Abstract
Two-component systems (TCSs) have the potential to be an effective target of the antimicrobials, and thus received much attention in recent years. VicK/VicR is one of TCSs in Streptococcus pneumoniae (S. pneumoniae), which is essential for pneumococcal survival. We have previously obtained several Traditional Chinese Medicine monomers using a computer-based screening. In this study, either alone or in combination with penicillin, their antimicrobial activities were evaluated based on in vivo and in vitro assays. The results showed that the MICs of 5′-(Methylthio)-5′-deoxyadenosine, octanal 2, 4-dinitrophenylhydrazone, deoxyshikonin, kavahin, and dodecyl gallate against S. pneumoniae were 37.1, 38.5, 17, 68.5, and 21 μg/mL, respectively. Time-killing assays showed that these compounds elicited bactericidal effects against S. pneumoniae D39 strain, which led to a 6-log reduction in CFU after exposure to compounds at four times of the MIC for 24 h. The five compounds inhibited the growth of Streptococcus pyogenes, Streptococcus mitis, Streptococcus mutans or Streptococcus pseudopneumoniae, meanwhile, deoxyshikonin and dodecyl gallate displayed strong inhibitory activities against Staphylococcus aureus. These compounds showed no obvious cytotoxicity effects on Vero cells. Survival time of the mice infected by S. pneumoniae strains was prolonged by the treatment with the compounds. Importantly, all of the five compounds exerted antimicrobial effects against multidrug-resistant clinical strains of S. pneumoniae. Moreover, even at sub-MIC concentration, they inhibited cell division and biofilm formation. The five compounds all have enhancement effect on penicillin. Deoxyshikonin and dodecyl gallate showed significantly synergic antimicrobial activity with penicillin in vivo and in vitro, and effectively reduced nasopharyngeal and lung colonization caused by different penicillin-resistant pneumococcal serotypes. In addition, the two compounds also showed synergic antimicrobial activity with erythromycin and tetracycline. Taken together, our results suggest that these novel VicK inhibitors may be promising compounds against the pneumococcus, including penicillin-resistant strains.
Highlights
Invasive pneumococcal infections, such as pneumonia, sepsis, and meningitis, commonly have high morbidity and mortality worldwide (Bandettini and Melioli, 2012)
The five compounds caused a maximum 5-log CFU reduction in S. pneumoniae NCTC7466 (Figure 3) at Minimum inhibitory concentration (MIC) and four times the MIC after 24 h of incubation. These results showed that the five compounds have significant antibacterial activities against S. pneumoniae in vitro
The results showed that deoxyshikonin and dodecyl gallate eliminated the bacterial colonization in the nasopharynx and lung of mice at 24 and 72 h after infection
Summary
Invasive pneumococcal infections, such as pneumonia, sepsis, and meningitis, commonly have high morbidity and mortality worldwide (Bandettini and Melioli, 2012). The development of novel antimicrobials against pneumococcal infections is indispensable. Two-component systems (TCS) are deserved to be considered as effective drug targets, because they are required for the regulation of bacterial virulence and growth (Barrett and Hoch, 1998; Fabret and Hoch, 1998) and TCSs have not been found in mammals (Worthington et al, 2013). Compared with drugs that target the sensory domains of HKs, those that target the conserved catalytic domains of HKs which could coordinately inhibit multiple TCSs are expected to reduce the virulence of pathogenic microorganisms more efficiently (Gotoh et al, 2010). Yamamoto and Watanabe (Yamamoto et al, 2001; Watanabe et al, 2003) have verified that HK inhibitors, such as synthetic imidazole, zerumbone derivatives, and aranorosinol B, were effective antibacterial agents against Bacillus subtilis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
