RESUMEN
Waldiomycin is an inhibitor of histidine kinases (HKs). Although most HK inhibitors target the ATP-binding region, waldiomycin binds to the intracellular dimerization domain (DHp domain) with its naphthoquinone moiety presumed to interact with the conserved H-box region. To further develop inhibitors targeting the H-box, various 2-aminonaphthoquinones with cyclic, aliphatic, or aromatic amino groups and naphtho [2,3-d] isoxazole-4,9-diones were synthesized. These compounds were tested for their inhibitory activity (IC50) against WalK, an essential HK for Bacillus subtilis growth, and their minimum inhibitory concentrations (MIC) against B. subtilis. As a result, 11 novel HK inhibitors were obtained as naphthoquinone derivatives (IC50: 12.6-305 µM, MIC: 0.5-128 µg ml-1). The effect of representative compounds on the expression of WalK/WalR regulated genes in B. subtilis was investigated. Four naphthoquinone derivatives induced the expression of iseA (formerly yoeB), whose expression is negatively regulated by the WalK/WalR system. This suggests that these compounds inhibit WalK in B. subtilis cells, resulting in antibacterial activity. Affinity selection/mass spectrometry analysis was performed to identify whether these naphthoquinone derivatives interact with WalK in a manner similar to waldiomycin. Three compounds were found to competitively inhibit the binding of waldiomycin to WalK, suggesting that they bind to the H-box region conserved in HKs and inhibit HK activity.
Asunto(s)
Antibacterianos , Bacillus subtilis , Histidina Quinasa , Pruebas de Sensibilidad Microbiana , Naftoquinonas , Naftoquinonas/farmacología , Naftoquinonas/síntesis química , Naftoquinonas/química , Histidina Quinasa/antagonistas & inhibidores , Histidina Quinasa/metabolismo , Bacillus subtilis/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Regulación Bacteriana de la Expresión Génica , QuinonasRESUMEN
OBJECTIVES: The purpose of this study was to clarify the contamination of mobile phones shared in hospital wards and its relationship with the consciousness and behavior of nurses about biological cleanliness. METHODS: Samples from mobile phones were cultured to detect viable bacteria (n=110) and Staphylococcus aureus (n=54). A questionnaire survey was conducted on 110 nurses carrying mobile phones on the day of sampling. RESULTS: Viable bacteria were detected on 79.1% of the mobile phones, whereas S. aureus was detected on 68.6%. All the nurses were aware of hand washing with water or alcohol after regular work, but 33.6% of the nurses were not conscious of hand washing with water or alcohol after using a mobile phone. There was a significant positive relationship between the frequency of using mobile phones and the number of hand washings with water or alcohol. A significant negative relationship was found between the detection of viable bacteria and the number of hand washings with alcohol. The results of logistic regression analysis showed that the detection of viable bacteria was related significantly with the number of hand washings with alcohol (Odds ratio, 0.350; 95%CI, 0.143-0.857) and that the detection of S. aureus was related significantly with the frequency of using mobile phones (Odds ratio, 0.183; 95%CI, 0.036-0.933). CONCLUSIONS: It is important to be conscious of the fact that mobile phones shared in hospital wards are easily contaminated. Because hand washing with water or alcohol prevents the contamination of the mobile phones, nurses should take standard precautions after using mobile phones.
