Researchers from IBM and the Institute of Bioengineering and Nanotechnology (IBN) in Singapore have made a nanomedicine breakthrough in which they converted common plastic materials such as polyethylene terephthalate (PET) into non-toxic and biocompatible materials that target and attack fungal infections. The research is published in the journal, Nature Comm.
More than a billion people are affected by fungal infections every year, ranging from topical skin conditions such as 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 such as HIV/AIDS, cancer, or when receiving antibiotic treatment.
There is a pressing need to develop efficient and disease-specific anti-fungal agents to mitigate against this growing drug-resistance problem.
Traditional anti-fungal 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.
Recognising this, IBM scientists applied an organic catalytic process to facilitate the transformation of PET, or waste plastic from a bottle, into new molecules that can be turned into anti-fungal agents.
These new anti-fungal agents self-assemble through a hydrogen-bonding process, sticking to each other like molecular Velcro in a polymer-like fashion to form nanofibres. This is important because these anti-fungal agents are only active as a therapeutic in the fibre or polymer-like form.
The nanofibre carries a positive charge and can selectively target and attach only to 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.
The ability of these molecules to self-assemble into nanofibres is important
Dr Yi Yan Yang, Group Leader at IBN, said: 'The ability of these molecules to self-assemble into nanofibres is important because unlike discrete molecules, fibres 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 anti-fungal assemblies, predicting which structural modifications would create the desired therapeutic effect.
'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 James Hedrick, Advanced Organic Materials Scientist, IBM Research – Almaden.
The minimum inhibitory concentration (MIC) of the nanofibres, which is the lowest concentration that inhibits the visible growth of fungi, demonstrated strong anti-fungal activity against multiple types of fungal infections.
In further studies conducted by IBN, testing showed that the nanofibres eradicated more than 99.9% of C. albicans, a fungal infection causing the third most common blood stream infection in the US, after a single hour of incubation and indicated no resistance after 11 treatments. Conventional anti-fungal drugs were only able to suppress additional fungal growth while the infection exhibited drug resistance after six treatments.
Additional findings of this research indicated that the nanofibres effectively dispersed fungal biofilms after one treatment while conventional anti-fungal drugs were not effective against biofilms.
As computational predictive methodologies continue to advance, we can begin to establish ground rules for self assembly to design complex therapeutics to fight infections
The in vivo anti-fungal activity of the nanofibres was also evaluated in a mouse model using a contact lens-associated C. albicans biofilm infection. The nanofibres 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 nanofibres, indicating excellent in vitro biocompatibility. In addition, no significant tissue erosion is observed in the mouse cornea after topical application of the nanofibres.
'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,' said Professor Jackie Ying, IBN Executive Director. 'Our latest breakthrough with IBM allows us specifically to target and eradicate drug-resistant and drug-sensitive fungi strains and fungal biofilms, without harming surrounding healthy cells.'
The IBM nanomedicine programme – which started in IBM's Research labs four years ago with the mission to improve human health – stems from decades of materials development traditionally used for semiconductor technologies.
