Engineering Synthetic Bacteriophage to Combat Antibiotic-Resistant Bacteria

Abstract

Antibiotic resistance is a rapidly evolving problem that is not being adequately met by new antimicrobial drugs. Thus, there is a pressing need for effective antibacterial therapies that can be adapted against antibiotic-resistant bacteria. Here, we engineered synthetic bacteriophage to combat antibiotic-resistant bacteria by overexpressing proteins and attacking gene networks which are not directly targeted by antibiotics. By suppressing the SOS network, our engineered phage enhance bacterial killing by quinolone antibiotics by several orders of magnitude in vitro and significantly increase the survival of infected mice in vivo. Our synthetic phage design can be extended to target non-SOS gene networks and overexpress multiple factors to produce additional effective antibiotic adjuvants. In addition, our synthetic phage act as strong adjuvants for other bactericidal antibiotics, improve the killing of antibiotic-resistant bacteria, and reduce the number of antibiotic-resistant bacteria that arise from antibiotic-treated populations. This work establishes a novel synthetic biology platform for translating identified targets into effective antibiotic adjuvants.