Schlievert_2025_mSphere__e0031825

Glycerol dithionomonolaurate (NB2) is an analog of the natural antimicrobial compound glycerol monolaurate (GML) with enhanced antimicrobial activity. The advantage of NB2 over GML is the presence of a dithionate to greatly reduce microbial cleavage through glycerol ester hydrolases, such as Staphylococcus aureus lipase. NB2 exhibited antimicrobial activity against Candida fungal species, including Candida auris, with comparable minimum bactericidal concentration (MBC) and minimum inhibitory concentration (MIC) of 50-100 microg/mL compared to 250-500 microg/mL for GML. NB2 exhibited a broad range of antibacterial activity including both gram-positive and gram-negative organisms, while sparing normal microbiome lactobacilli. When 10(8) C. auris and 10(9) S. aureus were incubated on Todd Hewitt agar plates in the presence of two times the MBC for NB2, no resistant colonies grew, likely the result of the large number of antimicrobial targets inhibited. Like GML, NB2 inhibited exotoxin production at non-antibacterial concentrations. NB2 exhibited anti-staphylococcal activity when tested topically on a dermatitis skin model on rabbits. NB2 inhibited the production of chemokines (interleukin-8 and macrophage inflammatory protein-3alpha) by human vaginal epithelial cells, suggesting anti-inflammatory activity. Unlike clear GML solutions, NB2 was pale yellow. The absorption spectrum of NB2 was not sufficient to raise Food and Drug Administration concerns over phototoxicity. Collectively, the data suggest that NB2 could become a useful topical agent for the prevention of both fungal and bacterial infections as a dual-active anti-infective, killing microbes and reducing harmful inflammation, such as seen in atopic dermatitis. IMPORTANCE: Fungi and many bacteria commonly develop resistance to antimicrobial agents or have inherent resistance. Many microbes initiate infections through the skin and mucous membranes, in part by producing toxins and causing harmful inflammation. We describe a novel topical antimicrobial agent, glycerol dithionomonolaurate (NB2), effective against Candida and a wide range of gram-positive and gram-negative bacteria; the compound did not kill normal microbiome lactobacilli. NB2 is likely to have many microbial targets for killing, suggesting resistance to the molecule may not develop. At sub-antibacterial concentrations, glycerol dithionomonolaurate inhibited exotoxin production by Staphylococcus aureus. The molecule was not inactivated by staphylococcal lipase. Glycerol dithionomonolaurate effectively treated S. aureus dermatitis in a rabbit skin model and reduced chemokine production by human epithelial cells. Glycerol dithionomonolaurate may prove useful to treat many types of skin and mucous membrane infections by both antimicrobial and anti-inflammatory activities, such as in atopic dermatitis.