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

• Main Authors: Aitor Rizo-Liendo, Ines Sifaoui, Luis Cartuche, Iñigo Arberas-Jiménez, María Reyes-Batlle, José J. Fernández, José E. Piñero, Ana R. Díaz-Marrero, Jacob Lorenzo-Morales
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: Microorganisms
• Subjects: indolocarbazoles; staurosporine; <i>Naegleria fowleri</i>; brain; amoeba; PAM
• Online Access: https://www.mdpi.com/2076-2607/8/5/789

<em>Naegleria fowleri</em> 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 <em>N. fowleri</em> 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 <em>Streptomyces sanyensis </em>which showed activity against kinetoplastids and the <em>Acanthamoeba </em>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 <em>N. fowleri</em>. 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.