Enterocin AS-48 as Evidence for the Use of Bacteriocins as New Leishmanicidal Agents

Author:

Abengózar María Ángeles1,Cebrián Rubén2,Saugar José María13,Gárate Teresa3,Valdivia Eva2,Martínez-Bueno Manuel2,Maqueda Mercedes2,Rivas Luis1

Affiliation:

1. Centro de Investigaciones Biológicas (CSIC), Physico-Chemical Biology Department Unidad Asociada Interacciones, Metabolismo y Bioanálisis CSIC-CEU, Madrid, Spain

2. Departamento de Microbiología, Facultad de Ciencias, Universidad de Granada, Granada, Spain

3. Helminth Unit, Parasitology Department, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain

Abstract

ABSTRACT We report the feasibility of enterocin AS-48, a circular cationic peptide produced by Enterococcus faecalis , as a new leishmanicidal agent. AS-48 is lethal to Leishmania promastigotes as well as to axenic and intracellular amastigotes at low micromolar concentrations, with scarce cytotoxicity to macrophages. AS-48 induced a fast bioenergetic collapse of L. donovani promastigotes but only a partial permeation of their plasma membrane with limited entrance of vital dyes, even at concentrations beyond its full lethality. Fluoresceinated AS-48 was visualized inside parasites by confocal microscopy and seen to cause mitochondrial depolarization and reactive oxygen species production. Altogether, AS-48 appeared to have a mixed leishmanicidal mechanism that includes both plasma membrane permeabilization and additional intracellular targets, with mitochondrial dysfunctionality being of special relevance. This complex leishmanicidal mechanism of AS-48 persisted even for the killing of intracellular amastigotes, as evidenced by transmission electron microscopy. We demonstrated the potentiality of AS-48 as a new and safe leishmanicidal agent, expanding the growing repertoire of eukaryotic targets for bacteriocins, and our results provide a proof of mechanism for the search of new leishmanicidal bacteriocins, whose diversity constitutes an almost endless source for new structures at moderate production cost and whose safe use on food preservation is well established.

Funder

Subdirección General de Redes y Centros de Investigación Cooperativa-FEDER, RICET

Subdirección General de Redes y Centros de Investigación Cooperativa FEDER, RICET

European Regional Development Fund

Research Group General, Universidad de Granada

Fondo de Investigaciones Sanitarias-ISCIII-FEDER

Secretaria de Estado de Investigación, Desarrollo e Innovación

Plan Secretaria de Estado de Investigación, Desarrollo e Innovación

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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