Insights into Chagas treatment based on the potential of bacteriocin AS-48

Abstract

Chagas disease caused by the protozoan parasite Trypanosoma cruzi represents a significant public health problem in Latin America, affecting around 8 million cases worldwide. Nowadays is urgent the identification of new antichagasic agents as the only therapeutic options available, Nifurtimox and Benznidazole, are in use for >40 years, and present high toxicity, limited efficacy and frequent treatment failures in the chronic phase of the disease. Recently, it has been described the antiparasitic effect of AS-48, a bacteriocin produced by Enterococcus faecalis , against Trypanosoma brucei and Leishmania spp. In this work, we have demonstrated the in vitro potential of the AS-48 bacteriocin against T. cruzi . Interesting, AS-48 was more effective against the three morphological forms of different T. cruzi strains, and displayed lower cytotoxicity than the reference drug Benznidazole. In addition, AS-48 combines the criteria established as a potential antichagasic agent, resulting in a promising therapeutic alternative. According to the action mechanism, AS-48 trypanocidal activity could be explained in a mitochondrion-dependent manner through a reactive oxygen species production and mitochondrial depolarization, causing a fast and severe bioenergetic collapse.

Preclinical studies of toxicity and safety of the AS-48 bacteriocin

“…However, in some eukaryotic organisms, such as parasites with negatively charged membranes (i.e. trypanosomatids), AS-48 is very effective (even more than against some bacteria) [53], [54], [55].…”

Current trends in the pharmacological management of Chagas disease

“…In addition to improving LYC pharmacokinetic parameters (iv), the NC protected the encapsulated LYC from degradation in mouse plasma.García-Huertaz et al (2018)Furofuran lignan ( Piper jericoense )Vero cells and Balb/c miceActive against all parasite forms and presented lower toxicity than Benznidazole. Reduced parasitemia in acute phaseVillanueva-Lizama et al (2018)TSA-1 and Tc24 antigensPatients (human)Results confirm the ability of both TSA-1 and Tc24 recombinant proteins to recall an immune response induced by native antigens during natural infection.Paixão et al (2019)1,10-phenanthroline2,2-bipyridine4-4′-dimethoxy-2-2′-bipyridineL929 cells and Balb/c miceHigher anti- Trypanosoma cruzi activity than benznidazole.Reduction of parasitemia during acute phase.Miana et al (2019)N-arylsulfonyl-benzimidazolesVero cellsBioactivity against epimastigote and amastigote forms, with less cytotoxicity than BenzinidazoleMartín-Escolano et al (2019)Tris(2-aminomethyl)amineVero cells and Balb/c miceTrypanocidal efficacy in acute and chronic Chagas disease, with lower toxicity than benznidazoleSülsen et al (2019)Estafietin (Sesquiterpene lactones derivatives)Vero cellsTrypanocidal activity, Epoxyestafietin was the most active compound against T. cruzi trypomastigotes and amastigotesBastos et al (2019)Natural compounds isolated from cashew nut ( Anacardium occidentale, L. Anacardiaceae )hFIB cellsInhibition the enzyme sirtuin, with anti- T. cruzi effects similar to those of benznidazole.Martín-Escolano et al (2019)AS-48 (Bacteriocin)Vero cellsEffective against all T. cruzi morphological forms, displaying lower cytotoxicity than Benznidazole.Do Carmo et al (2019)CordycepinPentostatinHeLa cells and swiss micePotent trypanocidal effect in vitro . However, reduced curative effect in vivo.ND* not determined.…”

Review on Experimental Treatment Strategies Against Trypanosoma cruzi

“… [ 87–89 ] Antimicrobial peptides AS-48 Bacteriocin AS-48 was active in vitro and in acute stage of mice infection it reduced parasitemia and in chronic stage the parasitic load. [ 98 , 99 ] Copper complexes Ternary copper (II) complexes Compounds with higher selectivity index were able to reduce parasitemia. [ 100 ] Cysteine protease inhibitors and Cruzipain inhibitors Fluoromethyl ketone–derivatized pseudopeptides K777 is an irreversible peptidyl inhibitor of cruzipain and it was able to reduce parasitemia and mortality, and induce cure in murine model.…”