Orientational Nanoconjugation with Gold Endows Marked Antimicrobial Potential and Drugability of Ultrashort Dipeptides

Antibiotic resistance is a global threat. Antimicrobial peptides (AMPs) are highly desirable to treat multidrug-resistant pathogen infection. However, few AMPs are clinically available, due to high cost, instability, and poor selectivity. Here, ultrashort AMPs (2–3 residues with an N-terminal cysteine) are designed and assembled as gold nanoparticles. Au–S conjugation and ultrashort size restrict nonspecific reactions and peptide orientation, thus concentrating positively charged residues on the surface. The nanostructured assemblies enormously enhance antimicrobial abilities by 1000–6000-fold and stability. One representative (Au-Cys-Arg-NH2, Au_CR) shows selective antibacterial activity against Staphylococcus aureus with 10 nM minimal inhibitory concentration. Au_CR has comparable or better in vivo antimicrobial potency than vancomycin and methicillin, with low propensity to induce resistance, little side effects, and high stability (17.5 h plasma half-life). Au_CR acts by inducing collapse of membrane potential and rupture of the bacterial membrane. The report provides insights for developing AMP–metal nanohybrids, particularly tethering nonspecific reactions and AMP orientation on the metal surface.