Electronically tuned N-terminal glycine selective bioconjugation enables in vitro and in vivo species-specific Staphylococcus aureus targeting

ABSTRACT: Precisely targeting a biomolecule within living systems could create unique opportunities at the biology-medicine interface. Such methods have been non-trivial due to the complex selectivity attributes. Here, we introduce an electronically tunable chemical technology that targets N-terminal glycine, a unique low-frequency molecular signature. Initially, we established the method using peptides and proteins, along with mechanistic insights. The reactivity, selectivity, and bioconjugate stability remain unaffected by diverse bioadditives. These unique attributes enable the selective targeting of the pentaglycine-based molecular signature in Staphylococcus aureus, a leading contributor to bacterial infection-associated mortality. Notably, the method facilitates species-specific detection of Staphylococcus aureus and its resistant strains. It enables late-stage bond-engineering to install multiple biorthogonal handles, downstream chemistry, and chemically orthogonal reversal. The specificity extends to in vivo labeling of Staphylococcus aureus within Drosophila melanogaster, as well as skin, tissue, and blood infections in mice. The N-terminal glycine modification inhibits drug-susceptible and drug-resistant clinical strains of Staphylococcus aureus, including biofilm formation and preformed biofilms. Finally, the in vivo efficiency is established using a wound-healing assay in mice. The exclusive N-terminal glycine residue-specific targeting across the molecular complexity spectrum, both in vitro and in vivo, establishes peptidoglycan as a potential diagnostic and therapeutic target.

INSTRUMENT(S):

ORGANISM(S): Bacteria Staphylococcus Aureus

SUBMITTER: Mohan Kumar  

LAB HEAD: Vishal Rai

PROVIDER: PXD082695 | Pride | 2026-10-05

REPOSITORIES: Pride