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

Abstract

The Pseudomonas quinolone signal (PQS) is an important quorum sensing signal of the pathogen Pseudomonas aeruginosa. 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 Moraxella catarrhalis. Synthetic optimization resulted in minimum inhibitory concentrations in the nanomolar range even for clinical isolates of M. catarrhalis. Surprisingly, the growth of other human pathogens and commensals, including closely related Moraxella 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.