Biology subjects

Bulman, C. A.

Publications and source records attributed to Bulman, C. A..

3 recordsLinked to original sources

bioRxiv2023

Discovery of New Broad-Spectrum Anti-Infectives for Eukaryotic Pathogens Using Bioorganometallic Chemistry

Drug resistance observed with many anti-infectives clearly highlights the need for new broad-spectrum agents to treat especially neglected tropical diseases (NTDs) caused by eukaryotic parasitic pathogens including fungal infections. Since these diseases target the most vulnerable communities who are disadvantaged by health and socio-economic factors, new agents should be, if possible, easy-to-prepare to allow for commercialization based on their low cost. In this study, we show that simple modification of one of the most well-known antifungal drugs, fluconazole, with organometallic moieties not only improves the activity of the parent drug but also broadens the scope of application of the new derivatives. These compounds were highly effective in vivo against pathogenic fungal infections and potent against parasitic worms such as Brugia, which causes lymphatic filariasis and Trichuris, one of the soil-transmitted helminths that infects millions of people globally. Notably, the identified molecular targets indicate a mechanism of action that differs greatly from the parental antifungal drug, including targets involved in biosynthetic pathways that are absent in humans, offering great potential to expand our armamentarium against drug-resistant fungal infections and NTDs targeted for elimination by 2030. Overall, the discovery of these new compounds with broad-spectrum activity opens new avenues for the development of treatments for several current human infections, either caused by fungi or by parasites, including other NTDs, as well as newly emerging diseases. ONE-SENTENCE SUMMARYSimple derivatives of the well-known antifungal drug fluconazole were found to be highly effective in vivo against fungal infections, and also potent against the parasitic nematode Brugia, which causes lymphatic filariasis and against Trichuris, one of the soil-transmitted helminths that infects millions of people globally.

pharmacology and toxicology↗

bioRxiv2019

De novo identification of toxicants that cause irreparable damage to parasitic nematode intestinal cells

Efforts to identify new drugs for therapeutic and preventive treatments against parasitic nematodes have gained increasing interest with expanding pathogen omics databases and drug databases from which new anthelmintic compounds might be identified. Here, a novel approach focused on integrating a pan-Nematoda multi-omics data targeted to a specific nematode organ system (the intestinal tract) with evidence-based filtering and chemogenomic screening was undertaken. Based on de novo computational target prioritization of the 3,564 conserved intestine genes in A. suum, exocytosis was identified as a high priority pathway, and predicted inhibitors of exocytosis were tested using the large roundworm (Ascaris suum larval stages), a filarial worm (Brugia pahangi adult and L3), a whipworm (Trichuris muris adult), and the non-parasitic nematode Caenorhabditis elegans. 10 of 13 inhibitors were found to cause rapid immotility in A. suum L3 larvae, and five inhibitors were effective against the three phylogenetically diverse parasitic nematode species, indicating potential for a broad spectrum anthelmintics. Several distinct pathologic phenotypes were resolved related to molting, motility, or intestinal cell and tissue damage using conventional and novel histologic methods. Pathologic profiles characteristic for each inhibitor will guide future research to uncover mechanisms of the anthelmintic effects and improve on drug designs. This progress firmly validates the focus on intestinal cell biology as a useful resource to develop novel anthelmintic strategies. Author summaryThe intestinal cells of parasitic nematodes are not known to regenerate, therefore disruption of essential processes that cause irreparable damage to intestinal cells is expected to promote worm expulsion. To facilitate improved methods of therapy we need to better understand the basic intestinal cell and tissue functions of this critical organ. To that end have undertaken a comprehensive analysis of multi-omics omics data and identify and prioritize intestinal genes/pathways with essential functions and associated drugs and established a foundational model of the STH intestinal system using the large roundworm Ascaris suum to test and validate inhibitors of these functions. We found 10 inhibitors to impacted motility, and seven of those showed severe pathology and an apparent irreparable damage to intestinal cells. Furthermore, five inhibitors were effective against the three phylogenetically diverse parasitic nematode species, indicating potential for a broad spectrum anthelmintics. Our results firmly validate the focus on intestinal cell biology as a useful resource to develop novel anthelmintic strategies.

pathology↗

bioRxiv2019

Chagas disease serological test performance in United States blood donor specimens

BackgroundChagas disease affects an estimated 300,000 individuals in the US. Diagnosis in the chronic phase requires positive results by two different IgG serological tests. Three ELISAs (Hemagen, Ortho, Wiener) and one rapid test (InBios) are FDA-cleared, but comparative data in US populations are sparse.\n\nMethodsWe evaluated 500 seropositive and 300 seronegative blood donor plasma samples. Country of birth was known for 255 seropositive specimens and grouped into regions: Mexico (n=94), Central America (n=88) and South America (n=73). Specimens were tested by the four FDA-cleared IgG serological assays. Test performance was evaluated by two comparators and latent class analysis.\n\nResultsInBios had the highest sensitivity (97.4-99.3%), but lowest specificity (87.5-92.3%). Hemagen had the lowest sensitivity (88.0-92.0%), but high specificity (99.0-100.0%). Sensitivity was intermediate for Ortho (92.4-96.5%) and Wiener (94.0-97.1%); both had high specificity (98.8-100.0% and 96.7-99.3%, respectively). Antibody reactivity and clinical sensitivity was lowest in donors from Mexico, intermediate in those from Central America and highest in those from South America.\n\nConclusionsOur findings provide an initial evidence base to improve laboratory diagnosis of Chagas disease in the US. The best current testing algorithm would employ a high sensitivity screening test followed by a high specificity confirmatory test.

microbiology↗