Current medicines hold promise in the treatment of orphan infections due to brain-eating amoebae

Abstract

Given the opportunity and access to susceptible hosts, freeliving amoebae (Naegleria fowleri, Acanthamoeba spp., Balamuthia mandrillaris) can produce fatal diseases involving the brain[1]. It is disturbing that the rate of mortality has remained over 90%, despite decades of research in drug discovery and major breakthroughs taking place in chemotherapy and supportive care. For example, N. fowleri, the causative agent of primary amoebic meningoencephalitis was first described in 1965, while granulomatous amoebic meningoencephalitis due to Acanthamoeba and B. mandrillaris were reported in 1978 and 1990, respectively. Yet, the treatment using a combination of drugs (often antifungals such as amphotericin B and azoles) remains a hit-and-miss approach [2]. Even with treatment, reported cases with successful prognosis have been few and far between, requiring high suspicion together with early diagnosis, and a favorable outcome is mostly seen in the cases reported in the USA. The very high mortality rate is attributed to (i) inefficacy of drugs to penetrate the otherwise highly restrictive blood–brain barrier to target the parasites residing within the central nervous system, and (ii) the lack of available parasite-specific drugs. At present, the management of brain-eating amoebae infection involves a combination of drugs including, amidines, neomycin, biguanides, ergosterol inhibitors such as azoles/amphotericin B, sulfadiazine, milfetosine, etc.[2]. Several compounds may not be effective in reaching the infection site (limited blood–brain barrier permeability), exhibit inadequate amoebicidal properties in vivo at physiologically relevant concentrations, and/or show high host cell cytotoxicity. Given the rarity of the disease, it is not surprising that the pharmaceutical industry has shown no interest in the development and/or modulation of compounds that are blood–brain barrier permeable with potential to target the brain-eating amoebae effectively at the infection site, without harming human cells. The reuse of medicines is a valid avenue to expedite our advances in the development of effective treatment options against neglected brain-eating amoebae infections. Herein, we discuss clinically used drugs for neuropathological conditions that are blood–brain barrier permeable, as well as parasitespecific compounds developed against related protozoa, as potential avenues to design chemotherapeutics against orphan infections due to pathogenic free-living amoebae (Figure 1). In this regard, there are three avenues to be explored;