Biodegradable polymer nanoparticles that can punch holes through the cell membranes of microbes could offer a new way to treat people infected with multidrug-resistant bacteria. “The physical destruction of the bacterial cell membrane, a fundamentally different approach to the targeted chemical attack of conventional antibiotics, should prevent bacteria from ever developing resistance to the treatment,” says Yiyan Yang at the A*STAR Institute of Bioengineering and Nanotechnology, who co-led the research with James Hedrick at the IBM Almaden Research Center.
The team’s polymers are inspired by the antimicrobial peptides found in nature, which also kill bacteria by puncturing them. These peptides form positively charged clusters that stick to and then penetrate the negatively charged bacterial cell wall, ultimately disintegrating the cell membrane and killing the cell. However, the clinical success of such peptides to treat bacterial infections has been limited, largely because they are quickly broken down by the body and as they are expensive to manufacture.
Yang, Hedrick and their co-workers have developed a polymer-based peptide alternative which avoids all of these problems. The polymer incorporates three key components: a non-polar hydrophobic head and tail, which drives the polymer to self-assemble into a nanoparticle; a positively charged block that selectively interacts with the bacterial cell membrane; and a carbonate backbone that slowly breaks down inside the cell, ensuring good biocompatibility. “The starting materials of our synthesis are inexpensive, and the synthesis of the antimicrobial nanoparticles is simple and can be scaled up easily for future clinical application,” Yang adds.
Tests confirm that the nanoparticles can efficiently kill fungi and multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), even at low concentrations. The nanoparticles also showed insignificant activity against red blood cells, and no significant toxicity was observed during the in vivo studies in mice, even at concentrations well above their effective dose.
“To translate this research finding into products and treatments, A*STAR researchers will work closely with IBM researchers and other industrial partners to evaluate the in vitro and in vivo efficacy, as well as toxicity of the macromolecular antimicrobials against MRSA-induced skin and bloodstream infections and multidrug-resistant tuberculosis,” Yang says. However, the nanoparticles may not be limited to drug applications, she adds. “We will also evaluate their application in the sterilization of surfaces, as well as in consumer products.”
The A*STAR-affiliated researchers contributing to this research are from the Institute of Bioengineering and Nanotechnology.