Identification of a Potential Lead Structure for Designing New Antimicrobials to Treat Infections Caused by Staphylococcus epidermidis-Resistant Strains

• Published in: Current microbiology 2008-11, Vol.57 (5), p.463-468
• Main Authors: Pinheiro, Luiz C. S, Abreu, Paula A, Afonso, Ilidio F, Leal, Bruno, Corrêa, Luiz C. D, Borges, Júlio C, Marques, Isakelly P, Lourenço, André L, Sathler, Plinio, dos Santos, Andre L, Medeiros, Cid A, Cabral, Lúcio M, Júnior, Maurício L. O, Romeiro, Gilberto A, Ferreira, Vitor F, Rodrigues, Carlos R, Castro, Helena C, Bernardino, Alice M. R
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Antibiotics; Antimicrobial agents; Bacteria - drug effects; Bacterial diseases; Biomedical and Life Sciences; Biotechnology; Drug Design; Drug Evaluation, Preclinical; Drug resistance; Drug Resistance, Bacterial; Humans; Lead; Life Sciences; Microbial Sensitivity Tests; Microbiology; Models, Molecular; Nosocomial infection; Pyridines; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacokinetics; Pyridines - pharmacology; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus; Staphylococcus epidermidis; Staphylococcus epidermidis - drug effects; Staphylococcus infections; Structure-Activity Relationship
• ISSN: 0343-8651; 1432-0991
• DOI: 10.1007/s00284-008-9234-5

Bacterial infections are a significant cause of morbidity and mortality among critically ill patients. The increase of antibiotic resistance in bacteria from human microbiota--such as Staphylococcus epidermidis, an important nosocomial pathogen that affects immunocompromised patients or those with indwelling devices--increased the desire for new antibiotics. In this study we designed, synthesized, and determined the antimicrobial activity of 27 thieno[2,3-b]pyridines (1, 2, 2a-2m, 3, 3a-3m) derivatives against a drug-resistant clinical S. epidermidis strain. In addition, we performed a structure-activity relationship analysis using a molecular modeling approach, and discuss the drug absorption, distribution, metabolism, excretion, and toxicity profile and Lipinski's “rule of five,” which are tools to assess the relationship between structures and drug-like properties of active compounds. Our results showed that compound 3b (5-(1H-tetrazol-5-yl)-4-(3`-methylphenylamino)thieno[2,3-b]pyridine) was as active as oxacillin and chloramphenicol but with lower theoretical toxicity risks and a better drug likeness and drug score potential than chloramphenicol. All molecular modeling and biological results reinforced the promising profile of 3b for further experimental investigation and development of new antibacterial drugs.