New synthetic molecules incorporated into polymeric micelles used for treatment against visceral leishmaniasis.

Treatment against visceral leishmaniasis (VL) presents problems, mainly related to drug toxicity, high cost and/or by emergence of resistant strains. In the present study, two vanillin synthetic derivatives, 3 s [4-(2-hydroxy-3-(4-octyl-1H-1,2,3-triazol-1-yl)propoxy)-3-methoxybenzaldehyde] and 3 t [4-(3-(4-decyl-1H-1,2,3-triazol-1-yl)-2-hydroxypropoxy)-3-methoxybenzaldehyde], were evaluated as therapeutic candidates in a murine model against Leishmania infantum infection. Molecules were used pure (3 s and 3 t) or incorporated into Poloxamer 407-based micelles (3 s/M and 3 t/M) in the infected animals, which also received amphotericin B (AmpB) or Ambisome® as control. Results showed that 3 s/M and 3 t/M compositions induced a Th1-type immune response in treated animals, with higher levels of IFN-γ, IL-2, TNF-α, IL-12, nitrite, and IgG2a antibodies. Animals presented also low toxicity and significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes, as compared as control groups mice, with the evaluations performed one and 30 days after the application of the therapeutics. In conclusion, preliminary data suggest that 3 s/M and 3 t/M could be considered for future studies as therapeutic agents against VL.

Insecticidal effect of metabolites identified in edible mushrooms against Rhyssomatus nigerrimus Fahraeus / Efeito inseticida dos metabólitos identificados nos cogumelos comestíveis contra Rhyssomatus nigerrimus Fahraeus

Excessive use of insecticides has led to resistance of some pathogenic organisms (nematodes, bacteria and fungi), environmental contamination, and the presence of hazardous residues. Therefore, the aim of the present study was to evaluate synthetic metabolites derived from previous studies with edible mushrooms against the soybean weevil Rhyssomatus nigerrimus Fahraeus (Curculonidae) because of the relevance of pest control in an economically important crop. Furthermore, this is one of the first studies where edible fungal molecules are evaluated for the control of these insects. Initially, two in vitro tests (toxic effect and immersion) were evaluated against R. nigerrimus. In these tests, sensitivity and viability were determined in the 2% Tween control in water. For these two tests, the synthetic metabolites pentadecanoic acid (PNA), palmitic acid (PMA), stearic acid (STA), linoleic acid (LNA), ß-sitosterol (ßT) were evaluated individually as well as in combinations, "the fraction of standards (E1)". Based on the results obtained, the dip test was selected to evaluate the mixtures of two standards (1. PMA + ßT, 2. PMA + PNA, 3. PMA + LNA, 4. PMA + STA, 5. STA + ßT, 6. STA + PNA, 7. STA + LNA, 8. PNA + ßT, 9. PNA + LNA, 10. LNA + ßT), three (1. PNA + ßT + LNA, 2. PNA + ßT + STA, 3. STA + LNA + PNA and 4. STA + LNA + ßT) and four (PNA, ßT, LNA and STA). The results showed that the mixture of three standards caused a higher percentage of mortality relative to the control group: l. PNA + ßT + LNA and 2. PNA + ßT + STA with 54.44 and 48% mortality of R. nigerrimus insects exposed for 15 days. These results show the importance of evaluating mixtures of molecules against R. nigerrimus.

O uso excessivo de inseticidas levou à resistência de alguns organismos patogênicos (nematódeos, bactérias e fungos), à contaminação ambiental e à presença de resíduos perigosos. Portanto, o objetivo do presente estudo foi avaliar a mortalidade de metabólitos sintéticos derivados de estudos anteriores com cogumelos comestíveis contra o gorgulho-da-soja Rhyssomatus nigerrimus Fahraeus (Curculonidae) por causa da relevância do controle de pragas em uma cultura economicamente importante. Além disso, este é um dos primeiros estudos em que as moléculas fúngicas comestíveis são avaliadas para o controle desses insetos. Inicialmente, dois testes in vitro (efeito tóxico e imersão) foram avaliados contra R. nigerrimus. Nesses testes, a sensibilidade e a viabilidade foram determinadas no controle de 2% de Tween na água. Para esses dois testes, os metabólitos sintéticos ­ ácido pentadecanoico (PNA), ácido palmítico (PMA), ácido esteárico (STA), ácido linoleico (LNA) e ß-sitosterol (ßT) ­ foram avaliados individualmente, bem como a combinação dos 5, "a fração de padrões (E1)". Com base nos resultados obtidos, o teste de imersão foi selecionado para avaliar as misturas de dois padrões (1. PMA + ßT, 2. PMA + PNA, 3. PMA + LNA, 4. PMA + STA, 5. STA + ßT, 6. STA + PNA, 7. STA + LNA, 8. PNA + ßT, 9. PNA + LNA, 10. LNA + ßT), três (1. PNA + ßT + LNA, 2. PNA + ßT + STA, 3. STA + LNA + PNA e 4. STA + LNA + ßT) e quatro (PNA, ßT, LNA e STA). Os resultados mostraram que a mistura de três padrões foi a com maior porcentagem de mortalidade em relação ao grupo controle, quais sejam, l. PNA + ßT + LNA e 2. PNA + ßT + STA, com 54,44% e 48% de mortalidade, respectivamente, em uma exposição de 15 dias contra R. nigerrimus. Estes resultados mostram a importância de avaliar as misturas entre moléculas contra R. nigerrimus.

Molecular Docking of Lac_CB10: Highlighting the Great Potential for Bioremediation of Recalcitrant Chemical Compounds by One Predicted Bacteroidetes CopA-Laccase.

Laccases are multicopper oxidases (MCOs) with a broad application spectrum, particularly in second-generation ethanol biotechnology and the bioremediation of xenobiotics and other highly recalcitrant compounds. Synthetic pesticides are xenobiotics with long environmental persistence, and the search for their effective bioremediation has mobilized the scientific community. Antibiotics, in turn, can pose severe risks for the emergence of multidrug-resistant microorganisms, as their frequent use for medical and veterinary purposes can generate constant selective pressure on the microbiota of urban and agricultural effluents. In the search for more efficient industrial processes, some bacterial laccases stand out for their tolerance to extreme physicochemical conditions and their fast generation cycles. Accordingly, to expand the range of effective approaches for the bioremediation of environmentally important compounds, the prospection of bacterial laccases was carried out from a custom genomic database. The best hit found in the genome of Chitinophaga sp. CB10, a Bacteroidetes isolate obtained from a biomass-degrading bacterial consortium, was subjected to in silico prediction, molecular docking, and molecular dynamics simulation analyses. The putative laccase CB10_180.4889 (Lac_CB10), composed of 728 amino acids, with theoretical molecular mass values of approximately 84 kDa and a pI of 6.51, was predicted to be a new CopA with three cupredoxin domains and four conserved motifs linking MCOs to copper sites that assist in catalytic reactions. Molecular docking studies revealed that Lac_CB10 had a high affinity for the molecules evaluated, and the affinity profiles with multiple catalytic pockets predicted the following order of decreasing thermodynamically favorable values: tetracycline (-8 kcal/mol) > ABTS (-6.9 kcal/mol) > sulfisoxazole (-6.7 kcal/mol) > benzidine (-6.4 kcal/mol) > trimethoprim (-6.1 kcal/mol) > 2,4-dichlorophenol (-5.9 kcal/mol) mol. Finally, the molecular dynamics analysis suggests that Lac_CB10 is more likely to be effective against sulfisoxazole-like compounds, as the sulfisoxazole-Lac_CB10 complex exhibited RMSD values lower than 0.2 nm, and sulfisoxazole remained bound to the binding site for the entire 100 ns evaluation period. These findings corroborate that LacCB10 has a high potential for the bioremediation of this molecule.

Candida albicans antibiofilm molecules: analysis based on inhibition and eradication studies.

Biofilms are communities of microbial cells surrounded by an extracellular polysaccharide matrix, recognized as a fungal source for local and systemic infections and less susceptible to antifungal drugs. Thus, treatment of biofilm-related Candida spp. infections with popular antifungals such as fluconazole is limited and species-dependent and alternatively demands the use of expensive and high toxic drugs. In this sense, molecules with antibiofilm activity have been studied but without care regarding the use of important criteria such as antibiofilm concentration lower than antifungal concentration when considering the process of inhibition of formation and concentrations equal to or lower than 300 µM. Therefore, this review tries to gather the most promising molecules regarding the activity against the C. albicans biofilm described in the last 10 years, considering the activity of inhibition and eradication. From January 2011 to July 2021, articles were searched on Scopus, PubMed, and Science Direct, combining the keywords "antibiofilm," "candida albicans," "compound," and "molecule" with AND and OR operators. After 3 phases of selection, 21 articles describing 42 molecules were discussed in the review. Most of them were more promising for the inhibition of biofilm formation, with SM21 (24) being an interesting molecule for presenting inhibitory and eradication activity in biofilms with 24 and 48 h, as well as alizarin (26) and chrysazine (27), with concentrations well below the antifungal concentration. Despite the detection of these molecules and the attempts to determine the mechanisms of action by microscopic analysis and gene expression, no specific target has been determined. Thus, a gap is signaled, requiring further studies such as proteomic analyses to clarify it.

New Approaches for Cryptococcosis Treatment.

Cryptococcosis is an important opportunistic infection and a leading cause of meningitis in patients with HIV infection. The antifungal pharmacological treatment is limited to amphotericin B, fluconazole and 5- flucytosine. In addition to the limited pharmacological options, the high toxicity, increased resistance rate and difficulty of the currently available antifungal molecules to cross the blood-brain barrier hamper the treatment. Thus, the search for new alternatives for the treatment of cryptococcal meningitis is extremely necessary. In this review, we describe the therapeutic strategies currently available, discuss new molecules with antifungal potential in different phases of clinical trials and in advanced pre-clinical phase, and examine drug nanocarriers to improve delivery to the central nervous system.