Researchers at the National University of Singapore’s Yong Loo Lin School of Medicine have made significant strides in understanding how the bacterium Streptococcus pneumoniae builds its protective capsule, a discovery that could lead to new ways to combat antibiotic-resistant infections. This bacterium, often found in the human respiratory tract, can cause severe illnesses like pneumonia and meningitis, particularly in vulnerable groups such as young children, the elderly, and immunocompromised individuals.
The study, published in Science Advances, focuses on the role of capsule transporters, which are part of the Multidrug/Oligosaccharidyl-lipid/Polysaccharide (MOP) transporter family. These transporters are crucial for moving sugar building blocks from inside the bacteria to the surface, where they form a capsule that shields the bacteria from the immune system. This protective barrier helps the bacteria evade immune defenses, allowing them to survive, multiply, and spread.
Assistant Professor Chris Sham Lok-To, from the Infectious Diseases Translational Research Programme and Department of Microbiology and Immunology at NUS Medicine, emphasized the importance of these findings. “The capsule is critical for pneumococcus to cause disease. By examining how capsule transporters select their substrates, we open new avenues for research in bacterial evolution, antibiotic resistance, and vaccine development,” he said.
The research team developed a large-scale method to analyze how bacteria transport sugars necessary for building their capsules. They tested over 6,000 combinations of transporters and sugar building blocks by inserting 80 different transporter genes into 79 strains of Streptococcus pneumoniae. Each transporter was marked with a unique DNA barcode, allowing the researchers to track which transporters successfully transported the sugars needed for capsule formation.
The study identified three categories of transporters based on their selectivity. The first group, strictly specific transporters, only worked with their original sugar building blocks, ensuring accuracy but limiting flexibility. The second group, type-specific transporters, could handle sugars with certain common features, allowing them to substitute for others within related capsule types but not beyond. The third group, relaxed specificity transporters, could transport a variety of sugars, although this flexibility sometimes led to the transport of incomplete or incorrect sugars, disrupting bacterial growth.
Dr. Chua Wan Zhen, first author of the study, noted the potential issues with relaxed specificity transporters. “This flexibility can cause problems by transporting incomplete or incorrect sugars, which disrupts bacterial growth. There are no known mechanisms for the bacteria to send them back,” she explained.
These findings not only enhance understanding of bacterial capsule formation but also have potential applications in glycoengineering, where modifying sugar structures can lead to the development of new drugs or improved biomaterials. Future research will focus on identifying specific amino acid residues responsible for transporter-substrate interactions and engineering transporters with optimized specificity for potential industrial and healthcare applications.
This research was supported by the National Research Foundation, Singapore under the National Medical Research Council (NMRC) Open Fund-Individual Research Grant, and administered by the Singapore Ministry of Health through the NMRC Office, MOH Holdings Pte Ltd, the Singapore National Research Foundation, and the Ministry of Education, Singapore.
