Identification of simple arylfluorosulfates as potent agents against resistant bacteria

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.

Antibiotic resistance is a tremendous threat to global health. Some of the most concerning multidrug-resistant pathogen strains include methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA, respectively), vancomycin-resistant Enterococcus faecium (VRE), Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp (1–3). Antibiotic resistance is one of the biggest public health challenges and is a leading cause of death with at least 2.8 million infected cases and more than 35,000 deaths every year in the United States (4). Therefore, the development of novel antibacterial drugs with the ability to overcome drug-resistance is urgently needed. Furthermore, our general understanding of the role of our microbiomes (i.e., skin, oral, gut, etc.) in antibiotic resistance and responses is ever increasing (5–7). The next generation of antibacterial agents will require limited drug promiscuity to eliminate resistance and decrease unwanted off-target effects on our symbiotic commensal organisms and immunity (8, 9).Sulfur fluoride exchange (SuFEx) (10), a new generation of click chemistry, has found diverse applications to chemical synthesis (11–16), materials science (17–22), chemical biology (23–28), and drug discovery (29, 30). In our previous studies, we demonstrated that SuFEx modification is a highly reliable approach for the late-stage functionalization of drugs and drug-like molecules to generate new compounds with improved properties (31, 32). Later on, Ravindar et al. reported the synthesis of arylfluorosulfate analogs and screened them for antimicrobial activity (33).Here we report further screening studies on arylfluorosulfate derivatives (Ar-O-SO₂-F) in our laboratory and have found several simple molecules which are potent against methicillin- and vancomycin-resistant strains (Fig. 1 and SI Appendix, Figs. S1 and S2). Through structure and activity relationship (SAR) studies, we determined that the -OSO₂F moiety is essential for these compounds’ antibacterial activities. Not only are they capable of inhibiting bacterial biofilm formation, but they are also able to disrupt established bacterial biofilm and induce the killing of persister cells. Significantly, these arylfluorosulfates are effective against MRSA infection in a Caenorhabditis elegans-based infection model. Our findings reported here thus may serve as the foundation toward the development of arylfluorosulfate-based antibacterial agents.Open in a separate windowFig. 1.(A) Arylfluorosulfates were derived from phenols or phenol’s precursors. (B) The structures of antibacterial arylfluorosulfates 3, 81, and 101 and their MIC values against MRSA.