Biology subjects

Söllner, J.

Publications and source records attributed to Söllner, J..

2 recordsLinked to original sources

bioRxiv2026

Multi-dimensional optimization of a lysin towards a ribolysin against life-threatening S. aureus infections: Fc-LysM-CHAP and its strong synergy with standard of care antibiotics

Bacterial lysins are promising novel antimicrobials but are limited by poor pharmacokinetics and challenging manufacturability. We developed a lysin discovery platform tailored for lysin delivery via mRNA: staphylococcal LysM-CHAP (cysteine, histidine-dependent amidohydrolases/peptidase) autolysin was selected and its serum half-life extended via Immunoglobulin G1-Fc-fusion. The Fc-induced drop in lysin potency was rescued by the concerted optimization of linkers, binding kinetics and catalytic activity, using a combination of rational and AI-guided approaches. The engineered Fc-LysM-CHAP was active against planktonic bacteria (minimum inhibitory concentration of 1 - 2 {micro}g/mL) and simulated endocardial vegetations and synergized strongly (Fractional eradication concentration index FECI = 0.06) with cell wall active antibiotics in vitro. In mouse models of Staphylococcus aureus sepsis, the recombinant Fc-LysM-CHAP - antibiotic combination was superior to single agent treatments and mRNA-delivered Fc-LysM-CHAP showed single agent activity at a mRNA-lipid nanoparticle dose as low as 0.2 mg/kg.

microbiology↗

bioRxiv2025

Distances and charges along the Orai1 nexus-TM3 interface control STIM1-binding and pore opening

Calcium (Ca2+) influx through the Ca2+ release-activated Ca2+ (CRAC) channel is triggered by binding of the Ca2+ sensor Stromal Interaction Molecule 1 (STIM1) to the pore-forming Orai1 complex, primarily to its cytosolic C-termini. These C-termini connect to the transmembrane domain (TM) 4 via the flexible nexus region, proposed to transmit the activation signal from the STIM1-binding site to the central pore via concentrically arranged TM domains. However, the conformational dynamics of the nexus-TM3 interface required for channel gating remain elusive. Here, we investigate its role using unnatural amino acid (UAA)-based photo- and chemical crosslinking at individual positions within the nexus-TM3 interface combined with conventional site-directed mutagenesis. We report that a widening of the nexus-TM3 interface is essential for STIM1-mediated pore opening, while hydrophobicity and contact distances in the upper nexus-TM3 interface fine-tune signal propagation to the pore. These findings underscore the relevance of the nexus-TM3 dynamics for proper Orai1 function.

biophysics↗