Selective inactivation of Gram-positive bacteria in vitro and in vivo through metabolic labelling

Bacterial infections are grave threats to human health,particularly those caused by the most common Grampositive bacteria.The massive administration of broad-spectrum antibiotics to treat various bacterial infections has led to the evolution and spread of drug resistance.As a universal antimicrobial technique unapt to induce drug resistance,photothermal therapy(PTT)is attracting extensive attention in recent years.However,its unspecific killing capability and side effects towards adjacent mammalian cells severely impede the practical applications.Herein,we proposed a metabolic engineering strategy to selectively inactivate Gram-positive bacteria by PTT.A bioorthogonal photothermal agent was prepared by the conjugation of IR-780 iodide and dibenzocyclooctyne(IR780-DBCO).Upon pre-metabolizing with 3-azido-D-alanine,Gram-positive bacteria rather than Gramnegative ones,such as Staphylococcus aureus and vancomycinresistant Enterococcus faecalis(VRE),could be specifically tied up by the explosive IR780-DBCO via copper-free click chemistry.Thereafter,they spontaneously detonated under 15 min near-infrared light irradiation and inactivated nearly 100% Gram-positive bacteria in vitro.Moreover,superbug VRE-induced infection was significantly inhibited by this approach in a mouse skin wound model.This metabolic labelling-based photothermal ablation strategy specific to Gram-positive microbes would stimulate the development of precise antibacterial candidates for preclinical applications.