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Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected Tropical Diseases affecting millions of people worldwide, mainly in vulnerable territories of tropical and subtropical areas. In general, current treatments against these diseases are old-fashioned, showing adverse effects and loss of efficacy due to misuse or overuse, thus leading to the emergence of resistance. For these reasons, searching for new antitrypanosomatid drugs has become an urgent necessity, and different metabolic pathways have been studied as potential drug targets against these parasites. Considering that trypanosomatids possess a unique redox pathway based on the trypanothione molecule absent in the mammalian host, the key enzymes involved in trypanothione metabolism, trypanothione reductase and trypanothione synthetase, have been studied in detail as druggable targets. In this review, we summarize some of the recent findings on the molecules inhibiting these two essential enzymes for Trypanosoma and Leishmania viability.

Chalcones, a subclass of flavonoid-derived phenolic compounds, have demonstrated promising anthelmintic activity against parasitic nematodes. This study aimed to obtain insights into the biological effects a cis/trans mixture of chalcone and its geometric isomer, trans-chalcone, using RNA sequencing in the model organism Caenorhabditis elegans. Fourth-stage larvae (L4) were exposed to cis/trans-chalcone or trans-chalcone for 3 h, and total RNA was extracted for high-throughput sequencing. Transcriptomic analysis revealed that exposure to cis/trans-chalcone and trans-chalcone induced pronounced modulation of genes involved in lipid metabolism and repression of collagen and structural genes, potentially leading to defective extracellular matrix maintenance, thereby suggesting these combined effects as potential mechanisms underlying their anthelmintic activity. Also, metabolic and stress response pathways, with several genes implicated in detoxification and cellular defense, were markedly upregulated. These findings provide new insights into the molecular mechanisms affected by chalcones, advancing our understanding of their anthelmintic potential and supporting future drug development efforts.

Polymers are essential materials in our daily life. The synthesis of value-added polymers is mainly performed from fossil fuel-derived monomers. However, the adoption of the circular economy model based on the bioeconomy will reduce the dependence on fossil fuels. In this context, biorefineries have emerged to convert biomass into bioenergy and produce high value-added products, including molecules that can be further used as building blocks for the synthesis of biopolymers and bioplastics. The achievement of catalytic systems able to polymerize the natural monomer counterparts, such as terpenes or terpenoids, is still a challenge in the development of polymers with good mechanical, thermal, and chemical properties. This review describes the most common types of bioplastics and biopolymers and focuses specifically on the polymerization of terpenes and terpenoids, which represent a source of promising monomers to create bio-based polymers and copolymers.

Diseases caused by trypanosomatids are serious public health concerns in low-income endemic countries. Leishmaniasis is presented in two main clinical forms, visceral leishmaniasis—caused by L . infantum and L . donovani —and cutaneous leishmaniasis—caused by many species, including L . major , L . tropica and L . braziliensis . As for certain other trypanosomatids, sexual reproduction has been confirmed in these parasites, and formation of hybrids can contribute to virulence, drug resistance or adaptation to the host immune system. In the present work, the capability of intraclonal and interspecies genetic exchange has been investigated using three parental strains: L . donovani , L . tropica and L . major , which have been engineered to express different fluorescent proteins and antibiotic resistance markers in order to facilitate the phenotypic selection of hybrid parasites after mating events. Stationary and exponential-phase promastigotes of each species were used, in in vitro experiments , some of them containing LULO cells (an embryonic cell line derived from Lutzomyia longipalpis ). Several intraclonal hybrids were obtained with L . tropica as crossing progenitor, but not with L . donovani or L . major . In interspecies crossings, three L . donovani x L . major hybrids and two L . donovani x L . tropica hybrids were isolated, thereby demonstrating the feasibility to obtain in vitro hybrids of parental lines causing different tropism of leishmaniasis. Ploidy analysis revealed an increase in DNA content in all hybrids compared to the parental strains, and nuclear analysis showed that interspecies hybrids are complete hybrids, i.e. each of them showing at least one chromosomal set from each parental. Regarding kDNA inheritance, discrepancies were observed between maxi and minicircle heritage. Finally, phenotypic studies showed either intermediate phenotypes in terms of growth profiles, or a decreased in vitro infection capacity compared to the parental cells. To the best of our knowledge, this is the first time that in vitro interspecies outcrossing has been demonstrated between Leishmania species with different tropism, thus contributing to shed light on the mechanisms underlying sexual reproduction in these parasites.

Visceral leishmaniasis caused by Leishmania donovani is one of the major neglected tropical diseases attributable to parasitic protozoa. In the absence of an effective vaccine, chemotherapy remains the only available therapeutic option. However, current treatments rely on a limited number of drugs that are largely obsolete, highly toxic or require intravenous administration, and their extensive use has led to the emergence of drug resistance. Consequently, the discovery of new antileishmanial agents is an urgent priority. In this study, a commercial library of 449 alkaloids in a high-throughput screening format was evaluated against both axenic bone marrow-derived amastigotes and intramacrophagic amastigotes from mice infected with L. donovani IRFP, a strain engineered to emit infrared fluorescence in its viable form. Six isoquinoline-type alkaloids showed the best antileishmanial efficacy against intramacrophagic amastigotes while exhibiting minimal cytotoxicity toward RAW 264.7 and HepG2 cell lines, with a promising selective index higher than four, and good mouse intestinal tolerance in mouse organoids. Among these compounds, the protoberberine scaffold emerged as the most promising candidate for further drug development.

Neglected Tropical Diseases (NTD) represent a serious threat to humans, especially for those living in poor or developing countries. Almost one-sixth of the world population is at risk of suffering from these diseases and many thousands die because of NTDs, to which we should add the sanitary, labor and social issues that hinder the economic development of these countries. Protozoan-borne diseases are responsible for more than one million deaths every year. Visceral leishmaniasis, Chagas disease or sleeping sickness are among the most lethal NTDs. Despite not being considered an NTD by the World Health Organization (WHO), malaria must be added to this sinister group. Malaria, caused by the apicomplexan parasite Plasmodium falciparum, is responsible for thousands of deaths each year. The treatment of this disease has been losing effectiveness year after year. Many of the medicines currently in use are obsolete due to their gradual loss of efficacy, their intrinsic toxicity and the emergence of drug resistance or a lack of adherence to treatment. Therefore, there is an urgent and global need for new drugs. Despite this, the scant interest shown by most of the stakeholders involved in the pharmaceutical industry makes our present therapeutic arsenal scarce, and until recently, the search for new drugs has not been seriously addressed. The sources of new drugs for these and other pathologies include natural products, synthetic molecules or repurposing drugs. The most frequent sources of natural products are microorganisms, e.g., bacteria, fungi, yeasts, algae and plants, which are able to synthesize many drugs that are currently in use (e.g. antimicrobials, antitumor, immunosuppressants, etc.). The marine environment is another well-established source of bioactive natural products, with recent applications against parasites, bacteria and other pathogens which affect humans and animals. Drug discovery techniques have rapidly advanced since the beginning of the millennium. The combination of novel techniques that include the genetic modification of pathogens, bioimaging and robotics has given rise to the standardization of High-Performance Screening platforms in the discovery of drugs. These advancements have accelerated the discovery of new chemical entities with antiparasitic effects. This review presents critical updates regarding the use of High-Throughput Screening (HTS) in the discovery of drugs for NTDs transmitted by protozoa, including malaria, and its application in the discovery of new drugs of marine origin.

Leishmania infantum is the vector-borne trypanosomatid parasite causing visceral leishmaniasis in the Mediterranean basin. This neglected tropical disease is treated with a limited number of obsolete drugs that are not exempt from adverse effects and whose overuse has promoted the emergence of resistant pathogens. In the search for novel antitrypanosomatid molecules that help overcome these drawbacks, drug repurposing has emerged as a good strategy. Nitroaromatic compounds have been found in drug discovery campaigns as promising antileishmanial molecules. Fexinidazole (recently introduced for the treatment of stages 1 and 2 of African trypanosomiasis), and pretomanid, which share the nitroimidazole nitroaromatic structure, have provided antileishmanial activity in different studies. In this work, we have tested the in vitro efficacy of these two nitroimidazoles to validate our 384-well high-throughput screening (HTS) platform consisting of L. infantum parasites emitting the near-infrared fluorescent protein (iRFP) as a biomarker of cell viability. These molecules showed good efficacy in both axenic and intramacrophage amastigotes and were poorly cytotoxic in RAW 264.7 and HepG2 cultures. Fexinidazole and pretomanid induced the production of ROS in axenic amastigotes but were not able to inhibit trypanothione reductase (TryR), thus suggesting that these compounds may target thiol metabolism through a different mechanism of action.

To maintain the world population demand, a sustainable agriculture is needed. Since current global vision is more friendly with the environment, eco-friendly alternatives are desirable. In this sense, plant growth–promoting rhizobacteria could be the choice for the management of soil-borne diseases of crop plants. These rhizobacteria secrete chemical compounds which act as phytohormones. Indole-3-acetic acid (IAA) is the most common plant hormone of the auxin class which regulates various processes of plant growth. IAA compound, in which structure can be found a carboxylic acid attached through a methylene group to the C-3 position of an indole ring, is produced both by plants and microorganisms. Plant growth–promoting rhizobacteria and fungi secrete IAA to promote the plant growth. In this review, IAA production and mechanisms of action by bacteria and fungi along with the metabolic pathways evolved in the IAA secretion and commercial prospects are revised.Key points• Many microorganisms produce auxins which help the plant growth promotion.• These auxins improve the plant growth by several mechanisms.• The auxins are produced through different mechanisms.

Due to the lack of specific vaccines, management of the trypanosomatid-caused neglected tropical diseases (sleeping sickness, Chagas disease and leishmaniasis) relies exclusively on pharmacological treatments. Current drugs against them are scarce, old and exhibit disadvantages, such as adverse effects, parenteral administration, chemical instability and high costs which are often unaffordable for endemic low-income countries. Discoveries of new pharmacological entities for the treatment of these diseases are scarce, since most of the big pharmaceutical companies find this market unattractive. In order to fill the pipeline of compounds and replace existing ones, highly translatable drug screening platforms have been developed in the last two decades. Thousands of molecules have been tested, including nitroheterocyclic compounds, such as benznidazole and nifurtimox, which had already provided potent and effective effects against Chagas disease. More recently, fexinidazole has been added as a new drug against African trypanosomiasis. Despite the success of nitroheterocycles, they had been discarded from drug discovery campaigns due to their mutagenic potential, but now they represent a promising source of inspiration for oral drugs that can replace those currently on the market. The examples provided by the trypanocidal activity of fexinidazole and the promising efficacy of the derivative DNDi-0690 against leishmaniasis seem to open a new window of opportunity for these compounds that were discovered in the 1960s. In this review, we show the current uses of nitroheterocycles and the novel derived molecules that are being synthesized against these neglected diseases.

One of the major drawbacks of current treatments for neglected tropical diseases is the low safety of the drugs used and the emergence of resistance. Leishmaniasis is a group of neglected diseases caused by protozoa of the trypanosomatidae family that lacks preventive vaccines and whose pharmacological treatments are scarce and unsafe. Combination therapy is a strategy that could solve the above-mentioned problems, due to the participation of several mechanisms of action and the reduction in the amount of drug necessary to obtain the therapeutic effect. In addition, this approach also increases the odds of finding an effective drug following the repurposing strategy. From the previous screening of two collections of repositioning drugs, we found that pyrvinium pamoate had a potent leishmanicidal effect. For this reason, we decided to combine it separately with two clinically used leishmanicidal drugs, miltefosine and paromomycin. These combinations were tested in axenic amastigotes of 'Leishmania infantum' obtained from bone marrow cells and in intramacrophagic amastigotes obtained from primary cultures of splenic cells, both cell types coming from experimentally infected mice. Some of the combinations showed synergistic behavior, especially in the case of the combination of pyrvinium pamoate with paromomycin, and exhibited low cytotoxicity and good tolerability on intestinal murine organoids, which reveal the potential of these combinations for the treatment of leishmaniasis.