Identification of simple arylfluorosulfates as potent agents against resistant bacteria

Jiong Zhang; Xiangxiang Zhao; John R Cappiello; Yi Yang; Yunfei Cheng; Guang Liu; Wenjing Fang; Yinzhu Luo; Yu Zhang; Jiajia Dong; Lixin Zhang; K Barry Sharpless

doi:10.1073/pnas.2103513118

Identification of simple arylfluorosulfates as potent agents against resistant bacteria

Proc Natl Acad Sci U S A. 2021 Jul 13;118(28):e2103513118. doi: 10.1073/pnas.2103513118.

Authors

Jiong Zhang¹, Xiangxiang Zhao², John R Cappiello³, Yi Yang³, Yunfei Cheng³, Guang Liu², Wenjing Fang², Yinzhu Luo⁴, Yu Zhang⁴, Jiajia Dong⁵, Lixin Zhang⁶, K Barry Sharpless⁷

Affiliations

¹ Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, 200032 Shanghai, China.
² State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 200237 Shanghai, China.
³ Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
⁴ Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, 510663 Guangzhou, China.
⁵ Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, 200032 Shanghai, China; jiajia@sioc.ac.cn lxzhang@ecust.edu.cn sharples@scripps.edu.
⁶ State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 200237 Shanghai, China; jiajia@sioc.ac.cn lxzhang@ecust.edu.cn sharples@scripps.edu.
⁷ Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; jiajia@sioc.ac.cn lxzhang@ecust.edu.cn sharples@scripps.edu.

Abstract

Sulfur fluoride exchange (SuFEx), a next generation of click chemistry, opens an avenue for drug discovery. We report here the discovery and structure-activity relationship studies of a series of arylfluorosulfates, synthesized via SuFEx, as antibacterial agents. Arylfluorosulfates 3, 81, and 101 showed potency to overcome multidrug resistance and were not susceptible to the generation of resistance. They exhibited rapid bactericidal potency and selectively killed gram-positive bacterial strains. These compounds also exhibited the ability to disrupt established bacterial biofilm and kill persisters derived from biofilm. Furthermore, arylfluorosulfate 3 had a synergistic effect with streptomycin and gentamicin. In addition, their anti-MRSA potency was evaluated and determined by the Caenorhabditis elegans model.

Keywords: SuFEx; antibacterial agents; biofilm disruption; click chemistry; multidrug resistance.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology*
Biofilms / drug effects
Biofilms / growth & development
Caenorhabditis elegans / microbiology
Disease Models, Animal
Drug Resistance, Bacterial* / drug effects
HEK293 Cells
Humans
Kinetics
Methicillin-Resistant Staphylococcus aureus / drug effects
Microbial Sensitivity Tests
Phenotype
Structure-Activity Relationship
Sulfates / chemistry
Sulfates / pharmacology*

Substances

Anti-Bacterial Agents
Sulfates

Grants and funding

R01 GM117145/GM/NIGMS NIH HHS/United States