Pathogenic and Opportunistic Free-living Amoebae

Visvesvara, Govinda S.

doi:10.1016/b978-0-7020-5101-2.00051-0

Cited by 12 publications

(20 citation statements)

References 181 publications

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“…2, Table S2). As demonstrated by the activity of 8-hydroxyquinoline [2], the 5-position nitro group is not necessary for activity, while in contrast, retaining the nitro group without the hydroxy group [3] 13, which we speculate may be due to differences in uptake or permeability.…”

Section: Nitroxoline Structure-activity-relationship Experimentsmentioning

confidence: 77%

“…Although the extent to which nitroxoline crosses the blood brain barrier is unknown, a recent study shows that systemically delivered nitroxoline exhibits efficacy against gliomas in mice, implying that efficacious concentrations reached the brain in this model (73). In addition, we previously noted that B. mandrillaris frequently causes a necrotizing vasculitis in the CNS with extensive BBB breakdown (3,36,56). As a result, the bioavailability of nitroxoline in the CNS will almost certainly be significantly increased in patients actively suffering from GAE.…”

Section: Direct Comparison Of Nitroxoline To Standard-of-care Drugs Fmentioning

confidence: 91%

“…Analogs lacking the 8-position hydroxyl group were generally inactive with IC 50 values greater than 80 µM (e.g. 5-Nitroquinoline [3]). Twelve nitroxoline analogs with predicted metal binding activity were tested and of these, 1,10-phenanthroline Fig.…”

Section: Author Contributionsmentioning

confidence: 99%

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Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoebaBalamuthia mandrillaris

Retallack

et al. 2018

Preprint

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Balamuthia mandrillaris is a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms of B. mandrillaris -a proliferative trophozoite form and a non-proliferative cyst form, which is highly resistant to harsh physical and chemical conditions -have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multi-drug regimens often including the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low and studies evaluating the susceptibility of B. mandrillaris to these compounds and other potential therapeutics are limited. To address the need for more effective treatments, we screened 2,177 clinically-approved compounds for in vitro activity against B. mandrillaris. The quinoline antibiotic nitroxoline, which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a physiologically relevant range. We compare the in vitro efficacy of nitroxoline to drugs currently used in the standard of care for GAE and find that nitroxoline is the most potent and selective inhibitor of B. mandrillaris tested. Furthermore, we demonstrate that nitroxoline prevents B. mandrillaris-mediated destruction of host cells in cultured fibroblast and primary brain explant models also at physiologically relevant concentrations. Together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment of B. mandrillaris infections. Laurie and White et al., Inhibition of Balamuthia mandrillaris by nitroxoline 3 Importance Balamuthia mandrillaris is responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen, B. mandrillaris is understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fight B. mandrillaris infections, mortality rates remain high even for patients receiving intensive care. This study addresses the need for new anti-amoebic drugs using a high-throughput screening approach to identify novel B. mandrillaris inhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans.We show that nitroxoline kills B. mandrillaris at physiologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life threatening B. mandrillaris infections.

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Section: Nitroxoline Structure-activity-relationship Experimentsmentioning

confidence: 77%

Section: Direct Comparison Of Nitroxoline To Standard-of-care Drugs Fmentioning

confidence: 91%

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Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoebaBalamuthia mandrillaris

Retallack

et al. 2018

Preprint

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“…Acanthamoeba castellanii originated from a keratitis patient of Siriraj Hospital was used as positive control. Enflagellation experiment was done to verify the presence of Naegleria spp 30 . Briefly, the suspected trophozoites grown on a NNA- E. coli plate were suspended in sterile distilled water and left at room temperature for at least one hour.…”

Section: Methodsmentioning

confidence: 99%

Potentially Pathogenic Free-Living Amoebae in Some Flood-Affected Areas During 2011 Chiang Mai Flood

Wannasan

Uparanukraw

Songsangchun

et al. 2013

Rev. Inst. Med. trop. S. Paulo

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SUMMARYThe survey was carried out to investigate the presence of potentially pathogenic free-living amoebae (FLA) during flood in Chiang Mai, Thailand in 2011. From different crisis flood areas, seven water samples were collected and tested for the presence of amoebae using culture and molecular methods. By monoxenic culture, FLA were detected from all samples at 37 °C incubation. The FLA growing at 37 °C were morphologically identified as Acanthamoeba spp., Naegleria spp. and some unidentified amoebae. Only three samples (42.8%), defined as thermotolerant FLA, continued to grow at 42 °C. By molecular methods, two non-thermotolerant FlA were shown to have 99% identity to Acanthamoeba sp. and 98% identity to Hartmannella vermiformis while the two thermotolerant FLA were identified as Echinamoeba exundans (100% identity) and Hartmannella sp. (99% identity). This first report of the occurrence of FLA in water during the flood disaster will provide information to the public to be aware of potentially pathogenic FLA.

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“…There are a number of issues involved in the culture of protozoan parasites, such as I. multifiliis, that make these procedures highly complex and subject to many variables, some of which are known (Nielsen & Buchmann, 2000;Xu et al, 2002). In vitro culture of organisms at any of these stages within the life cycle involves a tremendous number of variables, including parasite stage, host site, host temperature, host immune responses, parasite species and/or strain, and parasiteprotective mechanisms (Diamond, 1987;Evans, 1987;Visvesvara, 1999). The present study was conducted on adaptation and histopathology evaluation of the I. multifiliis to skin culture in vitro.…”

Section: Abstract: Fish Histopathological Evaluation Ichthyophthirmentioning

confidence: 99%

Histopathological evaluation of in vitro Ichthyophthirius multifiliis culture in Red koi (Aka Matsuba) tissue

Heidarieh¹,

Shahbazfar²,

Moodi³

et al. 2016

BJVM

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Pathogenic and Opportunistic Free-living Amoebae

Cited by 12 publications

References 181 publications

Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoebaBalamuthia mandrillaris

Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoebaBalamuthia mandrillaris

Potentially Pathogenic Free-Living Amoebae in Some Flood-Affected Areas During 2011 Chiang Mai Flood

Histopathological evaluation of in vitro Ichthyophthirius multifiliis culture in Red koi (Aka Matsuba) tissue

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