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

Badarau, A.; Bauer, B.; Visram, Z.; Qiao, R.; Majoros-Hashempour, A.; Söllner, J.; Durica-Mitic, S.; Dunne, O. M.; Kluj, R.; Kestemont, D.; Kieninger, A.-K.; Kulig, M.; Berdaguer, R.; Schwebs, T.; Zerbs, M.; Czermak, P.; von Freyberg, M.; Schmidt, J.; Schmidberger, L.; Mayer, D.; Protano, M.; Miller, H. A.; Palowitch, G. M.; Dulberger, C. L.; Massaro, M.; Ivanisenko, N.; Jacomet, H.; Ngatcha Bakoue, D.; Oteri, F.; Sela, G.; Corsini, L.

doi:10.64898/2026.04.27.720530

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bioRxiv · 10.64898/2026.04.27.720530

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

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Abstract

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.

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Badarau, A., Bauer, B., Visram, Z., Qiao, R., Majoros-Hashempour, A., Söllner, J., Durica-Mitic, S., Dunne, O. M., Kluj, R., Kestemont, D., Kieninger, A.-K., Kulig, M., Berdaguer, R., Schwebs, T., Zerbs, M., Czermak, P., von Freyberg, M., Schmidt, J., Schmidberger, L., Mayer, D., Protano, M., Miller, H. A., Palowitch, G. M., Dulberger, C. L., Massaro, M., Ivanisenko, N., Jacomet, H., Ngatcha Bakoue, D., Oteri, F., Sela, G., Corsini, L.. 2026-04-28. 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. https://doi.org/10.64898/2026.04.27.720530

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