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Discovery of novel inhibitors of Streptococcus pneumoniae based on the virtual screening with the homology-modeled structure of histidine kinase (VicK).

Li N, Wang F, Niu S, Cao J, Wu K, Li Y, Yin N, Zhang X, Zhu W, Yin Y - BMC Microbiol. (2009)

Bottom Line: Using a structure-based virtual screening (SBVS) method, 105 compounds were computationally identified as potential inhibitors of the histidine kinase (HK) VicK protein from the compound library SPECS.In mouse sepsis models, these compounds are still able to decrease the mortality of the mice infected by S. pneumoniae and one compound even has significant therapeutic effect.To our knowledge, these compounds are the first reported inhibitors of HK with antibacterial activity in vitro and in vivo, and are novel lead structures for developing new drugs to combat pneumococcal infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Faculty of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, PR China. linan101@tom.com

ABSTRACT

Background: Due to the widespread abusage of antibiotics, antibiotic-resistance in Streptococcus pneumoniae (S. pneumoniae) has been increasing quickly in recent years, and it is obviously urgent to develop new types of antibiotics. Two-component systems (TCSs) are the major signal transduction pathways in bacteria and have emerged as potential targets for antibacterial drugs. Among the 13 pairs of TCSs proteins presenting in S. pneumoniae, VicR/K is the unique one essential for bacterium growth, and block agents to which, if can be found, may be developed as effective antibiotics against S. pneumoniae infection.

Results: Using a structure-based virtual screening (SBVS) method, 105 compounds were computationally identified as potential inhibitors of the histidine kinase (HK) VicK protein from the compound library SPECS. Six of them were then validated in vitro to be active in inhibiting the growth of S. pneumoniae without obvious cytotoxicity to Vero cell. In mouse sepsis models, these compounds are still able to decrease the mortality of the mice infected by S. pneumoniae and one compound even has significant therapeutic effect.

Conclusion: To our knowledge, these compounds are the first reported inhibitors of HK with antibacterial activity in vitro and in vivo, and are novel lead structures for developing new drugs to combat pneumococcal infection.

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Related in: MedlinePlus

Therapeutic efficacies of each lead compound against infection with S. pneumoniae ATCC7466 in mice. Figure shows the cumulative survival (survival probability) of the mouse infection models treated differently in the following 8 days (survival time more than 8 days was censored). Data were analyzed by using the survival analysis approach (Kaplan-Meier Method). Significant treatment effects were found among the groups (P < 0.01) by an overall comparison. Pairwise comparisons revealed that compounds 1–6 prolonged survival time in mouse infection models as compared to negative control (p < 0.01), and that compound 4 and 5 were almost as effective as positive control PNC (P > 0.1), but the other compounds were less effective than it (P < 0.05 or P < 0.1). *P < 0.01 indicates significant differences as compared to negative control; #P < 0.05 and $P < 0.1 indicate significant differences as compared to positive control.
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Figure 7: Therapeutic efficacies of each lead compound against infection with S. pneumoniae ATCC7466 in mice. Figure shows the cumulative survival (survival probability) of the mouse infection models treated differently in the following 8 days (survival time more than 8 days was censored). Data were analyzed by using the survival analysis approach (Kaplan-Meier Method). Significant treatment effects were found among the groups (P < 0.01) by an overall comparison. Pairwise comparisons revealed that compounds 1–6 prolonged survival time in mouse infection models as compared to negative control (p < 0.01), and that compound 4 and 5 were almost as effective as positive control PNC (P > 0.1), but the other compounds were less effective than it (P < 0.05 or P < 0.1). *P < 0.01 indicates significant differences as compared to negative control; #P < 0.05 and $P < 0.1 indicate significant differences as compared to positive control.

Mentions: Mouse sepsis models by S. pneumoniae (ATCC 7466) were successfully established by intraperitoneal injection of 100 μl S. pneumoniae (5 × 103 CFU/ml). Generally, these mice began to die within 24 hours and couldn't survive more than 48 hours unless they got appropriate therapeutic treatments. For facilitation of comparisons between the effects of these compounds and positive control (penicillin), the concentration of penicillin used in this study almost equaled to that of the lead compounds. To rule out the direct antibacterial effects that may compromise with the efficiency of this model, the lead compounds and penicillin were administrated through caudal vein. As shown in Figure 7, these compounds were able to decrease, though slightly, the mortality of the infected mice in the first 24 hours as compared to negative control (normal sodium, NS) (p < 0.01). Significant treatment effects were found among the groups (p < 0.01) by an overall comparison. Pairwise comparisons revealed that compounds 1–6 prolonged survival time in mouse sepsis models as compared to negative control (p < 0.01). However, compound 1, 2, 3 and 6 were less effective than positive control PNC (p < 0.05 or p < 0.1). Although these compounds could not reverse the fatal pneumococcal infection with concentration used in this study, in vivo antibacterial activity of these six compounds suggested that it would be promising to develop lead-compound-based drugs against pneumococcal infection.


Discovery of novel inhibitors of Streptococcus pneumoniae based on the virtual screening with the homology-modeled structure of histidine kinase (VicK).

Li N, Wang F, Niu S, Cao J, Wu K, Li Y, Yin N, Zhang X, Zhu W, Yin Y - BMC Microbiol. (2009)

Therapeutic efficacies of each lead compound against infection with S. pneumoniae ATCC7466 in mice. Figure shows the cumulative survival (survival probability) of the mouse infection models treated differently in the following 8 days (survival time more than 8 days was censored). Data were analyzed by using the survival analysis approach (Kaplan-Meier Method). Significant treatment effects were found among the groups (P < 0.01) by an overall comparison. Pairwise comparisons revealed that compounds 1–6 prolonged survival time in mouse infection models as compared to negative control (p < 0.01), and that compound 4 and 5 were almost as effective as positive control PNC (P > 0.1), but the other compounds were less effective than it (P < 0.05 or P < 0.1). *P < 0.01 indicates significant differences as compared to negative control; #P < 0.05 and $P < 0.1 indicate significant differences as compared to positive control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2713251&req=5

Figure 7: Therapeutic efficacies of each lead compound against infection with S. pneumoniae ATCC7466 in mice. Figure shows the cumulative survival (survival probability) of the mouse infection models treated differently in the following 8 days (survival time more than 8 days was censored). Data were analyzed by using the survival analysis approach (Kaplan-Meier Method). Significant treatment effects were found among the groups (P < 0.01) by an overall comparison. Pairwise comparisons revealed that compounds 1–6 prolonged survival time in mouse infection models as compared to negative control (p < 0.01), and that compound 4 and 5 were almost as effective as positive control PNC (P > 0.1), but the other compounds were less effective than it (P < 0.05 or P < 0.1). *P < 0.01 indicates significant differences as compared to negative control; #P < 0.05 and $P < 0.1 indicate significant differences as compared to positive control.
Mentions: Mouse sepsis models by S. pneumoniae (ATCC 7466) were successfully established by intraperitoneal injection of 100 μl S. pneumoniae (5 × 103 CFU/ml). Generally, these mice began to die within 24 hours and couldn't survive more than 48 hours unless they got appropriate therapeutic treatments. For facilitation of comparisons between the effects of these compounds and positive control (penicillin), the concentration of penicillin used in this study almost equaled to that of the lead compounds. To rule out the direct antibacterial effects that may compromise with the efficiency of this model, the lead compounds and penicillin were administrated through caudal vein. As shown in Figure 7, these compounds were able to decrease, though slightly, the mortality of the infected mice in the first 24 hours as compared to negative control (normal sodium, NS) (p < 0.01). Significant treatment effects were found among the groups (p < 0.01) by an overall comparison. Pairwise comparisons revealed that compounds 1–6 prolonged survival time in mouse sepsis models as compared to negative control (p < 0.01). However, compound 1, 2, 3 and 6 were less effective than positive control PNC (p < 0.05 or p < 0.1). Although these compounds could not reverse the fatal pneumococcal infection with concentration used in this study, in vivo antibacterial activity of these six compounds suggested that it would be promising to develop lead-compound-based drugs against pneumococcal infection.

Bottom Line: Using a structure-based virtual screening (SBVS) method, 105 compounds were computationally identified as potential inhibitors of the histidine kinase (HK) VicK protein from the compound library SPECS.In mouse sepsis models, these compounds are still able to decrease the mortality of the mice infected by S. pneumoniae and one compound even has significant therapeutic effect.To our knowledge, these compounds are the first reported inhibitors of HK with antibacterial activity in vitro and in vivo, and are novel lead structures for developing new drugs to combat pneumococcal infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Faculty of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, PR China. linan101@tom.com

ABSTRACT

Background: Due to the widespread abusage of antibiotics, antibiotic-resistance in Streptococcus pneumoniae (S. pneumoniae) has been increasing quickly in recent years, and it is obviously urgent to develop new types of antibiotics. Two-component systems (TCSs) are the major signal transduction pathways in bacteria and have emerged as potential targets for antibacterial drugs. Among the 13 pairs of TCSs proteins presenting in S. pneumoniae, VicR/K is the unique one essential for bacterium growth, and block agents to which, if can be found, may be developed as effective antibiotics against S. pneumoniae infection.

Results: Using a structure-based virtual screening (SBVS) method, 105 compounds were computationally identified as potential inhibitors of the histidine kinase (HK) VicK protein from the compound library SPECS. Six of them were then validated in vitro to be active in inhibiting the growth of S. pneumoniae without obvious cytotoxicity to Vero cell. In mouse sepsis models, these compounds are still able to decrease the mortality of the mice infected by S. pneumoniae and one compound even has significant therapeutic effect.

Conclusion: To our knowledge, these compounds are the first reported inhibitors of HK with antibacterial activity in vitro and in vivo, and are novel lead structures for developing new drugs to combat pneumococcal infection.

Show MeSH
Related in: MedlinePlus