A thiochromenone antibiotic derived from the <i>Pseudomonas</i> quinolone signal selectively targets the Gram-negative pathogen <i>Moraxella catarrhalis</i>

Abstract

The <i>Pseudomonas</i> quinolone signal (PQS) is an important quorum sensing signal of the pathogen <i>Pseudomonas aeruginosa</i>. We discovered an additional activity of PQS as a narrow spectrum antibiotic. Exploiting the privileged structure of PQS by the synthesis of heteroatom-substituted analogues led to a class of 2-alkyl-3-hydroxythiochromen-4-ones with highly potent antibiotic activity against the nasopharyngeal pathogen <i>Moraxella catarrhalis</i>. Synthetic optimization resulted in minimum inhibitory concentrations in the nanomolar range even for clinical isolates of <i>M. catarrhalis</i>. Surprisingly, the growth of other human pathogens and commensals, including closely related <i>Moraxella</i> species, was not inhibited, indicating exceptional species selectivity. Mechanistic studies revealed that the antibiotic was bactericidal and likely inhibits a target in the primary energy metabolism causing rapid depletion of the cellular ATP pool.