Multi-armed antibiotics for Gram-positive bacteria

Yuexiao Jia; Wenwen Chen; Rongbing Tang; Jiangjiang Zhang; Xiaoyan Liu; Ruihua Dong; Fupin Hu; Xingyu Jiang

doi:10.1016/j.chom.2023.06.008

Multi-armed antibiotics for Gram-positive bacteria

Cell Host Microbe. 2023 Jul 12;31(7):1101-1110.e5. doi: 10.1016/j.chom.2023.06.008.

Authors

Yuexiao Jia¹, Wenwen Chen², Rongbing Tang³, Jiangjiang Zhang³, Xiaoyan Liu³, Ruihua Dong³, Fupin Hu⁴, Xingyu Jiang⁵

Affiliations

¹ Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, No. 1088 Xueyuan Rd., Nanshan District, Shenzhen, Guangdong 518055, P.R. China; Institute of Biomedical Engineering and Health Sciences, School of Medical and Health Engineering, Changzhou University, Changzhou, Jiangsu 213164, P.R. China.
² School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, P.R. China.
³ Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, No. 1088 Xueyuan Rd., Nanshan District, Shenzhen, Guangdong 518055, P.R. China.
⁴ Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.
⁵ Shenzhen Key Laboratory of Smart Healthcare Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, No. 1088 Xueyuan Rd., Nanshan District, Shenzhen, Guangdong 518055, P.R. China. Electronic address: jiang@sustech.edu.cn.

PMID: 37442098
DOI: 10.1016/j.chom.2023.06.008

Abstract

Antibiotic resistance is a serious threat to public health. Here, we propose a multi-armed chemical scaffold (MACS) for antibiotic screening, which refers to multi-armed molecules (MAMs) consisting of a core unit and three or four arms, neither of which is active for pathogens. Based on a structure-activity relationship study of MAMs, we discover a class of multi-armed antibiotics (MAAs) with a core similar to ethylene (E), carbon atom (C), benzene (B), nitrogen atom (N), and triazine (T) and three or four 4-phenylbenzoic acid (PBA) arms, or a B core and three 4-vinylbenzoic acid (VBA) or 4-ethynylbenzoic acid (EBA) arms. They can selectively interact with Gram-positive bacteria and inhibit cell wall assembly by targeting the lipid carriers of cell wall biosynthesis. MAAs have excellent antibacterial activities against Gram-positive bacteria, including clinical multi-drug-resistant (MDR) isolates. Our study provides a chemical scaffold and identifies eight antibacterial lead compounds for the development of antibiotics.

Keywords: antibiotics; cell wall assembly; low risk of resistance; multi-drug resistant bacteria.

MeSH terms

Anti-Bacterial Agents* / pharmacology
Anti-Bacterial Agents* / therapeutic use
Gram-Negative Bacteria*
Gram-Positive Bacteria
Microbial Sensitivity Tests

Substances

Anti-Bacterial Agents