Antibacterial effects of Traditional Chinese Medicine monomers against Streptococcus pneumoniae via inhibiting pneumococcal histidine kinase (VicK)

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.

Lauryl Gallate Activity and Streptococcus mutans: Its Effects on Biofilm Formation, Acidogenicity and Gene Expression

“…The results clearly indicate that the degree of the antibiofilm effect is positively correlated with the length of the alkyl chain in gallic acid esters, including lauryl gallate. Furthermore, in support of our findings, this type of suppressive activity, observed here in lauryl gallate, has also been noted by Zhang et al [37] against another biofilm-forming pathogen, Streptococcus pneumoniae. Values are presented as the mean ± standard error obtained from three independent experiments (n = 3-9).…”

Theaflavin-3,3′-Digallate Suppresses Biofilm Formation, Acid Production, and Acid Tolerance in Streptococcus mutans by Targeting Virulence Factors

“…Therefore, TCSs may have potential to be effective targets of anti- S. mutans agents. Of note, some natural agents have been found to suppress TCSs in S. mutans (Zhang et al, 2015; Li et al, 2018), but no similar studies have been reported on black tea extracts or theaflavins. In the present study, based on RT-PCR results, we speculate that TF3 suppresses at least three TCSs in S. mutans (LytST, VicRK, and ComDE), which might explain its inhibitory effect on biofilm formation, acid tolerance and acid production.…”

Application of Omics Technologies for Evaluation of Antibacterial Mechanisms of Action of Plant-Derived Products

“…These genes and their products are therefore potential new antimicrobial targets (Roemer and Boone, 2013 ; Scheffler et al, 2013 ). This knowledge is of utmost importance to the development of new screening platforms for identification and selection of compounds targeting specific essential genes based on protein interactions and mutant libraries (Zhang et al, 2015 ; Morita et al, 2016 ). A classical approach, applicable to select compounds that are able to interact with a specific target, is based on affinity chromatography systems.…”