The threat of multi-drug resistant Gram-negative pathogens and the dearth of treatment options is a significant public health problem. In the past 40 years, no new classes of antibiotics have been introduced into the clinic to treat Gram-negative bacterial infections. One approach to developing new antibiotics is to develop pathogen specific antibiotics to slow the evolution of resistant bacteria. 1,2,4-triazolidine-3-thiones are a new class of antibiotic that has shown specific activity against the Gram-negative bacterial pathogen Acinetobacter baumannii. Through an extensive structure-activity relationship study of the parent compound, a new small molecule with potent antibiotic activity against multiple strains of multi-drug and extensively drug resistant A. baumannii was identified. Initial mechanism of action studies suggests the inhibition of a fatty acid desaturation pathway as the mode of action. Additionally, this small molecule displayed single dose antibiotic activity against a hypervirulent clinical isolate of A. baumannii in the Galleria mellonella infection model increasing survival percentage more than 40% after 3 days compared to an untreated control.

1,2,4-triazolidine-3-thiones as narrow spectrum antibiotics against Acinetobacter baumannii

255th National Meeting (2018)

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