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A Search for Anti-Naegleria fowleri Agents Based on Competitive Exclusion Behavior of Microorganisms in Natural Aquatic Environments.

ABSTRACT: Naegleria fowleri causes deadly primary amoebic meningoencephalitis (PAM) in humans. Humans obtain the infection by inhaling water or dust contaminated with amebae into the nostrils, wherefrom the pathogen migrates via the olfactory nerve to cause brain inflammation and necrosis. Current PAM treatment is ineffective and toxic. Seeking new effective and less toxic drugs for the environmental control of the amoeba population to reduce human exposure is logical for the management of N. fowleri infection. On the basis of the concept of competitive exclusion, where environmental microorganisms compete for resources by secreting factors detrimental to other organisms, we tested cell-free culture supernatants (CFSs) of three bacteria isolated from a fresh water canal, i.e., Pseudomonas aeruginosa, Pseudomonas otitidis, and Enterobacter cloacae, were tested against N. fowleri. The CFSs inhibited growth and caused morphological changes in N. fowleri. At low dose, N. fowleri trophozoites exposed to P. aeruginosa pyocyanin were seen to shrink and become rounded, while at high dose, the trophozoites were fragmented. While the precise molecular mechanisms of pyocyanin and products of P. otitidis and E. cloacae that also exert anti-N. fowleri activity await clarification. Our findings suggest that P. aeruginosa pyocyanin may have a role in the control of amphizoic N. fowleri in the environment.

SUBMITTER: Ruenchit P

PROVIDER: S-EPMC7911858 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used systemically. Here, we describe findings that demonstrate these agents are potent inhibitors of N. fowleri ENO (NfENO) and are lethal to amoebae. In particular, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX) was a potent enzyme inhibitor (IC50 = 0.14 ± 0.04 μM) that was toxic to trophozoites (EC50 = 0.21 ± 0.02 μM) while the reported CC50 was >300 μM. Molecular docking simulation revealed that HEX binds strongly to the active site of NfENO with a binding affinity of -8.6 kcal/mol. Metabolomic studies of parasites treated with HEX revealed a 4.5 to 78-fold accumulation of glycolytic intermediates upstream of NfENO. Last, nasal instillation of HEX increased longevity of amoebae-infected rodents. Two days after infection, animals were treated for 10 days with 3 mg/kg HEX, followed by one week of observation. At the end of the one-week observation, eight of 12 HEX-treated animals remained alive (resulting in an indeterminable median survival time) while one of 12 vehicle-treated rodents remained, yielding a median survival time of 10.9 days. However, intranasal HEX delivery was not curative as brains of six of the eight survivors were positive for amoebae. These findings suggest that HEX requires further evaluation to develop as a lead for treatment of PAM.

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A Search for Anti-Naegleria fowleri Agents Based on Competitive Exclusion Behavior of Microorganisms in Natural Aquatic Environments.

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