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 (S. aureus), a leading contributor to bacterial infection-associated mortality. Notably, the method facilitates species-specific detection of S. 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 S. 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 S. 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.
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BibTeX
@article{kumar2026electronically,
title = {{Electronically tuned N-terminal glycine selective bioconjugation enables in vitro and in vivo species-specific Staphylococcus aureus targeting}},
author = {Mohan Kumar and Divya Bindra and Ashish Verma and Sisir Patra and Drishiya Vats and A. S. Kaveri and Nikita Sharma and Kartikay Tyagi and Rahul Maitra and Kamal Vats and Manoj V. Mane and Sidharth Chopra and Ram Kumar Mishra and Vishal Rai},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-77959-2},
url = {https://www.nature.com/articles/s41467-026-77959-2},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Electronically tuned N-terminal glycine selective bioconjugation enables in vitro and in vivo species-specific Staphylococcus aureus targeting
AU - Mohan Kumar
AU - Divya Bindra
AU - Ashish Verma
AU - Sisir Patra
AU - Drishiya Vats
AU - A. S. Kaveri
AU - Nikita Sharma
AU - Kartikay Tyagi
AU - Rahul Maitra
AU - Kamal Vats
AU - Manoj V. Mane
AU - Sidharth Chopra
AU - Ram Kumar Mishra
AU - Vishal Rai
PY - 2026
DA - 2026/10/05
JO - Nature Communications
DO - 10.1038/s41467-026-77959-2
UR - https://www.nature.com/articles/s41467-026-77959-2
AB - 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 (S. aureus), a leading contributor to bacterial infection-associated mortality. Notably, the method facilitates species-specific detection of S. 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 S. 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 S. 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.
SN - 2041-1723
ER -