SINGAPORE: Antibiotic-resistant bacteria pose a significant threat to public health, and researchers from the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine) have made key discoveries that could aid efforts to combat this growing issue.
Their study, published in Science Advances, sheds light on how Streptococcus pneumoniae, a bacterium responsible for diseases such as pneumonia and meningitis, constructs its protective capsule—a vital defence mechanism against the human immune system.
Understanding the Capsule’s Role in Disease
Streptococcus pneumoniae is often found in the upper respiratory tract of humans. While it can exist without causing harm, it can also become a dangerous pathogen, particularly affecting young children, the elderly, and individuals with weakened immune systems. Its ability to cause severe illness is largely attributed to its capsule, a shield-like structure composed of sugars that protects it from the body’s immune responses.
Vaccines targeting the bacterial capsule have proven effective in reducing the burden of pneumococcal diseases. However, the bacterium’s ability to evolve and modify its capsule remains a challenge for long-term disease management.
The research conducted by NUS Medicine provides crucial insights into how these capsules are formed, potentially paving the way for new treatment and prevention strategies.
The Role of Transporters in Capsule Formation
The study focused on the capsule transporters of Streptococcus pneumoniae, specifically those belonging to the Multidrug/Oligosaccharidyl-lipid/Polysaccharide (MOP) transporter family. These transporters are responsible for moving sugar building blocks from inside the bacterial cell to its outer surface, where the capsule is assembled. This process enables the bacterium to evade immune detection and survive within the body.
“By examining how capsule transporters choose their substrates, we hope to open new avenues for research in bacterial evolution, antibiotic resistance, and vaccine development,” said Assistant Professor Chris Sham Lok-To, the study’s lead researcher from the Infectious Diseases Translational Research Programme (TRP) and the Department of Microbiology and Immunology at NUS Medicine.
Three Categories of Transporters Identified
To investigate how these transporters function, the research team developed a large-scale method to test transporter-sugar interactions. By inserting 80 different transporter genes into 79 strains of Streptococcus pneumoniae and removing their original transporters, the researchers effectively created a survival test. Bacteria that could successfully form their capsule using the introduced transporters survived, allowing the team to identify which transporters were functional.
Based on their findings, the transporters were classified into three distinct categories:
- Strictly Specific Transporters: These transporters worked exclusively with their original sugar building blocks, ensuring high accuracy in capsule formation but limiting adaptability.
- Type-Specific Transporters: This group demonstrated the ability to transport sugars with certain shared characteristics. While not as restrictive as the strictly specific transporters, they were still limited to sugars within related capsule types.
- Relaxed Specificity Transporters: The most versatile group, these transporters were capable of transporting a variety of different sugars. However, their flexibility came with risks. When incomplete or incorrect sugars were transported, bacterial growth could be severely disrupted, sometimes leading to cell death.
“Transporters with relaxed specificity can cause issues because once they move incomplete building blocks across the cell membrane, there are no known mechanisms for the bacteria to send them back,” explained Dr. Chua Wan Zhen, first author of the study from NUS Medicine.
Implications for Antibiotic Resistance and Glycoengineering
The study’s findings suggest that minor genetic changes in transporter genes can impact their specificity, influencing how the bacterium adapts and evolves. This adaptability may contribute to antibiotic resistance, as bacteria with flexible transporters could potentially evade existing treatments.
Beyond medical applications, the research also offers possibilities for glycoengineering—a field that involves modifying sugar structures for use in drug development and biotechnology. By manipulating bacterial transporters, scientists may be able to produce new sugar-based materials for therapeutic or industrial use.
Future research will delve deeper into identifying the specific amino acid residues that influence transporter function. Assistant Professor Sham highlighted the potential for further discoveries, stating, “A better understanding of how transporters select sugars could lead to engineered transporters with optimized specificity, benefiting both healthcare and industrial applications.”
Looking Ahead
With antibiotic resistance continuing to threaten global health, studies like this offer valuable insights into bacterial biology and suggest novel strategies to counteract resistant strains. By targeting the mechanisms behind capsule formation, researchers hope to develop more effective vaccines and therapies to mitigate the impact of pneumococcal diseases.
The progress made by the team at NUS Medicine marks a significant step toward this goal, providing a stronger foundation for future advancements in combating antibiotic resistance.