Biology subjects

Davis, S. H.

Publications and source records attributed to Davis, S. H..

3 recordsLinked to original sources

bioRxiv2025

Design and development of lysyl tRNA synthetase inhibitors, for the treatment of tuberculosis

There is currently a public health crisis due to the rise of multi-drug-resistant tuberculosis cases, as well as the rise in number of deaths from tuberculosis. To achieve the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030, new treatments are urgently required. We previously reported the discovery of 49, a pre-clinical candidate that acted through inhibition of the Mycobacterium tuberculosis lysyl-tRNA synthetase (LysRS). In this report, the full medicinal chemistry program is reviewed from the original hit through to the optimised lead. The work was guided by the first crystal structure of M. tuberculosis LysRS. The physicochemical and pharmacokinetic properties were optimised to afford compounds suitable for evaluation in mouse efficacy models of tuberculosis and with the potential for clinical development.

microbiology↗

bioRxiv2022

Peptidyl tRNA hydrolase is required for robust prolyl-tRNA turnover in Mycobacterium tuberculosis

Enzymes involved in rescuing stalled ribosomes and recycling translation machinery are ubiquitous in bacteria and required for growth. Peptidyl tRNA drop-off is a type of abortive translation that results in the release of a truncated peptide that is still bound to tRNA (peptidyl tRNA) into the cytoplasm. Peptidyl tRNA hydrolase (Pth) recycles the released tRNA by cleaving off the unfinished peptide and is essential in most bacterial species. We developed a sequencing-based strategy called Cu-tRNAseq to study the physiological role of Pth in Mycobacterium tuberculosis (Mtb). While most peptidyl tRNA species accumulated in a strain with impaired Pth expression, peptidyl prolyl-tRNA was particularly enriched, suggesting that Pth is required for robust peptidyl prolyl-tRNA turnover. Reducing Pth levels increased Mtbs susceptibility to tRNA synthetase inhibitors that are in development to treat tuberculosis (TB) and rendered this pathogen highly susceptible to macrolides, drugs that are ordinarily ineffective against Mtb. Collectively, our findings reveal the potency of Cu-tRNAseq for profiling peptidyl tRNAs and suggest that targeting Pth would open new therapeutic approaches for TB.

microbiology↗

bioRxiv2019

Systemic Lymphoid Architecture Response Assessment (SYLARAS): An approach to multi-organ, discovery-based immunophenotyping implicates a role for CD45R/B220+ CD8T cells in glioblastoma immunology

Accurately profiling systemic immune responses to cancer initiation and progression is necessary for understanding tumor surveillance and, ultimately, improving therapy. Here, we describe the SYLARAS software tool (SYstemic Lymphoid Architecture Response ASsessment) and a data set collected with SYLARAS that describes the frequencies of immune cells in primary and secondary lymphoid organs and in the tumor microenvironment of mice engrafted with a standard syngeneic glioblastoma (GBM) model. The data resource involves profiles of 5 lymphoid tissues in 48 mice and shows that GBM causes wide-spread changes in the local and systemic immune architecture. We perform in-depth analysis of one significant tumor-induced change: depletion of a specialized subset of CD45R/B220+ CD8+ T cells from the circulation and their accumulation in the tumor mass. Immunoprofiling of tissue microarrays demonstrates the presence of similar cells in human GBM.

immunology↗