A deformylase inhibitor expands therapeutic options for Lyme disease

Lyme disease incidence continues to rise globally. This vector-borne infection remains a major public health burden. Broad-spectrum doxycycline and ceftriaxone disrupt the gut microbiome, drive resistance in commensals, and offer suboptimal efficacy against neuroborreliosis. Here we show that forazemin, previously known as BB-83698, is an orally bioavailable peptide deformylase inhibitor with potent and selective bactericidal activity against spirochaetes, including diverse Borrelia species. Targeting the deformylation of nascent peptides, forazemin halted protein synthesis, thereby killing the spirochaetes. In murine models of Lyme borreliosis and neuroborreliosis, short oral dosing regimens cleared infection, and forazemin was more effective than doxycycline in tick-bite prophylaxis. Forazemin preserved microbiome diversity and spared beneficial gut symbionts. These findings support forazemin as a candidate for the treatment and prevention of Lyme disease.