Over a billion people are affected by fungal infections every year, ranging in severity from topical skin conditions like athlete's foot to life-threatening fungal blood infections. The infection is more likely to occur when the body's immune system is compromised due to an illness like HIV/AIDS, cancer or when receiving antibiotic treatment. There is a pressing need to develop efficient and disease-specific antifungal agents to mitigate this growing drug resistance problem. Traditional antifungal therapeutics need to get inside the cell to attack the infection but have trouble targeting and penetrating the fungi membrane wall. Also, since fungi are metabolically similar to mammalian cells, existing drugs can have trouble differentiating between healthy and infected cells. Recognizing this, IBM scientists applied an organic catalytic process to facilitate the transformation of PET (waste), into entirely new molecules that can be transformed into antifungal agents. Researchers at Singapore's Institute of Bioengineering and Nanotechnology (IBN) and California's IBM Research -Almaden (IBM) have unveiled a nanomedicine breakthrough in common plastics like polyethylene terephthalate (PET) that can be converted into non-toxic and biocompatible materials designed to specifically target and attack fungal infections. This is significant as plastic bottles are typically recycled by mechanical grounding and can mostly be reused only in secondary products like clothes, carpeting or playground equipment. These new antifungal agents self-assemble through a hydrogen-bonding process, sticking to each other like molecular Velcro in a polymer-like fashion to form nanofibers. This is important because these antifungal agents are only active as a therapeutic in the fiber or polymer-like form. This novel nanofiber carries a positive charge and can selectively target and attach to only the negatively-charged fungal membranes based on electrostatic interaction. It then breaks through and destroys the fungal cell membrane walls, preventing it from developing resistance.
According to Dr Yi Yan Yang, Group Leader, IBN, "The ability of these 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." Leveraging IBM Research's computational capabilities, the researchers simulated the antifungal assemblies, predicting which structural modifications would create the desired therapeutic efficacy. "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 diseased sites," said Dr. James Hedrick, Advanced Organic Materials Scientist, IBM Research. The minimum inhibitory concentration (MIC) of the nanofibers, which is the lowest concentration that inhibits the visible growth of fungi, demonstrated strong antifungal activity against multiple types of fungal infections. In further studies conducted by Singapore's IBN, testing showed the nanofibers eradicated more than 99.9% of C. albicans, a fungal infection causing the third most common blood stream infection in the United States, after a single hour of incubation and indicated no resistance after 11 treatments. Conventional antifungal drugs were only able to suppress additional fungal growth while the infection exhibited drug resistance after six treatments.
Additional findings of this research indicated the nanofibers effectively dispersed fungal biofilms after one-time treatment while conventional antifungal drugs were not effective against biofilms. The in vivo antifungal activity of the nanofibers was also evaluated in a mouse model using a contact lens-associated C. albicans biofilm infection. The nanofibers significantly decreased the number of fungi, hindered new fungal structure growth in the cornea and reduced the severity of existing eye inflammation. These experiments also showed mammalian cells survived long after incubation with the nanofibers, indicating excellent in vitro biocompatibility. In addition, no significant tissue erosion is observed in the mouse cornea after topical application of the nanofibers.
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 US$3 bln worldwide in 2010 and is expected to increase to US$6 bln 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. 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. 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.