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 Gram-positive 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 dibenzo-cyclooctyne (IR780-DBCO). Upon pre-metabolizing with 3-azido-D-alanine, Gram-positive bacteria rather than Gram-negative ones, such as Staphylococcus aureus and vancomycin-resistant 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.

Automated summary

Bacterial infections are a serious threat to human health, especially those caused by common Gram-positive bacteria. Photothermal therapy (PTT) has shown potential as a universal antimicrobial technique without inducing drug resistance, but its unspecific killing capability and side effects hinder practical applications. A metabolic engineering strategy using a bioorthogonal photothermal agent was proposed to selectively inactivate Gram-positive bacteria by pre-metabolizing with 3-azido-D-alanine, demonstrating efficient eradication in vitro and in a mouse model. This strategy could lead to the development of precise antibacterial candidates for preclinical applications.