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Biology subjects

Schönfeld, J.

Publications and source records attributed to Schönfeld, J..

2 recordsLinked to original sources

Suppressing selection for antibiotic resistance in the environment: A transparent, ecology-based approach to predicted no-effect concentrations

Selection for antibiotic resistance has been demonstrated at low, environmentally-relevant antibiotic concentrations. Over the past decade, the concept of minimum selective concentrations (MSC) has been adopted in environmental regulation to define maximum permissible antibiotic concentrations. Such empirically determined MSC values often fail to reflect the complexity of natural communities, where susceptibility and resistance-associated fitness costs vary widely across species. To address this limitation, computational approaches have been developed to predict no-effect concentrations for selection of antibiotic resistance (PNECres) from routinely collected minimum inhibitory concentration (MIC) data. However, these approaches often lack a strong ecological basis, undermining confidence in their predictions. Here, we propose a simple but biologically consistent framework to derive PNECres values by integrating MIC data with probabilistic estimates of resistance-related fitness costs. Our results suggest that current regulatory environmental threshold concentrations should be lowered by at least one order of magnitude to guard against selection for antibiotic resistance.

microbiology↗

Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation

Structural resolution of protein interactions enables mechanistic and functional studies as well as interpretation of disease variants. However, structural data is still missing for most protein interactions because we lack computational and experimental tools at scale. We thoroughly assessed AlphaFold-Multimer accuracy for structure prediction of interactions involving folded domains binding to short linear motifs from the ELM database. The structure predictions were highly sensitive but not very specific when using small protein fragments. Sensitivity decreased substantially when using long protein fragments or full length proteins with intrinsically disordered regions. We delineated a fragmentation strategy to optimize sensitivity and applied it to interactions between proteins associated with neurodevelopmental disorders. This enabled prediction of highly confident and likely disease-related novel interfaces, but also resulted in many high scoring false positive predictions. Experiments supported predicted interfaces between CREBZF-HCFC1, FBXO23-STX1B, STX1B-VAMP2, ESRRG-PSMC5, PEX3-PEX19, PEX3-PEX16, and SNRPB-GIGYF1 providing novel molecular insights for diverse biological processes. Our work highlights exciting perspectives, but also reveals clear limitations and the need for future developments to maximize the power of Alphafold-Multimer for interface predictions.

systems biology↗