Evaluation of Indolocarbazoles from Streptomyces sanyensis as a Novel Source of Therapeutic Agents against the Brain-Eating Amoeba Naegleria fowleri.

Aitor Rizo-Liendo,Ines Sifaoui,Jacob Lorenzo-Morales,José E Piñero,Ana R Díaz-Marrero,José J Fernández,Iñigo Arberas-Jiménez,María Reyes-Batlle,Luis Cartuche

doi:10.3390/microorganisms8050789

Abstract

Naegleria fowleri is an opportunistic pathogenic free-living amoeba which is able to rapidly colonize the central nervous system (CNS) and causes a lethal infection known as primary amoebic meningoencephalitis (PAM). Furthermore, more than 98% of the known cases of PAM are fatal and affect mainly children under 12 and young adults. Until now, no fully effective therapeutic agents against N. fowleri are available and hence the urgent need to find novel agents to treat PAM. At present, PAM therapy is based on the combination of amphotericin B, miltefosine, among others, with unwanted toxic effects. Recently, our team isolated various indolocarbazoles (ICZs) from the culture of a mangrove strain of Streptomyces sanyensis which showed activity against kinetoplastids and the Acanthamoeba genus. Hence, in this study, the activity of the previously isolated ICZs, staurosporine (STS), 7-oxostaurosporine (7OSTS), 4′-demethylamino-4′-oxostaurosporine, and streptocarbazole B, was evaluated against two type strains of N. fowleri. Furthermore, the performed activity assays revealed that STS was the most active ICZ presenting an inhibitory concentration 50 (IC50) of 0.08 ± 0.02 µM (SI 109.3). Moreover, STS induced programmed cell death (PCD) in the treated amoebae by triggering DNA condensation, mitochondrial disfunction, cell membrane disruption, and reactive oxygen species (ROS) generation. Therefore, STS could be a promising therapeutic agent against PAM.

Highlights

The free-living amoeboid species Naegleria fowleri is the causal agent of a fatal encephalitis known as primary amoebic meningoencephalitis (PAM) [1,2,3,4]
Naegleria fowleri is an opportunistic pathogenic free-living amoeba which is able to rapidly colonize the central nervous system (CNS) and causes a lethal infection known as primary amoebic meningoencephalitis (PAM)
We aimed to evaluate the potential activity of four natural ICZs (1–4) previously isolated from the culture of the S. sanyensis PBLC04 strain which was collected from a mangrove in Ecuador [22,23,24]

Summary

Introduction

The free-living amoeboid species Naegleria fowleri is the causal agent of a fatal encephalitis known as primary amoebic meningoencephalitis (PAM) [1,2,3,4]. This species, named brain-eating amoeba by the media, is able to colonize the brain after amoeboid-contaminated water enMtiecrrosortghaneisnmas s2a02l0p, 8a,sxsFaOgRe PoEfEaRffReEcVtIeEdWindividuals [2,5,6]. Novel therapeutic molecules for PAM are needed since the current option. 56 presNenattsuuranldceosmirepdoutonxdics,seidsepeecffieaclltys [t1h3o]s.e of marine sources, have been recently reported to present

Objectives

Methods

Results

Discussion

Conclusion