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Chemical Communication, Membrane Vesicles, Secondary Metabolites, Silent Biosynthetic Gene Clusters Keywords: Chemical Communication; Membrane Vesicles; Secondary Metabolites; Silent Biosynthetic Gene Clusters EN Chemical Communication Membrane Vesicles Secondary Metabolites Silent Biosynthetic Gene Clusters 1 1 1 10/12/23 20231016 NES 231016 B Bacterial membrane vesicles b (MVs), which transport small molecules, proteins, and nucleotides within a lipid bilayer, serve as communication facilitators. Toshiyuki Wakimoto et al. revealed in their Research Article (e202307304) that MVs-mediated interbacterial communication triggers silent secondary metabolite production in various bacteria. [Extracted from the article]

ABSTRACT Trypanosomatids are the etiologic agents of numerous parasitic diseases that cause significant morbidity and mortality in millions of people and animals around the world. Approved antitrypanosomatid agents are limited by several drawbacks, such as severe toxicity, lengthy treatment, need for hospitalization, and susceptibility to drug resistance. Consequently, parasitic diseases remain a substantial public health problem, and new drugs are required, especially drugs suitable for rural health systems that have limited resources. In an attempt to find antitrypanosomatid agents to address this problem, we report here on the synthesis and biological efficacy of ferrocene derivatives of nifuroxazide and nitrofurazone, which were designed by replacing the nitrofuran scaffold within their structures with the ferrocene moiety. The 1,2‐disubstituted ferrocene intermediates 8 and 9, featuring amine and carboxaldehyde groups, exhibited the best in vitro antiamastigote activity against Leishmania major strain NIH S and Leishmania donovani strain 9515, respectively. Ferroxazide derivative 15 was revealed as a mammalian cell nontoxic hit compound against Trypanosoma congolense strain IL3000 trypomastigotes; however, no in vivo treatment efficacy was observed against T. congolense strain IL3000‐infected BALB/c mice during a preliminary animal study. The synthesized ferrocene derivatives were poorly soluble in the in vitro and in vivo testing media, hindering uniform sampling and dosing. This study's outcome indicates that replacing the 5‐nitrofuran moiety with ferrocene did not increase antitrypanosomatid activity compared to the nitrofuran parent drugs nifuroxazide and nitrofurazone. [ABSTRACT FROM AUTHOR]

Neglected tropical diseases are a group of infectious diseases with a high endemicity in developing countries of Africa, Asia, and the Americas. Treatment for these diseases depends solely on chemotherapy, which is associated with severe side effects, toxicity, and the development of parasitic resistance. This highlights a critical need to develop new and effective drugs to curb these diseases. As a result, a series of novel isatinylhydantoin derivatives were synthesized and evaluated for in vitro anti-kinetoplastid activity against seven human- or animal-infective Trypanosoma and two human-infective Leishmania species. The synthesized derivatives were tested for potential cytotoxicity against human, animal, and parasite host-related cell lines. The isatinylhydantoin hybrid 4 b bearing 5-chloroisatin and p-bromobenzyl moieties, showed strong trypanocidal activity against blood-stage T. congolense parasites; however, the promising in vitro trypanocidal potency of 4 b could not be translated to in vivo treatment efficacy in a preliminary animal study. Compounds 5, 2 b, and 5 b, were the most active against amastigotes of L. donovani, showing higher leishmanicidal activity than the reference drug, amphotericin B. These compounds were identified as early antileishmanicidal leads, and future investigations will focus on confirming their antileishmanial potential through in vivo efficacy evaluation as well as their exact mechanism of action., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

No abstract available.

Most bacterial biosynthetic gene clusters (BGCs) are "silent BGCs" that are expressed poorly or not at all under normal culture conditions. However, silent BGCs, even in part, may be conditionally expressed in response to external stimuli in the original bacterial habitats. The growing knowledge of bacterial membrane vesicles (MVs) suggests that they could be promising imitators of the exogenous stimulants, especially given their functions as signaling mediators in bacterial cell-to-cell communication. Therefore, we envisioned that MVs added to bacterial cultures could activate diverse silent BGCs. Herein, we employed Burkholderia multivorans MVs, which induced silent metabolites in a wide range of bacteria in Actinobacteria, Bacteroidetes and Proteobacteria phyla. A mechanistic analysis of MV-induced metabolite production in Xenorhabdus innexi suggested that the B. multivorans MVs activate silent metabolite production by inhibiting quorum sensing in X. innexi. In turn, the X. innexi MVs carrying some MV-induced peptides suppressed the growth of B. multivorans, highlighting the interspecies communication between B. multivorans and X. innexi through MV exchange., (© 2023 Wiley-VCH GmbH.)

Two benzophenone glucosides ( 1 and 2 ), five flavan-3-ol dimers ( 5 - 9 ), and 17 known compounds ( 3 , 4 , and 10 - 24 ) were identified from the bark extract of Cassia abbreviata . The chemical structures display two points of interest. First, as an unusual characteristic feature of the 1 H NMR spectra of 1 and 2 , the signals for the protons on glucosidic carbons C-2 are shielded as compared to those generally observed for glucosyl moieties. The geometrically optimized 3D structures derived from conformational analysis and density functional theory (DFT) calculations revealed that this shielding effect originates from intramolecular hydrogen bonds in 1 and 2 . Additionally, 3 - 15 were identified as dimeric B-type proanthocyanidins, which have 2 R ,3 S -absolute-configured C-rings and C-4-C-8″ linkages, as evidenced by X-ray crystallography and by NMR and ECD spectroscopy. These results suggest the structure-determining procedures for some reported dimers need to be reconsidered. The trypanocidal activities of the isolated compounds against Trypanosoma brucei brucei , T. b. gambiense , T. b. rhodesiense , T. congolense , and T. evansi were evaluated, and the active compounds were identified.

The Trypanosoma spp. cause animal and human trypanosomiasis characterized with appreciable health and economic burden mostly in developing nations. There is currently no effective therapy for this parasitic disease, due to poor drug efficacy, drug resistance, and unwanted toxicity, etc. Therefore, new anti- Trypanosoma agents are urgently needed. This study explored new series of imidazoles for anti- Trypanosoma properties in vitro and in vivo . The imidazoles showed moderate to strong and specific action against growth of T. congolense . For example, the efficacy of the imidazole compounds to restrict Trypanosoma growth in vitro was ≥ 12-fold specific towards T. congolense relative to the mammalian cells. Additionally, the in vivo study revealed that the imidazoles exhibited promising anti- Trypanosoma efficacy corroborating the in vitro anti-parasite capacity. In particular, three imidazole compounds (C1, C6, and C8) not only cleared the systemic parasite burden but cured infected rats after no death was recorded. On the other hand, the remaining five imidazole compounds (C2, C3, C4, C5, and C7) drastically reduced the systemic parasite load while extending survival time of the infected rats by 14 days as compared with control. Untreated control died 3 days post-infection, while the rats treated with diminazene aceturate were cured comparable to the results obtained for C1, C6, and C8. In conclusion, this is the first study demonstrating the potential of these new series of imidazoles to clear the systemic parasite burden in infected rats. Furthermore, a high selectivity index of imidazoles towards T. congolense in vitro and the oral LD 50 in rats support anti-parasite specific action. Together, findings support the anti-parasitic prospects of the new series of imidazole derivatives., (Copyright ©2021, Yale Journal of Biology and Medicine.)

We screened cattle and goats from the districts of Chama, Monze and Mumbwa in Zambia for animal African trypanosomes, Babesia bigemina and Theileria parva using PCRs; 38.1% of the samples tested positive for at least one of the parasite species. The most common parasite was Trypanosoma vivax (19.8%). Its incidence was significantly higher in goats than in cattle, (P<0.05). B. bigemina was found in samples from all the three areas, making it the most widespread of the parasites in Zambia. Among the tested samples, 12.0% of the positive samples were mixed infections. There were significant differences in the infection rates of T. vivax (Mumbwa had a significantly higher infection rate [39.6%, P<0.0001]), Th. parva (Monze had the only cases [P<0.0004]) and B. bigemina (Monze had a significantly higher infection rate [40.5%, P<0.0001]). According to the hematocrit values, the packed cell volume (%) among the cattle with mixed infections was significantly lower than that of the other cattle. The presence of multiple parasite species and mixed infections among the Zambian cattle and goat populations is of both clinical and economic importance to livestock farming. The absence of trypanosomosis among the samples from Monze can be attributed to tsetse eradication efforts that took place around Lake Kariba. This shows that the prevention and control of these parasitic diseases can have a significant impact on the disease status, which can translate directly into the improvement of the livestock sector in Zambia.

Cell viability assays using multi-well cell culture plates are frequently used for in vitro drug screening. We herein describe an ATP-based luciferase viability assay for animal African trypanosomes using a 96-well plate. This assay could be further applied to the screening of novel compounds for the treatment of animal African trypanosomiasis.