Harnessing RGDS peptides to regulate bacterial-host interfaces for targeted antimicrobial therapy

Refractory infections caused by pathogenic bacteria, particularly multidrug-resistant bacteria, pose a significant threat to global human health. Emerging host-directed antimicrobial strategies have the potential to prolong the effectiveness of existing treatments or eliminate the development of antibiotic resistance, representing a promising avenue for addressing infections caused by resistant bacteria. Here, we propose a mechanobiology-based host-directed antimicrobial strategy that utilizes an inhibitory fibronectin (Fn) peptide, Arg-Gly-Asp-Ser (RGDS), to regulate bacterial-host interfacial adhesion forces and thereby effectively combat multidrug-resistant bacterial infections. The RGDS peptides can competitively interfere with the physicochemical interactions at the bacterial-host adhesion interfaces, thereby inhibiting bacterial colonization on host surfaces. The alterations in bacterial-host adhesion forces regulated by RGDS peptides are quantified via single-cell force spectroscopy (SCFS), which elucidate the mechanobiological mechanisms underlying the presented host-targeted antimicrobial strategy. Furthermore, we reveal the antimicrobial potential of the RGDS peptide as an antibiotic adjuvant, achieving a 75 % reduction in antibiotic dosage. The in vivo antimicrobial efficacy of RGDS-enhanced low-dose antibiotics is also validated in three animal models. It is expected that a mechanobiology-based host-directed antimicrobial strategy could be broadly employed to address the global incidence and progression of drug-resistant bacteria.