Discovery of anti-amoebic inhibitors from screening the MMV Pandemic Response Box on<i>Balamuthia mandrillaris, Naegleria fowleri</i>and<i>Acanthamoeba castellanii</i>

Rice, Christopher A.; Troth, Emma V.; Russell, A Cassiopeia; Kyle, Dennis E.

doi:10.1101/2020.05.14.096776

Cited by 11 publications

(10 citation statements)

References 83 publications

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“…FDA-approved isavuconazole (marketed as a prodrug Cresemba TM ) has a good safety profile and is well-tolerated in humans [ 30 ]. Isavuconazole CC 50 against human A549 lung carcinoma cells was found > 10 µM [ 31 ]. This provides a selectivity index of about 400 to 10,000, depending on the strains of A. castellanii .…”

Section: Resultsmentioning

confidence: 99%

In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii

et al. 2020

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Acanthamoeba keratitis (AK) can occur in healthy individuals wearing contact lenses and it is a painful, blinding infection of the cornea caused by a free-living ameba Acanthamoeba. Current treatment for AK relies on a combination of chlorhexidine, propamidine isethionate, and polyhexamethylene biguanide. However, the current regimen includes an aggressive disinfectant and in 10% of cases recurrent infection ensues. Therefore, development of efficient and safe drugs is a critical unmet need to avert blindness. Acanthamoeba sterol biosynthesis includes two essential enzymes HMG-CoA reductase (HMGR) and sterol 14-demethylase (CYP51), and we earlier identified a CYP51 inhibitor isavuconazole that demonstrated nanomolar potency against A. castellanii trophozoites. In this study, we investigated the effect of well-tolerated HMGR inhibitors and identified pitavastatin that is active against trophozoites of three different clinical strains of A.castellanii. Pitavastatin demonstrated an EC50 of 0.5 to 1.9 µM, depending on strains. Combination of pitavastatin and isavuconazole is synergistic and led to 2- to 9-fold dose reduction for pitavastatin and 11- to 4000-fold dose reduction for isavuconazole to achieve 97% of growth inhibition. Pitavastatin, either alone or in combination with isavuconazole, may lead to repurposing for the treatment of Acanthamoeba keratitis.

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Section: Resultsmentioning

confidence: 99%

In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii

et al. 2020

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“…However, currently, there are no reports of cases treated with this drug. Other potential drugs have also been screened in vitro ; however, the clinical efficacy and side effects of these drugs need to be verified clinically [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Balamuthia mandrillaris infection in China: a retrospective report of 28 cases

Wang

Cheng

et al. 2020

Emerging Microbes & Infections

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Balamuthia mandrillaris infection is a rare and fatal disease. We have recorded 28 cases of Balamuthia mandrillaris infection during the past 20 years. Eighteen patients (64%) were male and 10 (36%) were female. Patient age ranged from 3 to 74 (mean, 27) years. Patient locations were distributed among 12 Provinces in China. Twenty-seven (96%) patients lived in rural areas, and 17 (61%) patients reported a history of trauma before the appearance of skin lesions. All cases presented with skin lesions as the primary symptom, and 16 (57%) cases developed encephalitis. Histopathology of skin lesions revealed granulomatous changes with histiocytes, lymphocytes, and plasma cells infiltration. Amebas were identified in all cases with immunohistochemical staining. Follow-up information was available in 27 (96%) cases. Fifteen (56%) patients died due to encephalitis and 12 (44%) were free of disease after treatment. Our results show that the clinical characteristics of Balamuthia mandrillaris infection in China are very different from those in the US. Infection of traumatized skin may play an important role in the pathogenesis of the disease in China. Encephalitis usually develops 3-4 years after skin lesions in Chinese cases. Patients with only skin lesions have a higher cure rate than patients with encephalitis.

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“…Moreover, other compounds such as Corifungin revealed potent anti‐ Naegleria effects (Debnath et al, 2012). Another recent study elucidated 22 novel compounds against free‐living amoebae (Rice et al, 2020). These nano‐conjugated compounds and novel compounds could be utilized to develop biosensors in combination with drug release in target tissues, in keratitis patients or combined with photodynamic therapy, which has shown promise against Acanthamoeba infections (Aqeel et al, 2015).…”

Section: Theranostics As An Approachmentioning

confidence: 99%

The increasing importance of Vermamoebavermiformis

Siddiqui

Makhlouf

Khan

2021

J Eukaryotic Microbiology

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Vermamoeba vermiformis are one of the most prevalent free‐living amoebae. These amoebae are ubiquitous and also thermotolerant. Of concern, V. vermiformis have been found in hospital water networks. Furthermore, associations between V. vermiformis and pathogenic bacteria have been reported, such as Legionella pneumophila. Moreover, V. vermiformis are well known to host viruses, bacteria, and other microorganisms and cases of keratitis due to V. vermiformis in conjunction with other amoebae have been reported. Despite the preceding, the medical importance of V. vermiformis is still an ongoing discussion and its genome has been only recently sequenced. Herein, we present a review of the current understanding of the biology and pathogenesis pertaining to V. vermiformis, as well as its’ role as an etiological agent and trojan horse. An approach known as theranostics which combines both diagnosis and therapy could be utilized to eradicate and diagnose keratitis cases caused by such amoebae. Given the rise in global warming, it is imperative to investigate these rarely studied amoebae and to understand their importance in human health.

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Discovery of anti-amoebic inhibitors from screening the MMV Pandemic Response Box onBalamuthia mandrillaris, Naegleria fowleriandAcanthamoeba castellanii

Cited by 11 publications

References 83 publications

In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii

In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii

Balamuthia mandrillaris infection in China: a retrospective report of 28 cases

The increasing importance of Vermamoebavermiformis

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