Molecular Dynamics Simulation of the Complex PBP-2x with Drug Cefuroxime to Explore the Drug Resistance Mechanism of Streptococcus suis R61

Drug resistance of Streptococcus suis strains is a worldwide problem for both humans and pigs. Previous studies have noted that penicillin-binding protein (PBPs) mutation is one important cause of β-lactam antibiotic resistance. In this study, we used the molecular dynamics (MD) method to study the interaction differences between cefuroxime (CES) and PBP2x within two newly sequenced Streptococcus suis: drug-sensitive strain A7, and drug-resistant strain R61. The MM-PBSA results proved that the drug bound much more tightly to PBP2x in A7 (PBP2x-A7) than to PBP2x in R61 (PBP2x-R61). This is consistent with the evidently different resistances of the two strains to cefuroxime. Hydrogen bond analysis indicated that PBP2x-A7 preferred to bind to cefuroxime rather than to PBP2x-R61. Three stable hydrogen bonds were formed by the drug and PBP2x-A7, while only one unstable bond existed between the drug and PBP2x-R61. Further, we found that the Gln569, Tyr594, and Gly596 residues were the key mutant residues contributing directly to the different binding by pair wise energy decomposition comparison. By investigating the binding mode of the drug, we found that mutant residues Ala320, Gln553, and Thr595 indirectly affected the final phenomenon by topological conformation alteration. Above all, our results revealed some details about the specific interaction between the two PBP2x proteins and the drug cefuroxime. To some degree, this explained the drug resistance mechanism of Streptococcus suis and as a result could be helpful for further drug design or improvement

Comparative Genomics Study of Multi-Drug-Resistance Mechanisms in the Antibiotic-Resistant Streptococcus suis R61 Strain

BACKGROUND: Streptococcus suis infections are a serious problem for both humans and pigs worldwide. The emergence and increasing prevalence of antibiotic-resistant S. suis strains pose significant clinical and societal challenges. RESULTS: In our study, we sequenced one multi-drug-resistant S. suis strain, R61, and one S. suis strain, A7, which is fully sensitive to all tested antibiotics. Comparative genomic analysis revealed that the R61 strain is phylogenetically distinct from other S. suis strains, and the genome of R61 exhibits extreme levels of evolutionary plasticity with high levels of gene gain and loss. Our results indicate that the multi-drug-resistant strain R61 has evolved three main categories of resistance. CONCLUSIONS: Comparative genomic analysis of S. suis strains with diverse drug-resistant phenotypes provided evidence that horizontal gene transfer is an important evolutionary force in shaping the genome of multi-drug-resistant strain R61. In this study, we discovered novel and previously unexamined mutations that are strong candidates for conferring drug resistance. We believe that these mutations will provide crucial clues for designing new drugs against this pathogen. In addition, our work provides a clear demonstration that the use of drugs has driven the emergence of the multi-drug-resistant strain R61

The immunoglobulin M-degrading enzyme of Streptococcus suis, Ide(Ssuis), is involved in complement evasion

Streptococcus (S.) suis is one of the most important pathogens in pigs causing meningitis, arthritis, endocarditis and serositis. Furthermore, it is also an emerging zoonotic agent. In our previous work we identified a highly specific IgM protease in S. suis, designated IdeSsuis. The objective of this study was to characterize the function of IdeSsuis in the host-pathogen interaction. Edman-sequencing revealed that Ide(Ssuis) cleaves the heavy chain of the IgM molecule between constant domain 2 and 3. As the C1q binding motif is located in the C3 domain, we hypothesized that IdeSsuis is involved in complement evasion. Complement-mediated hemolysis induced by porcine hyperimmune sera containing erythrocyte-specific IgM was abrogated by treatment of these sera with recombinant IdeSsuis. Furthermore, expression of IdeSsuis reduced IgM-triggered complement deposition on the bacterial surface. An infection experiment of prime-vaccinated growing piglets suggested attenuation in the virulence of the mutant 10 Delta IdeSsuis. Bactericidal assays confirmed a positive effect of IdeSsuis expression on bacterial survival in porcine blood in the presence of high titers of specific IgM. In conclusion, this study demonstrates that IdeSsuis is a novel complement evasion factor, which is important for bacterial survival in porcine blood during the early adaptive (IgM-dominated) immune response

Risk factors for Streptococcus suis infection: A systematic review and meta-analysis

Abstract Streptococcus suis (S. suis) is a gram-positive bacterial pathogen in pigs which can cause serious infections in human including meningitis, and septicaemia resulting in serious complications. There were discrepancies between different data and little is known concerning associated risk factors of S. suis. A systematic review and meta-analysis was conducted to investigate on S. suis infection risk factors in human. We searched eight relevant databases using the MeSH terms “Streptococcus suis” OR “Streptococcus suis AND infection” limited in human with no time nor language restriction. Out of 4,999 articles identified, 32 and 3 studies were included for systematic review and meta-analysis respectively with a total of 1,454 Streptococcus suis cases reported. S. suis patients were generally adult males and the elderly. The mean age ranged between 37 to 63 years. Meningitis was the most common clinical manifestation, and deafness was the most common sequelae found among survivors followed by vestibular dysfunction. Infective endocarditis was also noted as among the most common clinical presentations associated with high mortality rate in a few studies. Meta-analyses categorized by type of control groups (community control, and non-S. suis sepsis) were done among 850 participants in 3 studies. The combined odd ratios for studies using community control groups and non-S. Suis sepsis as controls respectively were 4.63 (95% CI 2.94–7.29) and 78.00 (95% CI 10.38–585.87) for raw pork consumption, 4.01 (95% CI 2.61–6.15) and 3.03 (95% CI 1.61–5.68) for exposure to pigs or pork, 11.47, (95% CI 5.68–23.14) and 3.07 (95% CI 1.81–5.18) for pig-related occupation and 3.56 (95% CI 2.18–5.80) and 5.84 (95% CI 2.76–12.36) for male sex. The results were found to be significantly associated with S. suis infection and there was non-significant heterogeneity. History of skin injury and underlying diseases were noted only a small percentage in most studies. Setting up an effective screening protocol and public health interventions would be effective to enhance understanding about the disease