RESUMO
The main components of the quorum-sensing system are expected to be favorable targets for drug development to combat various chronic infectious diseases. ComA of Streptococcus is an ATP-binding cassette transporter containing a peptidase domain (PEP), which is essential for the quorum-sensing signal production. Using high-throughput screening, we found a potent small molecule that suppressed the S. mutans quorum-sensing pathway through inhibition of PEP activity. The compound effectively attenuated the biofilm formation and competence development of S. mutans without inhibiting cell growth. The kinetic and structural studies with this molecule and a related compound unexpectedly revealed an allosteric site of PEP. This relatively hydrophobic site is thought to undergo large structural changes during the catalytic process. These compounds inhibit PEP activity by binding to and suppressing the structural changes of this site. These results showed that PEP is a good target for inhibitors of the Streptococcus quorum-sensing system.
Assuntos
Antibacterianos/farmacologia , Ensaios de Triagem em Larga Escala , Percepção de Quorum/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Streptococcus/efeitos dos fármacos , Streptococcus/fisiologia , Antibacterianos/química , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Chemical transformation of an early intermediate in our synthesis of huperzine A provided a diverse array of molecules in which a variety of functional groups could be embedded.
