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Prochazkova, J.

Publications and source records attributed to Prochazkova, J..

2 recordsLinked to original sources

Trichomonas vaginalis targets Lactobacillus jensenii via pseudopodia-independent phagocytosis and secreted lysozyme TvGH25

A low abundance or absence of protective lactobacilli during acute trichomoniasis is a well-known phenomenon that is associated with T. vaginalis (TV) infection. However, a crucial question that remains unanswered is whether alterations in the lactobacilli population precede TV infection or whether the parasite plays an active role in lactobacilli disappearance. Our findings showed that TV efficiently phagocytosed one of the dominant Lactobacillus species L. jensenii (LJ). Phagocytosis proceeds via a pseudopodia-independent mechanism reminiscent of sinking with a preference for viable cells. The presence of viable LJ leads to an increase in secretion of 27 TV proteins, including TvGH25 lysozyme. This enzyme cleaves peptidoglycan, a major component of the bacterial cell wall. TV overexpressing TvGH25 effectively lowers the bacterial cell count, evidencing the enzymes antimicrobial potential. These data support the notion that TV cells can suppress the Lactobacillus population through a combination of targeted secretory response and phagocytic activity, revealing novel potential targets for developing alternative therapeutic strategies against trichomoniasis. Significance StatementTrichomonas vaginalis (TV) is a sexually transmitted parasite that causes trichomoniasis and is connected to the disruption of the healthy vaginal microbiome, dominated by Lactobacillus species. However, the nature of the interactions between TV and Lactobacillus is poorly understood. In this study, we show that TV uses an unusual form of pseudopodia-independent phagocytosis to engulf L. jensenii alongside a targeted secretory response to the bacterial encounter, involving TvGH25 lysozyme. We found that TV acquired this enzyme by lateral gene transfer from bacteria and repurposed it against bacteria to degrade the major bacterial cell wall component peptidoglycan. TvGH25 thus represents an effective component of TVs antibacterial arsenal. Our findings provide new insights into the mechanistic disruption of the protective Lactobacillus microbiota.

microbiology↗

Discovery of two structurally distinct classes of inhibitors targeting the nuclease MUS81 and enhancing efficacy of chemotherapy in cancer cells

Nucleases are emerging as promising pharmacological targets due to their essential role in maintaining genomic stability, which is crucial for cellular viability and can be exploited in the prevention and treatment of various diseases, including cancer. The conserved structure-specific endonuclease MUS81 is required for resolving branched DNA intermediates during replication, repair, and recombination. Aberrant activity of MUS81 leads to DNA damage, chromosomal abnormalities and genome instability, and contributes to oncogenesis. Pharmacological targeting of MUS81 thus represents an attractive underexplored therapeutic approach. Here we describe the discovery of two chemically distinct classes of small-molecule inhibitors of MUS81, exemplified by the compounds MU262 and MU876. Both compounds can effectively inhibit MUS81 in vitro and in the cell-based context and sensitize cancer cells to DNA-damaging agents through impairing their ability to repair DNA lesions. These compounds can be also used as chemical biology tools for further exploration of MUS81 function, and as leads in the process of drug discovery focused on development of new therapies that exploit DNA repair vulnerabilities in the treatment of cancer.

molecular biology↗