Transcriptomic Changes in Cisplatin-Resistant MCF-7 Cells.

Breast cancer is a leading cause of cancer-related deaths among women. Cisplatin is used for treatment, but the development of resistance in cancer cells is a significant concern. This study aimed to investigate changes in the transcriptomes of cisplatin-resistant MCF7 cells. We conducted RNA sequencing of cisplatin-resistant MCF7 cells, followed by differential expression analysis and bioinformatic investigations to identify changes in gene expression and modified signal transduction pathways. We examined the size and quantity of extracellular vesicles. A total of 724 genes exhibited differential expression, predominantly consisting of protein-coding RNAs. Notably, two long non-coding RNAs (lncRNAs), NEAT1 and MALAT, were found to be dysregulated. Bioinformatic analysis unveiled dysregulation in processes related to DNA synthesis and repair, cell cycle regulation, immune response, and cellular communication. Additionally, modifications were observed in events associated with extracellular vesicles. Conditioned media from resistant cells conferred resistance to wild-type cells in vitro. Furthermore, there was an increase in the number of vesicles in cisplatin-resistant cells. Cisplatin-resistant MCF7 cells displayed differential RNA expression, including the dysregulation of NEAT1 and MALAT long non-coding RNAs. Key processes related to DNA and extracellular vesicles were found to be altered. The increased number of extracellular vesicles in resistant cells may contribute to acquired resistance in wild-type cells.

OSMAC Approach and Cocultivation for the Induction of Secondary Metabolism of the Fungus Pleotrichocladium opacum.

The application of an OSMAC (One Strain-Many Compounds) approach on the fungus Pleotrichocladium opacum, isolated from a soil sample collected on the coast of Asturias (Spain), using different culture media, chemical elicitors, and cocultivation techniques resulted in the isolation and identification of nine new compounds (8, 9, 12, 15-18, 20, 21), along with 15 known ones (1-7, 10, 11, 14, 19, 22-25). Compounds 1-9 were detected in fungal extracts from JSA liquid fermentation, compounds 10-12 were isolated from a solid rice medium, whereas compounds 14 and 15 were isolated from a solid wheat medium. Addition of 5-azacytidine to the solid rice medium caused the accumulation of compounds 16-18, whereas adding N-acetyl-d-glucosamine triggered the production of two additional metabolites, 19 and 20. Finally, cocultivation of the fungus Pleotrichocladium opacum with Echinocatena sp. in a solid PDA medium led to the production of five additional natural products, 21-25. The structures of the new compounds were elucidated by HRESIMS and 1D and 2D NMR as well as by comparison with literature data. DP4+ and mix-J-DP4 computational methods were applied to determine the relative configurations of the novel compounds, and in some cases, the absolute configurations were assigned by a comparison of the optical rotations with those of related natural products.

Tanzawaic Acids, a Chemically Novel Set of Bacterial Conjugation Inhibitors.

Bacterial conjugation is the main mechanism for the dissemination of multiple antibiotic resistance in human pathogens. This dissemination could be controlled by molecules that interfere with the conjugation process. A search for conjugation inhibitors among a collection of 1,632 natural compounds, identified tanzawaic acids A and B as best hits. They specially inhibited IncW and IncFII conjugative systems, including plasmids mobilized by them. Plasmids belonging to IncFI, IncI, IncL/M, IncX and IncH incompatibility groups were targeted to a lesser extent, whereas IncN and IncP plasmids were unaffected. Tanzawaic acids showed reduced toxicity in bacterial, fungal or human cells, when compared to synthetic conjugation inhibitors, opening the possibility of their deployment in complex environments, including natural settings relevant for antibiotic resistance dissemination.

Synthetic Fatty Acids Prevent Plasmid-Mediated Horizontal Gene Transfer.

UNLABELLED: Bacterial conjugation constitutes a major horizontal gene transfer mechanism for the dissemination of antibiotic resistance genes among human pathogens. Antibiotic resistance spread could be halted or diminished by molecules that interfere with the conjugation process. In this work, synthetic 2-alkynoic fatty acids were identified as a novel class of conjugation inhibitors. Their chemical properties were investigated by using the prototype 2-hexadecynoic acid and its derivatives. Essential features of effective inhibitors were the carboxylic group, an optimal long aliphatic chain of 16 carbon atoms, and one unsaturation. Chemical modification of these groups led to inactive or less-active derivatives. Conjugation inhibitors were found to act on the donor cell, affecting a wide number of pathogenic bacterial hosts, including Escherichia, Salmonella, Pseudomonas, and Acinetobacter spp. Conjugation inhibitors were active in inhibiting transfer of IncF, IncW, and IncH plasmids, moderately active against IncI, IncL/M, and IncX plasmids, and inactive against IncP and IncN plasmids. Importantly, the use of 2-hexadecynoic acid avoided the spread of a derepressed IncF plasmid into a recipient population, demonstrating the feasibility of abolishing the dissemination of antimicrobial resistances by blocking bacterial conjugation. IMPORTANCE: Diseases caused by multidrug-resistant bacteria are taking an important toll with respect to human morbidity and mortality. The most relevant antibiotic resistance genes come to human pathogens carried by plasmids, mainly using conjugation as a transmission mechanism. Here, we identified and characterized a series of compounds that were active against several plasmid groups of clinical relevance, in a wide variety of bacterial hosts. These inhibitors might be used for fighting antibiotic-resistance dissemination by inhibiting conjugation. Potential inhibitors could be used in specific settings (e.g., farm, fish factory, or even clinical settings) to investigate their effect in the eradication of undesired resistances.

New cytotoxic indolic metabolites from a marine Streptomyces.

Three new cytotoxic 3,6-disubstituted indoles (1-3) were isolated from the mycelium of a strain identified as Streptomyces sp. (BL-49-58-005), which was separated from a Mexican marine invertebrate, and their structures established by analysis of NMR and mass spectral data. GI(50) values for 1 and 2 in cytotoxic bioassays against a panel of 14 different tumor cell lines were estimated at micromolar range, while compound 3 showed no activity in the same assays.