A dual-action combination therapy targeting bacteria and host immunity against bacterial infections

ABSTRACT The escalating crisis of antimicrobial resistance, coupled with a stagnant novel antibiotic discovery pipeline, underscores the urgent need for innovative strategies to combat bacterial infections. The development of antibiotic adjuvants that increase the efficacy of existing drugs represents a critical approach for addressing this challenge. We demonstrate that combining the conventional antibiotic azithromycin with the quorum-sensing inhibitor norharmane exerts potent antibacterial effects through both direct bactericidal activity and host immune activation. This combination not only disrupts bacterial structural integrity but also promotes macrophage polarization toward the M1-type phenotype and upregulates the expression of the important mediator, Muc5b, through activation of the IL-17 signaling pathway, ultimately enhancing mucosal immune defense and tissue repair functions. This regimen shows potent antibacterial efficacy against a range of pathogens in vitro and in vivo , along with a favorable safety profile. These findings highlight a promising combinatorial therapeutic strategy against the growing threat of antibiotic resistance. IMPORTANCE Antibiotic resistance has become one of the most urgent threats to global public health, yet the development of new antibiotics has slowed dramatically. In this study, we propose a promising alternative strategy that combines azithromycin with a small-molecule compound capable of inhibiting bacterial quorum sensing. This combination not only kills bacteria more effectively than the antibiotic alone but also harnesses the body’s own immune system to fight infection. Its mechanisms of action include disrupting bacterial structure, promoting the polarization of macrophages toward the M1-type phenotype, and enhancing bactericidal capacity by activating the IL-17 signaling pathway to stimulate the production of the Muc5b protein. Our findings suggest that this dual-pronged approach could help revitalize existing antibiotics, offering a practical pathway to combat drug-resistant infections.