Therapeutic effect of rokitamycin in vitro and on experimental meningoencephalitis due to Naegleria fowleri

Kim, Jong-Hyun; Lee, Yang-Jin; Sohn, Hae-Jin; Song, Kyoung-Ju; Kwon, Daeho; Kwon, Myung-Hee; Im, Kyongok; Shin, Ho‐Joon

doi:10.1016/j.ijantimicag.2008.05.018

Cited by 12 publications

(9 citation statements)

References 27 publications

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“…The most active compound was azithromycin, a drug already used to treat PAM. We also found that clarithromycin, erythromycin, and roxithromycin have nanomolar activity as previously reported from in vitro studies [20]. We also identified 3 veterinary antibiotics-valnemulin, retapamulin, and tilmicosin [21,22]-that potentially could be used to treat animal infections.…”

Section: Discussionsupporting

confidence: 79%

Phenotypic Screens Reveal Posaconazole as a Rapidly Acting Amebicidal Combination Partner for Treatment of Primary Amoebic Meningoencephalitis

Colon

Rice

Guy

et al. 2018

The Journal of Infectious Diseases

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Naegleria fowleri is the causative agent of primary amoebic meningoencephalitis (PAM), which is fatal in >97% of cases. In this study, we aimed to identify new, rapidly acting drugs to increase survival rates. We conducted phenotypic screens of libraries of Food and Drug Administration-approved compounds and the Medicines for Malaria Venture Pathogen Box and validated 14 hits (defined as a 50% inhibitory concentration of <1 μM). The hits were then prioritized by assessing the rate of action and efficacy in combination with current drugs used to treat PAM. Posaconazole was found to inhibit amoeba growth within the first 12 hours of exposure, which was faster than any currently used drug. In addition, posaconazole cured 33% of N. fowleri-infected mice at a dose of 20 mg/kg and, in combination with azithromycin, increased survival by an additional 20%. Fluconazole, which is currently used for PAM therapy, was ineffective in vitro and vivo. Our results suggest posaconazole could replace fluconazole in the treatment of PAM.

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Section: Discussionsupporting

confidence: 79%

Phenotypic Screens Reveal Posaconazole as a Rapidly Acting Amebicidal Combination Partner for Treatment of Primary Amoebic Meningoencephalitis

Colon

Rice

Guy

et al. 2018

The Journal of Infectious Diseases

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“…Endpoints for growth usually include morphology and visual counting of amoebae, assessment of viability that requires days to weeks, or release of lactate dehydrogenase (11,(42)(43)(44)(45). In addition, these methods use large volumes of culture media (e.g., Ͼ10 ml) in flasks and require extended incubation periods of up to 6 days (11,(42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Bis-Benzimidazole Hits against Naegleria fowleri Discovered with New High-Throughput Screens

Rice

Colon

Alp

et al. 2015

Antimicrob Agents Chemother

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Naegleria fowleri is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new in vitro assays suitable for medium-or high-throughput drug discovery and used these for N. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono-and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC 50 ) of 177 nM. Similarly, we identified 10 additional analogues with IC 50 s of <1 M, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono-and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with N. fowleri. The first report of animal pathogenicity by free-living amoebae (FLA) was by Culbertson et al., who identified Acanthamoeba in necrotic lesions of monkeys and mice (1). He later suggested that FLA causes similar disease in humans. Fowler and Carter reported the first cases of an acute fatal disease caused by Naegleria fowleri in four victims in Australia in 1965 (2). Since the identification of primary amoebic meningoencephalitis (PAM), hundreds of cases have been reported worldwide, including 142 cases in the United States (3-5). Most infections with N. fowleri occur during the summer months, victims usually are symptomatic within 5 days, and the disease is almost always fatal. Infection usually occurs after the victim swam in warm, fresh, or brackish water or from exposure to contaminated tap water associated with the use of Neti pots for nasal irrigation (4-7). Amoebic invasion occurs via disruption of the olfactory mucosa, penetration of organisms into the submucosal nervous plexus, and ultimately passage through the cribriform plate to the frontal lobes of the brain (8, 9). Although most cases of PAM occur in warm climates, such as the southern tier states of the United States, pathogenic amoeba found in thermally polluted water sources, hot springs, and poorly chlorinated pools have been linked to infections (10, 11). Interestingly, most of the PAM cases have been diagnosed in developed countries, including the United States, Australia, and Europe. Although sporadic cases have been d...

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“…Although RKM’s mechanism of action is still unclear, it is a good candidate to treat PAM. It has shown amoebicidal effects against N. fowleri and presented no liver or kidney toxicity in the infected mice [ 78 ].…”

Section: Potential Treatmentmentioning

confidence: 99%

Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis and Treatments

Güémez

García

2021

Biomolecules

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Naegleria fowleri is a free-living amoeba (FLA) that is commonly known as the “brain-eating amoeba.” This parasite can invade the central nervous system (CNS), causing an acute and fulminating infection known as primary amoebic meningoencephalitis (PAM). Even though PAM is characterized by low morbidity, it has shown a mortality rate of 98%, usually causing death in less than two weeks after the initial exposure. This review summarizes the most recent information about N. fowleri, its pathogenic molecular mechanisms, and the neuropathological processes implicated. Additionally, this review includes the main therapeutic strategies described in case reports and preclinical studies, including the possible use of immunomodulatory agents to decrease neurological damage.

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Therapeutic effect of rokitamycin in vitro and on experimental meningoencephalitis due to Naegleria fowleri

Cited by 12 publications

References 27 publications

Phenotypic Screens Reveal Posaconazole as a Rapidly Acting Amebicidal Combination Partner for Treatment of Primary Amoebic Meningoencephalitis

Phenotypic Screens Reveal Posaconazole as a Rapidly Acting Amebicidal Combination Partner for Treatment of Primary Amoebic Meningoencephalitis

Bis-Benzimidazole Hits against Naegleria fowleri Discovered with New High-Throughput Screens

Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis and Treatments

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