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|The novel small molecule compounds readily form nanofibers with strong antifungal capability.|
Researchers at Singapore's Institute of Bioengineering and Nanotechnology (IBN) and California's IBM Research - Almaden (IBM) have discovered a new, potentially life-saving application for polyethylene terephthalate (PET), which is widely used to make plastic bottles. They have successfully converted PET into a non-toxic biocompatible material with superior fungal killing properties. As reported in Nature Communications1, their new material proved particularly effective in destroying drug-resistant fungi and fungal biofilm, displaying great potential as an antifungal agent to prevent and treat topical fungus-induced diseases such as skin infections and keratitis.
IBN Executive Director Professor Jackie Y. Ying shared that, "A key focus of IBN's nanomedicine research efforts is the development of novel polymers and materials for more effective treatment and prevention of various diseases. Our latest breakthrough with IBM allows us to specifically target and eradicate drug-resistant and drug-sensitive fungi strains and fungal biofilms, without harming surrounding healthy cells. We hope to eventually apply this technology clinically to help the large number of patients worldwide who suffer from fungal infections."
In recent years, the number of opportunistic fungal infections has increased due to growing populations of patients with weakened immune systems, for example due to cancer, organ transplant or HIV/AIDS. In such patients, invasive infections caused by Candida, Aspergillus and Cryptococcus neoformans (C. neoformans) fungi strains may take the form of potentially lethal blood stream infections, lung infections and meningitis. Candida, for example, causes candidiasis, which is the fourth most common fungal blood stream infection among hospitalized patients in the United States according to the Centers for Disease Control & Prevention.
BCC Research reported that the treatment cost for fungal infections was USD 3 billion worldwide in 2010 and this is expected to increase to USD 6 billion in 2014. Of great concern to the clinical and healthcare communities is the rise in fungal infections, which are resistant to conventional antifungal drugs, as well as increasing reports of resistance development in patients toward antifungal agents. These trends necessitate the urgent development of suitable alternatives to the limited selection of available antifungal agents. Further, most conventional antifungal agents do not completely destroy the fungi but merely inhibit their growth, which may lead to future infections.
A particular challenge facing researchers lies in fungi's metabolic similarity to mammalian cells. Existing antifungal agents are unable to distinguish between infected and healthy cells, and frequently end up attacking the latter. Hence, patients commonly report hemolysis and nephrotoxicity as treatment side effects.
Leveraging IBM's polymer synthesis and computational expertise, as well as IBN's nanomedicine and biomaterials research expertise, the researchers transformed PET, a common plastic material, into novel small molecule compounds that self-assemble in water into nanofibers. Via electrostatic interaction, the nanofibers are able to selectively target fungal cells and penetrate their membrane, killing them in the process.
According to Dr Yi Yan Yang, Group Leader, IBN, "The ability of our molecules to self-assemble into nanofibers is important because unlike discrete molecules, fibers increase the local concentration of cationic charges and compound mass. This facilitates the targeting of the fungal membrane and its subsequent lysis, enabling the fungi to be destroyed at low concentrations. The result is a highly efficient killing strategy that causes minimal damage or toxicity to surrounding healthy cells."
In vitro studies conducted at IBN demonstrated that the nanofibers eradicated over 99.9% of C. albicans after just one hour of incubation and did not develop any drug resistance, even after 11 treatments. C. albicans causes the third most common fungal blood stream infection in the United States. The nanofibers were also used to effectively treat contact lens-associated fungal biofilm eye infection in mice without causing any toxicity to the eye. In comparison, the conventional antifungal drug, Fluconazole, was only able to inhibit additional fungal growth, and the infection exhibited drug resistance after six treatments. Further, Fluconazole was not effective against biofilms.
According to Dr James Hedrick, Advanced Organic Materials Scientist, IBM Research - Almaden, "As computational predictive methodologies continue to advance, we can begin to establish ground rules for self-assembly to design complex therapeutics to fight infections, as well as the effective encapsulation, transport and delivery of a wide variety of cargos to their targeted disease sites."
The IBN and IBM scientists have made other recent breakthroughs in antimicrobial research. By combining their antimicrobial polymers with conventional antibiotics or antifungal drugs, they were able to induce the formation of pores in microbial membranes, which promotes the penetration of antibiotics into the microbial cells, and kills highly infectious, drug-resistant P. aeruginosa at significantly lower concentrations when compared to the antimicrobial polymers and antibiotics alone.2,3 In addition, the researchers have also fine-tuned their biodegradable antimicrobial polycarbonates to produce polymers with strong and broad-spectrum antimicrobial activity and negligible toxicity to mammals.4,5
IBN and IBM's research collaboration has resulted in more than 20 platform technologies on drug, protein and gene delivery, as well as macromolecular antimicrobial agents to treat MRSA infections, other infectious diseases and cancers. The research team is now actively seeking pharmaceutical companies to further develop their newest breakthrough for future clinical applications.
K. Fukushima, S. Liu, H. Wu, A. C. Engler, D. J. Coady, H. Maune, J. Pitera, A. Nelson, N. Wiradharma, S. Venkataraman, Y. Huang, W. Fan, J. Y. Ying, Y. Y. Yang and J. L. Hedrick, "Supramolecular High Aspect Ratio Assemblies with Strong Antifungal Activity," Nature Communications, (2013) DOI: 10.1038/ncomms3861.
V. W. L. Ng, X. Ke, A. L. Z. Lee, J. L. Hedrick and Y. Y. Yang, "Synergistic Co-Delivery of Membrane-Disrupting Polymers with Commercial Antibiotics Against Highly Opportunistic Bacteria," Advanced Materials, (2013) DOI: 10.1002/adma/201302952.
A. L. Z. Lee, V. W. L. Ng, W. Wang, J. L. Hedrick and Y. Y. Yang, "Block Copolymer Mixtures as Antimicrobial Hydrogels for Biofilm Eradication," Biomaterials, 34 (2013) 10278-10286.
W. Chin, C. Yang, V. W. L. Ng, Y. Huang, J. Cheng, Y. W. Tong, D. J. Coady, W. Fan, J. L. Hedrick and Y. Y. Yang, "Biodegradable Broad-Spectrum Antimicrobial Polycarbonates: Investigating the Role of Chemical Structure on Activity and Selectivity," Macromolecules, 46 (2013) 8797-8807.
A. C. Engler, J. P. K. Tan, Z. Y. Ong, D. J. Coady, V. W. L. Ng, Y. Y. Yang and J. L. Hedrick, "Antimicrobial Polycarbonates: Investigating the Impact of Balancing Charge and Hydrophobicity Using a Same-Centered Polymer Approach," Biomacromolecules, (2013) DOI: 10.1021/bm401248t.
About Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that fosters world-class scientific research and talent to drive economic growth and transform Singapore into a vibrant knowledge-based and innovation driven economy.
In line with its mission-oriented mandate, A*STAR spearheads research and development in fields that are essential to growing Singapore’s manufacturing sector and catalysing new growth industries. A*STAR supports these economic clusters by providing intellectual, human and industrial capital to its partners in industry.
A*STAR oversees 20 biomedical sciences and physical sciences and engineering research entities, located in Biopolis and Fusionopolis as well as their vicinity. These two R&D hubs, house a bustling and diverse community of local and international research scientists and engineers from A*STAR’s research entities as well as a growing number of corporate laboratories.
About the Institute of Bioengineering and Nanotechnology
The Institute of Bioengineering and Nanotechnology (IBN) was established in 2003 and is spearheaded by its Executive Director, Professor Jackie Yi-Ru Ying.
Professor Ying was a Professor of Chemical Engineering at the Massachusetts Institute of Technology (1992 – 2005). She was recognized as one of “One Hundred Engineers of the Modern Era” by the American Institute of Chemical Engineers in 2008 for her groundbreaking work on nanostructured systems, nanoporous materials and host matrices for quantum dots and wires.
Under her direction, IBN conducts research at the cutting-edge of bioengineering and nanotechnology. Its programs are geared towards linking multiple disciplines across engineering, science and medicine to produce research breakthroughs that will improve healthcare and our quality of life.
IBN’s research activities are focused in the following areas:
Nanomedicine, where functionalized polymers, hydrogels and biologics are developed as therapeutics and carriers for the controlled release and targeted delivery of therapeutics to diseased cells and organs.
Cell and Tissue Engineering, where biomimicking materials, stem cell technology, microfluidic systems and bioimaging tools are combined to develop novel approaches to regenerative medicine and artificial organs.
Biodevices and Diagnostics, which involve nanotechnology and microfabricated platforms for high-throughput biomarker and drug screening, automated biologics synthesis, and rapid disease diagnosis.
Green Chemistry and Energy, which encompass the green synthesis of chemicals and pharmaceuticals, catalytic conversion of biomass, utilization of carbon dioxide, and new nanocomposite materials for energy applications.
IBN's innovative research is aimed at creating new knowledge and intellectual properties in the emerging fields of bioengineering and nanotechnology to attract top-notch researchers and business partners to Singapore. Since 2003, IBN researchers have published over 890 papers in leading journals.
IBN also plays an active role in technology transfer and spinning off companies, linking the research institute and industrial partners to other global institutions. The Institute has a portfolio of over 620 patents/patent applications, and welcomes industrial and clinical partners to collaborate on and co-develop its technologies. IBN has successfully commercialized 50 patents/patent applications, and has established 7 spin-off companies.
IBN's current staff and students strength stands at over 155 scientists, engineers and medical doctors. With its multinational and multidisciplinary research staff, the institute is geared towards generating new biomaterials, devices, systems and processes to boost Singapore’s economy in the medical technology, pharmaceuticals, chemicals, consumer products and clean technology sectors.
IBN is also committed to nurturing young talents. Besides the training of PhD students, IBN has a Youth Research Program (YRP) for students and teachers from secondary schools, junior colleges, polytechnics, and universities. Since its inception in October 2003, YRP has reached out to more than 69,500 students and teachers from 290 local and overseas schools and institutions. Over 1,790 students and teachers have completed research attachments at IBN for a minimum period of four weeks.
For more information, visit www.ibn.a-star.edu.sg.
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Phone: 65 6824 7032
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