The Development of Drugs against Acanthamoeba Infections

Siddiqui, Ruqaiyyah; Aqeel, Yousuf; Khan, Naveed Ahmed

doi:10.1128/aac.00686-16

Cited by 85 publications

(85 citation statements)

References 79 publications

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“…APCs and QACs are effective antimicrobials against fungi, bacteria, some protists and also have anti-tumour properties. In this study, we have confirmed their toxicity against Acanthamoeba trophozoites 34,35 , and showed that QACs were more effective than their APCs counterpart, perhaps due to the formation of larger micelles (QACs, 8.8 ± 0.8 nm; APCs, 5.8 ± 1.0 nm) 36 . Interestingly, the activities from both compound-types were strongly correlated with their alkyl-carbon chain lengths against trophozoites, a key indicator for micellar size and hydrophobicity.…”

Section: Discussionsupporting

confidence: 66%

“…Finally, we have presented sufficient evidence to show QAC18 alone and QAC12 in combination with APC16 are efficacious against Acanthamoeba castellanii, trophozotes and cysts, enough for consideration as a preventative management strategy for cleansing contact lens 5,32,34 . At present, cytotoxicity information of these mixed surfactants provided in this study against human epithelial and corneal cell lines are absent and as such are a significant barrier for use as a medical device.…”

Section: Discussionmentioning

confidence: 93%

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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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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 93%

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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“…In this study, a single drug chlorhexidine was therefore used against A. triangularis and successfully exhibited inhibitory activity on trophozoites and cysts with MIC values of 7.81 and 62.5 µg/mL (Table 1), respectively. Our nding is in consistent with an earlier report on chlorhexidine used against A. triangularis exhibited amoebicidal and cysticidal properties at 200 µg/mL (0.02%) [30]. While, a recent study [3] evaluated the e cacy of miltefosine, another orphan drug for the treatment of keratitis and encephalitis, against Acanthamoeba spp.…”

Section: Discussionsupporting

confidence: 91%

Synergistic Effect of Garcinia Mangostana Combined With Chlorhexidine on Acanthamoeba Triangularis Trophozoites and Cysts

Sangkanu

Mitsuwan

Mahabusarakam

et al. 2020

Preprint

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Background: Various parts of Garcinia mangostana Linn, including its pericarp have been traditionally used to treat different types of diseases. This study was carried out to determine the anti-Acanthamoeba activity of G. mangostana pericarp extract against Acanthamoeba triangularis. Methods: The G. mangostana ethanolic pericarp extract was screened for the anti-Acanthamoeba activity and determined its minimal inhibition concentrations (MICs) by the microdilution method. Then, the time-kill kinetic assay of the extract was determined. The synergistic effect of G. mangostana extract and chlorhexidine was performed using the checkerboard method. Parasite morphology was detected by scanning electron microscopy (SEM).Results: The MICs of extract were assessed on trophozoites and cysts with 250 and 4000 µg/mL, respectively. More so, at 2×MIC of extract exhibited inhibitory activity against trophozoites and cyst of A. triangularis for up to 7 days. Checkerboard assays showed synergistic activity of extract (500-1000 μg/mL) plus chlorhexidine (3.90-15.62 μg/mL) at a fractional inhibitory concentration index (FICI) of 0.18-0.37. The lowest FICI (0.18) displayed good synergism resulting in up to 16-fold reduction of drug MIC and reducing to 8-fold of extract MIC. The viability of cysts decreased to 12.28±3.03 cells/mL. FICI interpretation equal to 1 is considered an additive effect on Acanthamoeba trophpzoites. The SEM results clearly showed that Acanthamoeba cells treated with a single drug of chlorhexidine and its combination with G. mangostana extract caused cell membrane damage and irregular cell shapes comparing with the control. Conclusion: A good combinatorial relationship displayed by G. mangostana extract and chlorhexidine suggest a more reliable evidenced based therapeutic strategy. Therefore, this approach is promising and could be employed as an alternative treatment method for the management of Acanthamoeba infection.

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“…This exemplifies the robustness of our high-throughput screening assays as well as true hit inhibitors of N. fowleri (IC 50 = 20 nM), it has a lag phase of ~30 hours before inhibiting growth. The compounds regimen, were firstly not classified as potent inhibitors within a standard in vitro drug susceptibility screening assays and 343 secondly, they were not effective in our rate of action assay at the respective IC 50…”

mentioning

confidence: 99%

Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae

Rice¹,

Colon

Chen

et al. 2020

Preprint

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33Diseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria 34 fowleri), granulomatous amoebic encephalitis (Acanthamoeba spp.), Acanthamoeba keratitis, and Balamuthia amoebic 35 encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and have high morbidity and mortality rates 36 due to lack of effective therapeutics. In pursuit of repurposing drugs for chemotherapies, we conducted a high throughput 37 phenotypic screen of 12,000 compounds from the Calibr ReFRAME library. We discovered a total of 58 potent inhibitors 38 (IC 50 <1 M) against N. fowleri (n=19), A. castellanii (n=12), and B. mandrillaris (n=27) plus an additional 90 micromolar 39 inhibitors. Of these, 113 inhibitors have never been reported to have activity against Naegleria, Acanthamoeba or 40 Balamuthia. Rapid onset of action is important for new anti-amoeba drugs and we identified 19 compounds that inhibit 41 N. fowleri in vitro within 24 hours (halofuginone, NVP-HSP990, fumagillin, bardoxolone, belaronib, and BPH-942, 42 solithromycin, nitracrine, quisinostat, pabinostat, pracinostat, dacinostat, fimepinostat, sanguinarium, radicicol, 43 acriflavine, REP3132, BC-3205 and PF-4287881). These compounds inhibit N. fowleri in vitro faster than any of the 44 drugs currently used for chemotherapy. The results of these studies demonstrate the utility of phenotypic screens for 45 discovery of new drugs for pathogenic free-living amoebae, including Acanthamoeba for the first time. Given that many 46 of the repurposed drugs have known mechanisms of action, these compounds can be used to validate new targets for 47 structure-based drug design. 48 49 Author Summary 50 Free-living amoebae (FLA) are ubiquitous in soil and freshwater and most are non-pathogenic to people; 51 however, three different pathogenic FLA have been found to cause severe, most often fatal diseases in humans. Due to 52 poor detection and inadequate treatment options available for pathogenic FLA, the fatality rates are still > 90% for the 53 diseases caused by Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba spp. With hundreds of cases in the 54 United States and many more cases reported worldwide, there is still an urgent clinical need for effective diagnosis and 55 specific treatments discovered against these opportunistic parasites. Drug repurposing is a powerful approach for drug-56 discovery because it significantly improves the discovery time, reduces the amount of resources, and decreases costs 57 required to advance lead candidate drugs of interest into the clinic. This is extremely helpful for neglected diseases 58 including pathogenic FLA where there is a need for new active therapies with limited budgets. This report addresses the 59 discovery of new active drugs with potential for repurposing, multiple new drug classes that inhibit pathogenic FLA, and 60 numerous putative drug targets that can be used as tools for further investigation and structure-based drug design. 61 7 . Naegleria, being ther...

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The Development of Drugs against Acanthamoeba Infections

Cited by 85 publications

References 79 publications

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

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

Synergistic Effect of Garcinia Mangostana Combined With Chlorhexidine on Acanthamoeba Triangularis Trophozoites and Cysts

Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae

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