Drug discovery for primary amebic meningoencephalitis: from screen to identification of leads

ABSTRACT

Introduction: Naegleria fowleri is responsible for primary amebic meningoencephalitis (PAM) which has a fatality rate of >97%. Because of the rarity of the disease, pharmaceutical companies do not pursue new drug discovery for PAM. Yet, it is possible that the infection is underreported and finding a better drug would have an impact on people suffering from this deadly infection.

Areas covered: This paper reports the efforts undertaken by different academic groups over the last 20 years to test different compounds against N. fowleri. The drug discovery research encompassed synthesis of new compounds, development and use of high-throughput screening methods and attempts to repurpose clinically developed or FDA-approved compounds for the treatment of PAM.

Expert opinion: In absence of economic investment to develop new drugs for PAM, repurposing the FDA-approved drugs has been the best strategy so far to identify new leads against N. fowleri. Increasing use of high-throughput phenotypic screening has the potential to accelerate the identification of new leads, either in monotherapy or in combination treatment. Since phase II clinical trial is not possible for PAM, it is critical to demonstrate in vivo efficacy of a clinically safe compound to translate the discovery from lab to the clinic.

KEYWORDS:

• Naegleria fowleri
• primary amebic meningoencephalitis
• drugs
• leads
• screen
• high-throughput

Article highlights

• Naegleria fowleri is a free-living ameba that causes a brain infection called primary amebic meningoencephalitis.

• Current treatment relies on amphotericin B, an azole drug, azithromycin, rifampin, and miltefosine, but the combination treatment does not provide uniform protection.

• High-throughput screens identified FDA-approved drugs including sterol biosynthesis inhibitors as new leads for the treatment of PAM.

• Natural product-derived compounds and newly synthesized azoles demonstrated activity against N. fowleri. Nanoparticle conjugation enhanced the activity of compounds against N. fowleri.

• Drug combination experiments and testing of compounds on diverse strains have the potential to bring better outcome to patients.

• In absence of a phase II clinical trial, demonstration of in vivo efficacy of compounds is critical to obtain approval for future clinical use.

Acknowledgments

The author is grateful to Jose Ignacio Escrig for designing the figure.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

A Debnath was supported by a grant [R21AI146460] from NIH.