The freshwater cyanobacterium Phormidium sp. LEGE 05292 produces allelochemicals, including the cyclic depsipeptides portoamides, that influence the growth of heterotrophic bacteria, cyanobacteria, and eukaryotic algae. Using 16S rRNA gene amplicon metagenomics, we show here that, under laboratory conditions, the mixture of metabolites exuded by Phormidium sp. LEGE 05292 markedly reduces the diversity of a natural planktonic microbial community. Exposure of the same community to the portoamides alone resulted in a similar outcome. In both cases, after 16 days, alpha-diversity estimates for the allelochemical-exposed communities were less than half of those for the control communities. Photosynthetic organisms, but also different heterotrophic-bacteria taxa were found to be negatively impacted by the allelochemicals. Intriguingly, when Phormidium sp. LEGE 05292 was co-cultured with the microbial community, the latter remained stable and closer to non-exposed than to allelochemical-exposed communities. Overall, our observations indicate that although under optimal growth conditions Phormidium sp. LEGE 05292 is able to synthesize potent allelochemicals that severely impact different microorganisms, its allelopathic effect is not pronounced when in contact with a complex microbial community. Therefore, under ecologically relevant conditions, the allelopathic behavior of this cyanobacterium may be regulated by nutrient availability or by interactions with the surrounding microbiota.

Leishmania infantum (L. infantum) and Leishmania major (L. major) are phylogenetically related protozoan parasites that cause different pathologies in humans (visceral and cutaneous infections, respectively). Here, we report on how these obligatory intracellular pathogens differentially affect the migration of macrophages. Resorting to gap closure assays of infected murine bone marrow derived macrophages, we observed that L. infantum enhances the mobility of these cells. This is not the case of L. major, whose impact on macrophage migration is null. Resorting to kinase inhibition assays, we witnessed that chemical inhibition of phosphoinositide 3-kinase-γ (PI3Kγ) critically impairs cell mobility in all experimental conditions. Importantly, the blockade of tyrosine kinases with dasatinib also slows down naı̈ve and L. major-parasitized cells but not macrophages exposed to L. infantum. The dasatinib-resistant phenotype of L. infantum-infected macrophages aligns with the hypothesis that this parasite invokes a tyrosine kinase-independent pathway to increase the PI3Kγ activity of macrophages and enhance migration.

Leishmaniasis is one of the most neglected diseases in modern times, mainly affecting people from developing countries of the tropics, subtropics and the Mediterranean basin, with approximately 350 million people considered at risk of developing this disease. The incidence of human leishmaniasis has increased over the past decades due to failing prevention and therapeutic measures—there are no vaccines and chemotherapy, which is problematic. Acridine derivatives constitute an interesting group of nitrogen-containing heterocyclic compounds associated with numerous bioactivities, with emphasis to their antileishmanial potential. The present work builds on computational studies focusing on a specific enzyme of the parasite, S-adenosylmethionine decarboxylase (AdoMet DC), with several 1,2,3,4-tetrahydro-acridines emerging as potential inhibitors, evidencing this scaffold as a promising building block for novel antileishmanial pharmaceuticals. Thus, several 1,2,3,4-tetrahydroacridine derivatives have been synthesized, their activity against Leishmania (Leishmania) infantum promastigotes evaluated and a structure–activity relationship (SAR) study was developed based on the results obtained. Even though the majority of the 1,2,3,4-tetrahydroacridines evaluated presented high levels of toxicity, the structural information gathered in this work allowed its application with another scaffold (quinoline), leading to the obtention of N1,N12-bis(7-chloroquinolin-4-yl)dodecane-1,12-diamine (12) as a promising novel antileishmanial agent (IC50 = 0.60 ± 0.11 μM, EC50 = 11.69 ± 3.96 μM and TI = 19.48).

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