Gadakh, S. | Search bioRxiv

bioRxiv2024

On the mode of anti-C. albicans activity of a bis(benzoxaborole) analogue of Tavaborole

We presented the pharmacodynamic relationship between benzoxaborole concentrations and Candida albians blastoconidial population dynamics. Bis(benzoxaborole) analogue (2) and Tavaborole (ref.) showed comparable moderate effects against C. albicans (time-kill kinetic assays). Benzoxaboroles inhibited the C. albicans growth during 72 h (fungicidal after 2 h of that time) with metabolic reduction (%R=64). Biofilm-inhibiting concentration (BIC50=2 g/mL) is the lowest concentration of bezoxaboroles that presented 50% inhibition of biofilm metabolic activity vs non-treated control. 2 displayed poor ability to inhibit morphogenesis of C. albicans. Safety and fungicidal activity are still in high demand against biofilm grown on fibroblasts and the zebrafish model in vivo. This biofilm model was used to study the interactions between the C. albicans morphogenesis and benzoxaboroles. Benzoxaboroles displayed selectivity in cytotoxic effects. 2 exhibited significantly lower embryotoxicity vs ref. IC50>128 g/mL for 2. Ref. at 256 g/mL showed approximately 80% viability of VERO E6 cells. A higher selectivity of the ref--drug to the pathogen than to the mammalian cells was observed. Contrariwise, ref. and 2 showed IC50=2 g/mL against PBMCs. Benzoxaborole antifungal development targets ergosterol binding. RNAseq data indicated that efflux pumps (MDR) in C. albicans were upregulated. Inositol-1-phosphate synthase was repressed under the benzoxaborole treatment. MDR1 upregulation by 2 was accompanied by the IFD6 (aldo-keto reductase) increase and the coordination of multiple coactivators (IFD6, TNA1 encoding putative nicotinic acid transporter). Benzoxaboroles represent a similar resistance mechanism to azoles due to the subsequent expression of MDR1 and IDF6. Docking studies confirmed the proposed interactions of benzoxaborole adenosinemonophosphate adduct with LeuRS. Moreover, C5_04480C_A (cell wall biogenesis, protein folding, modification, and destination) was negatively regulated in response to the benzoxaborole stress. Benzoxaborole-altering efflux inhibitors are important for the development of combination strategies in candidiasis. Our findings present an innovative concept that can inspire further studies for designing and building new antifungal benzoxaborole. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/605614v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@10d0037org.highwire.dtl.DTLVardef@894266org.highwire.dtl.DTLVardef@1663f05org.highwire.dtl.DTLVardef@1b3736b_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

ConsensuSV-ONT - a modern method for accurate structural variant calling

The improvements in sequencing technology make the development of new tools for the detection of structural variance more and more common. However, the tools available for the long-read Oxford Nanopore sequencing are limited, and it is hard to choose one, which is the best. That is why there is a need to create a tool based on consensus that combines existing work in order to discover a set of high-quality, reliable structural variants that can be used for further downstream analysis. The field has also been subject to revolution in machine learning techniques, especially deep learning. In the spirit of the aforementioned need and developments, we propose a novel, fully automated ConsensuSV-ONT algorithm. The method uses six independent, state-of-the-art structural variant callers for long-read sequencing along with a convolutional neural network for filtering high-quality variants. We provide a runtime environment in the form of a docker image, wrapping a nextflow pipeline for efficient processing using parallel computing. The solution is complete in its form and is ready to use not only by computer scientists but accessible and easy to use for everyone working with Oxford Nanopore long-read sequencing data.

bioinformatics↗