthamoeba spp. Several prescription eye medications are used to treat Acanthamoeba keratitis, but the infection can be difficult to control because of recurrence of infection. For the treatment of encephalitis, no single drug was found useful, and in spite of the use of a combination of multiple drugs, the mortality rate remains high. Therefore, efficient, novel drugs are urgently needed for the treatment of amebic keratitis and granulomatous amebic encephalitis. In this study, we identified corifungin, a water-soluble polyene macrolide, as amebicidal. In vitro, it was effective against both the trophozoites and the cysts. Transmission electron microscopy of Acanthamoeba castellanii incubated with corifungin showed the presence of swollen mitochondria, electrondense granules, degeneration of cytoplasm architecture, and loss of nuclear chromatin structure. These changes were followed by lysis of amebae. Corifungin also induced the encystment process of A. castellanii. There were alterations in the cyst cell wall followed by lysis of the cysts. Corifungin is a promising therapeutic option for keratitis and granulomatous amebic encephalitis. Free-living Acanthamoeba spp. cause keratitis, a serious eye infection that can occur in healthy individuals wearing contact lenses, as well as chronic granulomatous amebic encephalitis (GAE) leading to death in immunocompromised persons. Acanthamoeba has a worldwide distribution and is the most common ameba found in the environment. Coincident with the number of Acanthamoeba keratitis cases in the United States has been an increase in developing countries. Wearing of contact lenses is now recognized as the leading risk factor for keratitis (1-3). In the United States, the estimated number of keratitis cases is 1.36 per million contact lens wearers (4, 5). GAE is a relatively rare disease. Approximately 150 cases have been reported worldwide (5). GAE results from inhalation of amebae through the nasal cavities and lungs, or introduction through skin lesions followed by access to the central nervous system by hematogenous spread or through the olfactory neuroepithelium (6). Clinical manifestations include headache, fever, nausea, vomiting, behavioral changes, stiff neck, lethargy, increased intracranial pressure, and, in the later stage, loss of consciousness, seizures, coma, and death (7-9).The drugs recommended for the treatment of Acanthamoeba keratitis include polyhexamethylene biguanide (0.02%) or chlorhexidine (0.02%) along with a diamidine (either 0.1% propamidine or 0.1% hexamidine) (10). Corticosteroids are applied topically to control corneal inflammation, pain, and scleritis, particularly following keratoplasty (11). While this antimicrobial treatment can kill the trophozoites, the resistance of Acanthamoeba cysts to antimicrobials can lead to the recurrence of keratitis. For GAE, combination therapies were found more successful than single-drug therapies, a...

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“…The combination of different administration routes has also provided positive outcomes, for example topical and systemic administration using topical chlorhexidine 0.06% and propamidine isetionate 0.1% and the zwitterionic alkylphosphocholine (APC) called miltefosine 25,26 . APCs are also effective against kinetoplastids (Trypanosoma and Leishmania), anaerobic parasites (Trichomonas and Entamoeba) and other amoebae (Naegleria, as well as Acanthamoeba) trophozoites and cysts, but can induce encystation in Acanthamoeba [27][28][29][30][31][32] . Structure-activities studies in Leishmania 33 and Acanthamoeba 29 have demostrated that changes in the physical strucure of the APC can increase efficacy.…”

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confidence: 99%

Alkyl-carbon chain length of two distinct compounds and derivatives are key determinants of their anti-Acanthamoeba activities

Mooney

Masala

Martial

et al. 2020

Sci Rep

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the opportunistic pathogen, Acanthamoeba castellanii is the causative agent for the sight threatening infection Acanthamoeba keratitis (AK). it is commonly associated with contact lens wearers, and prevalence is increasing at an alarming rate due to an inadequate preventive strategy to protect the lens from this protist. This problem is compounded by the lack of an effective acanthamoebocide, particularly with cysticidal activity in the contact lens solutions. We have used cytotoxicity assays and a variety of biophysical approaches to show that two molecules with tails made of alkyl carbon, alkylphosphocholines (APCs) and quaternary ammonium compounds (QACs) had significant chain-length dependent efficacy against A. castellanii trophozoites, the latter producing death via permeabilization, and DNA complexing. QACs were more effective than APCs and had activity against cysts. Conversely, the QAC with 12 alkyl carbon chain, was non toxic, its presence increased A. castellanii trophozoites biomass and delayed encystation by 96 h. Interestingly, it was unable to induce excystation and increased trophozoite sensitivity to APC16. These results present a mono-and multi-inhibitor management strategy effective against trophozoites and cysts that may be useful for formulating into contact lense cleaning solutions and reducing AK incidence. Acanthamoeba are free-living protists, existing as active trophozoites and non-replicative cysts characterised by double cellulose cell walls 1. They have opportunistic tendencies and can cause the diseases, Acanthamoeba keratitis (AK), cutaneous acanthamoebiasis (CA) and granulomatous amoebic encephalitis (GAE) 2,3. Whilst CA and GAE are lethal but rare and affect the skin and CNS, respectively, the non-lethal AK causes severe infection in the cornea, threatening sight loss and causing emotional and psychological trauma, described as life-changing in patients 4. Trophozoites to cysts interconversion and vice versa (encystation and excystation) is induced by external environmental cues 5,6 and poses significant challenges for curative treatment particularly causing AK resurgences and relapses 7. AK cases are increasing and prevalence is high amongst contact lens users 8,9. Cases of AK within the UK have risen drastically within the last 20 years and continue to do so 10. The reason for this upsurge in incidence rates does not appear to be as a result of increased lens wearers but is as of yet unknown, likely the result of multiple factors 10. Spatial geographic differences are common with 15 times more cases reported in the UK than the USA 11,12 , and 8 times more in Scotland than England 13. These differences are strongly linked with water supply, quality and usage 12. Indeed, the incidence of AK in contact lens users is believed to be due to rinsing of contact lenses with domestic tap water 14. Further, the lack of anti-acanthamoebocides in cleaning solutions is another issue. Despite the presence of preservative compounds such as polyhexamethylene biguanide used in existing solutions,...

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Differential cytotoxicity of phospholipid analogues to pathogenic Acanthamoeba species and mammalian cells

Cited by 21 publications

References 17 publications

Identification of Unusual Phospholipid Fatty Acyl Compositions of Acanthamoeba castellanii

Identification of Unusual Phospholipid Fatty Acyl Compositions of Acanthamoeba castellanii

In Vitro Efficacy of Corifungin against Acanthamoeba castellanii Trophozoites and Cysts

Alkyl-carbon chain length of two distinct compounds and derivatives are key determinants of their anti-Acanthamoeba activities

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