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The rise of antibiotic-resistant bacteria presents a critical challenge to public health. A deeper understanding of their biology, notably the mechanisms behind their protective capsules, is crucial for formulating effective strategies to combat antibiotic resistance.
Streptococcus pneumoniae is frequently found in the upper respiratory tract of humans. While many carry it without any ill effects, the bacterium poses a significant health risk as a pathogen, particularly for young children, the elderly, and immunocompromised individuals. It is associated with severe diseases, including pneumonia and meningitis, which can be life-threatening. The bacterium’s capability to bypass the body’s immune defenses is largely attributed to its capsule, which acts as a formidable barrier. Consequently, efforts to develop vaccines often focus on targeting this capsule.
Researchers at the Yong Loo Lin School of Medicine, part of the National University of Singapore (NUS Medicine), have advanced our understanding of how Streptococcus pneumoniae builds its capsule. Their research indicates that the flexibility of the capsules and the pathways for their assembly may significantly contribute to the bacteria’s evolutionary adaptability, offering valuable insights into managing diseases caused by pneumococcus.
Understanding Cellular Transporters
The study, published in Science Advances, emphasizes the role of capsule transporters in this assembly process. These transporters are part of the Multidrug/Oligosaccharidyl-lipid/Polysaccharide (MOP) transporter family and facilitate the movement of sugar precursors from within the bacterium to the exterior, where the capsule is formed. This capsule not only shields the bacterium from the immune system but also enables its survival and proliferation by thwarting immune responses designed to eliminate bacteria from the airways or mark them for destruction. Furthermore, the ability to create capsules using a broad spectrum of sugar building blocks opens avenues in glycoengineering—a discipline focused on modifying sugar structures for various applications, including drug development and enhancing biomaterials.
Lead researcher, Assistant Professor Chris Sham Lok-To from the Infectious Diseases Translational Research Programme and the Department of Microbiology and Immunology at NUS Medicine, expresses that grasping the mechanics of capsule synthesis is vital to fighting pneumococcal infections. He stated, “The capsule is essential for pneumococcus to cause disease. By studying how capsule transporters select their substrates, we aim to uncover new pathways for research into bacterial evolution, resistance to antibiotics, and vaccine advancements.”
Categorization of Transporters
The research team devised an extensive method to analyze how these bacteria transport sugars to construct their protective capsules. They explored over 6,000 transporter and sugar combinations by integrating 80 different transporter genes into 79 strains of Streptococcus pneumoniae. Assistant Professor Chris noted, “Each transporter was assigned a unique genetic code (a DNA barcode) for identification. By eliminating the original transporter in each strain, we created a survival test: only bacteria with a functionally replacement transporter could continue to exist. Through analyzing the surviving bacteria’s barcodes, we were able to determine which transporters efficiently transported the sugars necessary for capsule formation.”
The analysis revealed that these transporters could be divided into three distinct categories based on their selectivity. The first category consisted of strictly specific transporters that only functioned with their designated sugar building blocks, ensuring precision but limiting adaptability. The second category comprised type-specific transporters capable of handling sugars with shared characteristics, permitting substitutions among related capsule types but not beyond. Lastly, the third category was identified as relaxed specificity transporters, which could manage a diverse range of sugars.
Dr. Chua Wan Zhen, the study’s first author from the Infectious Diseases TRP and Department of Microbiology and Immunology at NUS Medicine, commented, “While this flexibility is beneficial, it can occasionally lead to complications due to the incorrect or incomplete sugars being transported, which disrupts bacterial growth. Transporters with relaxed specificity can create issues since there are no known mechanisms for returning these incomplete building blocks back, leading to accumulation and interference with essential processes like cell wall synthesis, which may result in impaired growth or even cellular death.” This observation sheds light on why most bacteria have evolved to maintain high selectivity in their transporters, despite the advantages of broader sugar transport capabilities.
These significant findings suggest that slight modifications in transporter genes can influence specificity, which may affect bacterial adaptability and virulence. Understanding these dynamics provides a foundation for developing novel approaches to treat bacterial infections and investigating how these transport systems can be utilized to engineer beneficial sugar-based materials.
Future investigations will aim to pinpoint specific amino acid residues responsible for interactions between transporters and their substrates, with the goal of engineering enhanced transporters for potential applications in industry and healthcare.
This research received support from the National Research Foundation, Singapore under the National Medical Research Council (NMRC) Open Fund-Individual Research Grant (MOH-001395) and was administered by the Singapore Ministry of Health through the NMRC Office, MOH Holdings Pte Ltd, the Singapore National Research Foundation (NRFF11-2019-0005), and the Ministry of Education, Singapore (MOE-T2EP30220-0012).
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