Dual-mode ClfA-targeting DARPin biologics protect against diverse methicillin-resistant <i>Staphylococcus aureus</i> strains.

ABSTRACT: Staphylococcus aureus uses the adhesin clumping factor A (ClfA) to bind fibrinogen and promote invasive infection through two distinct interfaces: an exposed, low-affinity site on the N3 head domain and a buried, high-affinity "dock, lock, and latch" (DLL) trench that is exposed only under shear. This dual-interface architecture allows limited antibody penetration, as antibodies typically block only the exposed site. Here, we establish a dual-mode inhibition strategy that overcomes this constraint by combining a high-affinity ClfA-binding designed ankyrin repeat protein (DARPin) with a fibrinogen γ-chain peptide capable of occupying the DLL trench. Using cell-free click display and kinetics-guided affinity maturation, we engineer DARPin-γ-peptide fusion biologics that simultaneously

SUBMITTER: Chockalingam K 

PROVIDER: S-EPMC12803223 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature