Biology subjects

Caudy, A.

Publications and source records attributed to Caudy, A..

4 recordsLinked to original sources

bioRxiv2026

Toxicity Prediction Tools Do Not Generalize to Novel Chemistry

Computational toxicity prediction rests on an assumption that is rarely tested directly: that molecular structure carries enough information to anticipate whether a compound will have adverse effects in human patients. We benchmark toxicity prediction methods on a curated panel of 569 approved drugs, labeled toxic if they carry a black-box warning or were withdrawn from the market. We evaluate 35 model readouts spanning fingerprint-based QSAR, fine-tuned foundation encoders, and toxicity-targeted tools. No learned representation outperforms a plain fingerprint, suggesting the bottleneck is not the sophistication of the representation. Of the tools trained specifically for toxicity prediction, only one performs above chance, and none matches what approval year alone explains, a predictor containing no chemistry at all. No tool dedicated to drug-induced liver injury (DILI) reliably beats chance on our panel, and the external set where some succeed is one that approval year alone largely predicts. These results point to a limit of molecular structure as an input, and suggest that progress will depend on inputs that capture exposure and metabolism rather than better models over structure alone.

pharmacology and toxicology↗

bioRxiv2024

MOB rules: Antibiotic Exposure Reprograms Metabolism to Mobilize Bacillus subtilis in Competitive Interactions

Antibiotics have dose-dependent effects on exposed bacteria. The medicinal use of antibiotics relies on their growth-inhibitory activities at sufficient concentrations. At subinhibitory concentrations, exposure effects vary widely among different antibiotics and bacteria. Bacillus subtilis responds to bacteriostatic translation inhibitors by mobilizing a population of cells (MOB-Mobilized Bacillus) to spread across a surface. How B. subtilis regulates the antibiotic-induced mobilization is not known. In this study, we used chloramphenicol to identify regulatory functions that B. subtilis requires to coordinate cell mobilization following subinhibitory exposure. We measured changes in gene expression and metabolism and mapped the results to a network of regulatory proteins that direct the mobile response. Our data reveal that several transcriptional regulators coordinately control the reprogramming of metabolism to support mobilization. The network regulates changes in glycolysis, nucleotide metabolism, and amino acid metabolism that are signature features of the mobilized population. Among the hundreds of genes with changing expression, we identified two, pdhA and pucA, where the magnitudes of their changes in expression, and in the abundance of associated metabolites, reveal hallmark metabolic features of the mobilized population. Using reporters of pdhA and pucA expression, we visualized the separation of major branches of metabolism in different regions of the mobilized population. Our results reveal a regulated response to chloramphenicol exposure that enables a population of bacteria in different metabolic states to mount a coordinated mobile response.

microbiology↗

bioRxiv2019

Fitness and productivity increase with ecotypic diversity among E. coli evolved in a simple, constant environment

Community productivity often correlates with diversity. In the microbial world this phenomenon can sometimes be explained by highly-specific metabolic interactions that include cross-feeding and syntrophy. Such interactions help account for the astonishing variety of microbial life, and drive many of the biogeochemical cycles without which life as we know it could not exist. While it is difficult to recapitulate experimentally how these interactions evolved among multiple taxa, we can explore in the laboratory how they arise within one. These experiments provide insight into how different bacterial ecotypes evolve and from these, possibly new species. We have previously shown that in a simple, constant environment a single clone of E. coli can give rise to a consortium of genetically-and physiologically-differentiated strains, in effect, a set of ecotypes, that coexist by cross-feeding. We marked these different ecotypes and their shared ancestor by integrating fluorescent protein into their genomes. We then used flow cytometry to show that each strain by itself is more fit than the shared ancestor, that pairs of evolved strains are fitter still, and that the entire consortium is fittest of all. We further demonstrate that the rank order of fitness values agrees with estimates of yield, indicating that an experimentally evolved consortium more efficiently converts resources to offspring than its ancestor or any member acting in isolation.\n\nImportanceIn the microbial world, diversity and productivity of communities and consortia often correlate positively. However, it is challenging to tease apart a consortium whose members have co-evolved, and connect estimates of their fitness and the fitness of their ancestor(s) with estimates of productivity. Such analyses are prerequisite to understanding the evolutionary origins of all biological communities. Here we dissect an E. coli consortium that evolved in the laboratory and show that cooperative interactions are favored under continuous glucose limitation because a partnership of ecotypes is better able to scavenge all available resources and more efficiently convert those resources to offspring than any single individual. Such interactions may be a prelude to a special form of syntrophy, and are likely to be key determinants of microbial community structure in nature, including those having clinical significance, such as chronic infections.

microbiology↗

bioRxiv2019

Identification of the pathway of Rhodoquinone biosynthesis in C. elegans

Parasitic helminths infect over a billion humans. To survive in the low oxygen environment of their hosts, these parasites use unusual anaerobic metabolism. This requires Rhodoquinone (RQ), an electron carrier that is made by very few animal species -- crucially it is not present in any parasitic hosts. RQ synthesis is thus an ideal target for anthelmintics but little is known about how RQ is made and no drugs are known to block RQ synthesis. C.elegans makes RQ and can use RQ-dependent metabolic pathways -- here, we use C.elegans genetics to identify the pathway for RQ synthesis and show that C.elegans requires RQ for survival in hypoxic conditions. Finally, we establish a robust assay for drugs that block RQ-dependent metabolism. This study identifies for the first time how RQ is made in any animal and establishes a novel assay that can drive the development of a new class of anthelmintic drugs.

biochemistry↗