Phage-antibiotic conjugates enable targeted therapeutic for infections.

Phage-antibiotic combination therapy has gained great attention as a promising approach for combating drug resistant bacterial infections. However, simply combination between antibiotics and phages shows limited efficacy for reducing antibiotic usage and preventing further multidrug resistance. Herein, we developed a phage-vancomycin conjugate, Van@vB_C4, with 1.86 ± 0.07 μg of vancomycin (Van) on 107 PFU of vB_C4. Van@vB_C4 allows the phage to deliver Van directly to the environment near host to raise localized antibiotic concentration. Van@vB_C4 demonstrates superior antibacterial activity on Van resistance Aeromonas veronii C4 (VR A. veronii C4) compared with the combination between vB_C4 and Van. Remarkably, Van@vB_C4 establishes an environment with concentrated Van around the VR A. veronii C4 biofilm, and effectively kills more than 50 % of mature biofilm cells. Furthermore, Van@vB_C4 reduces the colonization of VR A. veronii C4 in major organs of mice and alleviates the inflammatory response, achieving a potent therapeutic effect, which opens a new window for phage-antibiotic combination therapy, supporting the targeted treatment of specific antibiotic-resistant bacterial infections.