Biology subjects

Axtman, M.

Publications and source records attributed to Axtman, M..

2 recordsLinked to original sources

bioRxiv2025

Open-Source DNA-Encoded Library Package for Design, Decoding, and Analysis: DELi

DNA-encoded library (DEL) technology has become a powerful tool in modern drug discovery. Fully harnessing its potential requires the use of extensive computational methodologies, which are often available only through proprietary software. This restricts accessibility for small teams lacking robust informatics support, hindering the growth of the technology. Here, we present DELi, an open-source DEL informatics platform designed for library design, NGS decoding and calling, and enrichment analysis. DELi supports a simple and easy to understand configuration setup to present a straightforward user interface. To showcase its capabilities, we used DELi to design an in-house custom, benzimidazole-based DEL (UNC DEL006), and performed proof-of-concept selection experiments against Bromodomain-containing Protein 4 (BRD4). The DELi decoding and analysis modules identified top-performing compounds, leading to the off-DNA synthesis of UNC11951, which was confirmed as a nanomolar BRD4 binder via isothermal titration calorimetry (ITC) and differential scanning fluorimetry (DSF). These results demonstrate DELi as an effective tool for DEL design and analysis. Furthermore, its open-source nature will promote ongoing development and contributions from the DEL community to expand its applications and capabilities, making DEL technology more widely accessible. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/640184v3_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1d4ca88org.highwire.dtl.DTLVardef@13cb4feorg.highwire.dtl.DTLVardef@8ea7ecorg.highwire.dtl.DTLVardef@1b294fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

A host-directed adjuvant resuscitates and sensitizes intracellular bacterial persisters to antibiotics

There are two major problems in the field of antimicrobial chemotherapy-antibiotic resistance and antibiotic tolerance. In the case of antibiotic tolerance, antibiotics fail to kill the bacteria as their phenotypic state affords them protection from the bactericidal activity of the antibiotic. Antibiotic tolerance can affect an entire bacterial population, or a subset of cells known as persister cells. Interaction with the host induces the formation of persister cells in numerous pathogens, with reactive oxygen and nitrogen species production being heavily implicated in the collapse of bacterial energy levels and entrance into an antibiotic tolerant state. Here, we developed a high-throughput screen to identify energy modulators for intracellular Staphylococcus aureus. The identified compound, KL1, increases intracellular bacterial energy and sensitizes the persister population to antibiotics, without causing cytotoxicity or bacterial outgrowth. We demonstrate that KL1 exhibits adjuvant activity in a murine model of S. aureus bacteremia and intracellular infection of Salmonella Typhimurium. Transcriptomic analysis and further studies on its mechanism of action reveal that KL1 modulates host immune response genes and suppresses the production of reactive species in host macrophages, alleviating one of the major stressors that induce antibiotic tolerance. Our findings highlight the potential to target intracellular persister cells by stimulating their metabolism and encourage larger efforts to address antibiotic tolerance at the host-pathogen interface, particularly within the intracellular milieu.

microbiology↗