Opportunistic bacteria Staphylococcus aureus and Staphylococcus epidermidis often form rigid biofilms on tissues and inorganic surfaces. In the biofilm bacterial cells are embedded in a self-produced polysaccharide matrix and thereby are inaccessible to biocides, antibiotics, or host immune system. Here we show the antibacterial activity of newly synthesized cationic biocides, the quaternary ammonium, and bisphosphonium salts of pyridoxine (vitamin B6) against biofilm-embedded Staphylococci. The derivatives of 6-hydroxymethylpyridoxine were ineffective against biofilm-embedded S. aureus and S. epidermidis at concentrations up to 64 μg/mL, although all compounds tested exhibited low MICs (2 μg/mL) against planktonic cells. In contrast, the quaternary ammonium salt of pyridoxine (N,N-dimethyl-N-((2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methyl)octadecan-1-aminium chloride (3)) demonstrated high biocidal activity against both planktonic and biofilm-embedded bacteria. Thus, the complete death of biofilm-embedded S. aureus and S. epidermidis cells was obtained at concentrations of 64 and 16 μg/mL, respectively. We suggest that the quaternary ammonium salts of pyridoxine are perspective to design new synthetic antibiotics and disinfectants for external application against biofilm-embedded cells.

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A series of novel quaternary ammonium 4-deoxypyridoxine derivatives was synthesized. Two compounds demonstrated excellent activity against a panel of Gram-positive methicillin-resistant S. aureus strains with MICs in the range of 0.5–2 μg/mL, exceeding the activity of miramistin. At the same time, both compounds were inactive against the Gram-negative E. coli and P. aeruginosa strains. Cytotoxicity studies on human skin fibroblasts and embryonic kidney cells demonstrated that the active compounds possessed similar toxicity with benzalkonium chloride but were slightly more toxic than miramistin. SOS-chromotest in S. typhimurium showed the lack of DNA-damage activity of both compounds; meanwhile, one compound showed some mutagenic potential in the Ames test. The obtained results make the described chemotype a promising starting point for the development of new antibacterial therapies.

A series of 26 quaternary ammonium pyridoxine derivatives were synthesized and their cytotoxicity and antibacterial activities against clinically relevant bacterial strains were tested in vitro. The antibacterial activity of mono-ammonium salts increased with the rise of the lipophilicity and compound 3,3,5-trimethyl-8,8-dioctyl-1,7,8,9-tetrahydro-[1,3]dioxino[5,4-d]pyrrolo[3,4-b]pyridin-8-ium chloride (2d) reaches a maximum among them. Bis-ammonium salt of pyridoxine 4 with two dimethyloctylamine groups also demonstrated high antibacterial activity despite lower lipophilicity. The results of MTT assay indicated that HEK 293 cells were more sensitive than HSF to quaternary ammonium pyridoxine derivatives. Compounds 2d and 4 did not induce the damage of the DNA and might be of interest in the development of new antimicrobials.