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

Jin Feng, Youle Zheng, Wanqing Ma, Defeng Weng, Dapeng Peng, Yindi Xu, Zhifang Wang and Xu Wang ()
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Jin Feng: Huazhong Agricultural University
Youle Zheng: Huazhong Agricultural University
Wanqing Ma: Huazhong Agricultural University
Defeng Weng: Huazhong Agricultural University
Dapeng Peng: Huazhong Agricultural University
Yindi Xu: Henan Academy of Agricultural Sciences
Zhifang Wang: Henan Academy of Agricultural Sciences
Xu Wang: Huazhong Agricultural University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract The lack of new drugs that are effective against antibiotic-resistant bacteria has caused increasing concern in global public health. Based on this study, we report development of a modified antimicrobial drug through structure-based drug design (SBDD) and modular synthesis. The optimal modified compound, F8, was identified, which demonstrated in vitro and in vivo broad-spectrum antibacterial activity against drug-resistant bacteria and effectively mitigated the development of resistance. F8 exhibits significant bactericidal activity against bacteria resistant to antibiotics such as methicillin, polymyxin B, florfenicol (FLO), doxycycline, ampicillin and sulfamethoxazole. In a mouse model of drug-resistant 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 antimicrobial target of F8. Further molecular docking, Isothermal Titration Calorimetry (ITC), and Differential Scanning Fluorimetry (DSF) studies verified arcB as a 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. Here, we report F8 as a promising candidate drug for the development of antibiotic formulations to combat antibiotic-resistant bacteria-associated infections.

Date: 2024
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DOI: 10.1038/s41467-024-50453-3

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