Isothiazolone-Nitroxide Hybrids with Activity against Antibiotic-Resistant Biofilms.

Isothiazolones are widely used as biocides in industrial processing systems and personal care products, but their use to treat infections in humans has been hampered by their inherent cytotoxicity. Herein, we report a strategy to alleviate isothiazolone toxicity and improve antibacterial and antibiofilm potency by functionalization with a nitroxide moiety. Isothiazolone-nitroxide hybrids and were prepared over three steps in moderate yields (58 and 36%, respectively) from ()-3-(benzylsulfanyl)-propenoic acid. Hybrid displayed better activity (minimum inhibitory concentration (MIC) = 35 μM) than the widely used methylisothiazolinone (MIT , MIC = 280 μM) against methicillin-susceptible (MSSA). Hybrid was even more active against drug-resistant strains, such as vancomycin-resistant (VRSA, MIC = 8.75 μM) over MIT (MIC = 280 μM). The enhanced antibacterial activity of hybrid over MIT was retained against established MSSA and VRSA biofilms, with minimum biofilm eradication concentration (MBEC) values of 35 and 70 μM, respectively, for (the MBEC value for MIT against both strains was ≥280 μM). No toxicity was observed in human epithelial T24 cells treated with hybrid in concentrations up to 560 μM using a lactate dehydrogenase assay.