A chimeric, half-life extended lysin with a unique mode of action

Visram, Z.; Kestemont, D.; Bauer, B.; Qiao, R.; Durica-Mitic, S.; Majoros-Hashempour, A.; Schmidt, J.; Berdaguer, R.; Krey, K.; Mutti, M.; Zerbs, M.; von Freyberg, M.; Corsini, L.; Badarau, A.

doi:10.64898/2026.05.13.724763

bioRxiv · 10.64898/2026.05.13.724763

A chimeric, half-life extended lysin with a unique mode of action

Visram, Z.·Kestemont, D.·Bauer, B.·Qiao, R.·Durica-Mitic, S.·Majoros-Hashempour, A.·Schmidt, J.·Berdaguer, R.·Krey, K.·Mutti, M.·Zerbs, M.·von Freyberg, M.·Corsini, L.·Badarau, A.

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Abstract

Anti-staphylococcal lytic agents, such as lysostaphin (LSN), a glycyl-glycyl (Gly-Gly) peptidase, have long been considered for the management of chronic and complicated bacterial infections typically resistant to conventional antibiotics, but their use is restricted by poor pharmacokinetic properties. We generated half-life extended lysostaphin constructs by fusing the lysin - either alone or chimerized with an additional enzymatic cysteine, histidine-dependent amidohydrolases/peptidase (CHAP) domain - to the human IgG1 Fc fragment. The Fc-CHAP-LSN constructs retain high potency against Staphylococcus aureus and coagulase negative staphylococcal strains in vitro and are efficacious in S. aureus ex vivo biofilm models and in vivo sepsis models. A detailed investigation of the Fc-CHAP-LSN mode of action revealed that upon binding to the bacterial cell, but not in solution, LSN mediates its own release by cleaving the Gly-Gly CHAP-LSN linker. The bactericidal activity of Fc-CHAP-LSN is driven by the LSN-catalyzed and target cell-dependent release of free LSN. The half-life extended lysin acts as a pro-drug, unveiling a novel mechanism of targeted release and an alternative approach to half-life extension.

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Visram, Z., Kestemont, D., Bauer, B., Qiao, R., Durica-Mitic, S., Majoros-Hashempour, A., Schmidt, J., Berdaguer, R., Krey, K., Mutti, M., Zerbs, M., von Freyberg, M., Corsini, L., Badarau, A.. 2026-05-15. A chimeric, half-life extended lysin with a unique mode of action. https://doi.org/10.64898/2026.05.13.724763

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