RESUMO
Bacterial resistance to the main widespread antibiotics, such as those based on quinolones, is a concern of the scientific community, leading to the search for new classes of molecules that can be used as an alternative. Here, we investigate the crystalline and chemical characteristics of a thioxopyrimide to understand its demonstrated biological activity and to identify which portion of the molecule can be used as a framework to develop new antibiotics. For this purpose, structural studies of ethyl 4-methyl-2-phenyl-6-thioxo-1,6-dihydro-5-pyrimidinecarboxylate were carried out aided by Hirshfeld surface analysis, as well as theoretical calculations on frontier molecular orbitals, molecular electrostatic potential, and conformational stability, in addition to docking studies targeting topoisomerase IV. The docking results show a reasonable accommodation of the molecule at the topoisomerase IV binding site and interact mainly by hydrogen bonds between the thioxopyrimidine portion with Glu198, Thr292, and Gly225, aided by hydrophobic interactions involving the rest of the molecule. These results suggest a relationship between the antibacterial activity shown mainly with the 4-thioxopyrimidine portion, leading to the investigation of new compounds that use this scaffold.
Assuntos
Modelos Moleculares , Conformação Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Sítios de Ligação , DNA Topoisomerase IV/química , DNA Topoisomerase IV/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeAssuntos
DNA Topoisomerase IV/genética , Farmacorresistência Bacteriana/genética , Mutação , Vibrio cholerae O1/genética , Sequência de Aminoácidos , Antibacterianos/química , Antibacterianos/farmacologia , Sequência de Bases , Cólera/tratamento farmacológico , Cólera/microbiologia , Toxina da Cólera/genética , Ciprofloxacina/química , Ciprofloxacina/farmacologia , DNA Topoisomerase IV/química , Proteínas de Fímbrias/genética , Humanos , Índia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Tipagem de Sequências Multilocus , Termodinâmica , Vibrio cholerae O1/efeitos dos fármacos , Vibrio cholerae O1/enzimologia , Vibrio cholerae O1/isolamento & purificaçãoRESUMO
Toxin-antitoxin (TA) proteic systems encode a toxin and an antitoxin that regulate the growth and death of bacterial cells under various stress conditions. The ParE protein is a toxin that inhibits DNA gyrase activity and thereby blocks DNA replication. Based on the Escherichia coli ParE structure, a series of linear peptides were designed and synthesized by solid-phase methodology. The ability of the peptides to inhibit the activity of bacterial topoisomerases was investigated. Four peptides (ParELC3, ParELC8, ParELC10 and ParELC12), showed complete inhibition of DNA gyrase supercoiling activity with an IC(100) between 20 and 40 µmol L(-1). In contrast to wild-type ParE, the peptide analogues were able to inhibit the DNA relaxation of topoisomerase IV, another type IIA bacterial topoisomerase, with lower IC(100) values. Interestingly only ParELC12 displayed inhibition of the relaxation activity of human topoisomerase II. Our findings reveal new inhibitors of bacterial topoisomerases and are a good starting point for the development of a new class of antibacterial agents that targets the DNA topoisomerases.