A synthetic antibiotic class with a deeply-optimized design for overcoming bacterial resistance

Abstract

Abstract The lack of new drugs that are effective against antibiotic-resistant bacteria has caused increasing concern in global public health. As antibiotic resistance continues to escalate worldwide, the development of new antibiotics that can effectively treat bacterial infections is crucial. Based on this study, we report the development of a hybrid antimicrobial drug that is rationally designed through drug structural hybridization-based structure-guided design and component-based synthesis. The optimal modified compound, F8, was identified, which demonstrated excellent in vitro and in vivo anti-resistant bacterial activity and effectively mitigated the development of resistance. F8 exhibits significant bactericidal activity against bacteria resistant to antibiotics such as methicillin, polymyxin B, florfenicol, doxycycline, ampicillin and sulfamethoxazole. In the mouse model of drug-resistant bacterial bacteremia, F8 was found to increase survival and significantly reduce bacterial load in infected mice. Multi-omics analysis (transcriptomics, proteomics, and metabolomics) have indicated that ornithine carbamoyl transferase (arcB) is a novel antimicrobial target of F8. Further molecular docking, Isothermal Titration Calorimetry (ITC), and Differential Scanning Fluorimetry (DSF) studies verified arcB as a novel and effective target for F8. Finally, mechanistic studies suggest that F8 competitively binds to arcB, disrupting the bacterial cell membrane and inducing a certain degree of oxidative damage. The findings of this study highlight F8 as a promising candidate drug for the development of novel antibiotic formulations to combat antibiotic-resistant bacteria-associated infections.