Biology subjects

Doyle, R.

Publications and source records attributed to Doyle, R..

4 recordsLinked to original sources

bioRxiv2025

Targeting intracellular of populations Pseudomonas aeruginosa with peptide-mimetic therapies: individual efficacy and synergistic rescue of obsolete antibiotics.

Pseudomonas aeruginosa is a leading cause of human infections, with current treatment options severely limited by high levels of antimicrobial resistance. Historically considered to be an extracellular pathogen, recent evidence has emerged that P. aeruginosa is able to survive and replicate within human cells. These intracellular niches present an additional clinical challenge and may serve as bacterial reservoirs associated with chronic infections that are particularly difficult to eradicate. Here we describe the application of a novel peptide-based therapeutic against recalcitrant populations of bacteria residing within lung epithelial cells. This antimicrobial "peptoid" is able to target intracellular bacteria without harming host cells. In addition, we have shown that peptoid TM5 exhibits synergy with three antibiotics that otherwise have low efficacy against P. aeruginosa, effectively rescuing drugs that have become clinically obsolete. These synergistic combination therapies are also capable of reducing intracellular bacterial reservoirs, opening the door for potential new strategies against chronic P. aeruginosa infections.

microbiology↗

bioRxiv2018

1,4-dihydroxy Quininib Attenuates Growth of Colorectal Cancer Cells and Xenografts and Regulates the TIE-2 Signaling Pathway in Patient Tumours

Colorectal cancer (CRC) is the second leading cause of cancer associated deaths in developed countries. Cancer progression and metastatic spread is reliant on new blood vasculature, or angiogenesis. Tumour-related angiogenesis is regulated by pro- and anti-angiogenic factors secreted from malignant tissue in a stepwise process. Previously we structurally modified the small anti-angiogenic molecule quininib and discovered a more potent anti-angiogenic compound 1, 4 dihydroxy quininib (Q8), an antagonist of cysteinyl leukotriene receptor-1 with VEGF-independent bioactivity. Here, Q8, quininib (Q1) and five structural analogues were assayed for anti-tumorigenic effects in pre-clinical cancer models. Q8 reduced clone formation of the human colorectal cancer cell line HT29-Luc2. Gene silencing of CysLT1 in HT29-Luc2 cells significantly reduced expression of calpain-2. In human ex vivo colorectal cancer tumour explants, Q8 significantly decreased the secretion of both TIE-2 and VCAM-1 expression. In vivo Q8 was well tolerated up to 50 mg/kg by Balb/C mice and significantly more effective at reducing tumour volume in colorectal tumour xenografts compared to the parent drug quininib. In tumour xenografts, Q8 significantly reduced expression of the angiogenic marker calpain-2 in. In summary, we propose Q8 may act on the TIE-2-Angiopoietin signalling pathway to significantly inhibit the process of tumour angiogenesis in colorectal cancer.

cancer biology↗

bioRxiv2018

Genome-wide association study of diabetic kidney disease highlights biology involved in renal basement membrane collagen

Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions basedon albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD (BMP7) or renal biology (COLEC11 and DDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.

genetics↗

bioRxiv2018

Whole genome sequencing Mycobacterium tuberculosis directly from sputum identifies more genetic diversity than sequencing from culture

BackgroundRepeated culture reduces within-sample Mycobacterium tuberculosis genetic diversity due to selection of clones suited to growth in culture and/or random loss of lineages, but it is not known to what extent omitting the culture step altogether alters genetic diversity. We compared M. tuberculosis whole genome sequences generated from 33 paired clinical samples using two methods. In one method DNA was extracted directly from sputum then enriched with custom-designed SureSelect (Agilent) oligonucleotide baits and in the other it was extracted from mycobacterial growth indicator tube (MGIT) culture.\n\nResultsDNA directly sequenced from sputum showed significantly more within-sample diversity than that from MGIT culture (median 5.0 vs 4.5 heterozygous alleles per sample, p=0.04). Resistance associated variants present as HAs occurred in four patients, and in two cases may provide a genotypic explanation for phenotypic resistance.\n\nConclusionsCulture-free M. tuberculosis whole genome sequencing detects more within-sample diversity than a leading culture-based method and may allow detection of mycobacteria that are not actively replicating.

genomics↗