Sulfur(VI) fluoride exchange (SuFEx) chemistry, the next generation of click chemistry, was first proposed by Professor Sharpless in 2014 (Angew. Chem. Int. Ed. Engl. 2014, 53, 9430-9448.). Sulfur(VI) fluoride groups have unusually high chemical stability but can achieve extraordinary high reactivity under specific conditions. SuFEx click chemistry is widely applied in chemical synthesis, materials chemistry, chemical biology, and drug discovery. In previous studies, Professor Sharpless’s group reported that SuFEx-based modifications could help to improve the drugs’ anti-cancer activity and could be used in the high-throughput preparation of derivatives for activity screening (J. Am. Chem. Soc. 2018, 140, 2919-2925.; Nat. Chem. 2020, 12, 906-913.; J. Am. Chem. Soc. 2020, 142, 10899-10904.). Fig. 1 structure modification based on sufex enhances antibacterial activity of compounds (Image by DONG Jiajia) Antibiotic resistance is one of the biggest public health challenges. Multidrug-resistant pathogen strains, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), and vancomycin-resistant Enterococcus faecium (VRE), are a tremendous threat to global health and cause countless deaths every year. Therefore, the development of novel antimicrobial drugs with the ability to overcome drug resistance remains urgently needed. In response to this threat, an international team composed of Prof DONG Jiajia ’s group from SIOC, Prof ZHANG Lixin’s group from ECUST, and Prof K. Barry Sharpless’s group from Scripps Institute synthesized hundreds of aryl fluorosulfates derived from phenols or phenol precursors via SuFEx chemistry. Through phenotypic screening, it’s found that several simple aryl fluorosulfates, especially the derivatives of hexylresorcinol, resveratrol, and honokiol, could quickly kill a panel of Gram-positive bacteria strains, including MRSA, VRSA, VRE, and clinically isolated multidrug-resistant Staphylococcus aureus. These aryl fluorosulfates had greatly improved antibacterial activity compared to their parent compounds which are clinically used antibacterial drugs or active ingredients of traditional Chinese medicines. They exhibited low mammalian cytotoxicity and hemolytic activity and could quickly kill bacteria. Furthermore, they could inhibit biofilm formation and kill persister cells. In addition, these aryl fluorosulfates were not susceptible to the generation of drug resistance and could extend the survival time of MRSA infected C. elegans. The aryl fluorosulfates derived from hexrasorcin also had a synergistic effect with gentamicin and streptomycin. This study suggests that aryl fluorosulfates derived from SuFEx-based modification of phenols could be a convenient strategy to develop antimicrobial candidates. The research result was published online recently in Proc. Natl. Acad. Sci. U.S.A. entitled “Identification of Simple Arylfluorosulfates as Potent Agents against Resistant Bacteria.”
DONG Jiajia Shanghai Institute of Organic Chemistry Chinese Academy of Sciences Tel:021-54925579 E-mail:jiajia@sioc.ac.cn |
