The first shots in the ongoing battle between pathogenic bacteria and medical science were fired in 1928, when Sir Alexander Flemming discovered penicillin. His landmark discovery kicked off a chemical arms race that continues to this day, with scientists striving to develop effective antibiotics faster than their disease-causing counterparts can evolve strategies to foil them.
In the past few years a disturbing truth has become clear: the bacteria are winning. In order for medicine to regain the upper hand, strategies for combating infections need a creative overhaul. A recent paper published in Nature Biotechnology outlines a new and promising approach for treating some infections without the development of new antibiotics.
Bacteria can produce disease in their hosts in a myriad of ways, but one of the favorites is through the production of toxins. According to the Nature Biotechnology paper, the common pathogens Staphylococcus aureus and Streptococcus pneumonia are well known for secreting toxins. In particular, these pathogens produce “cholesterol-dependent cytolysins,” a class of toxins that target and damage the cell membranes of the host. If the bacterial load gets high enough, and sufficient toxin is produced, the infected host will die. Also, these pathogens are well known for being highly resistant to antibiotics; the much-talked-about MRSA infection is simply a methicillin-resistant strain of S. aureus. So how do you combat a toxin producer that you can’t easily kill? Simple: you target the toxin.
The paper in Nature Biotechnology describes a method for sequestering bacterial toxins through the use of tiny lipid spheres. Because of the structural properties of lipids, when they are placed in an aquatic environment they naturally form microscopic spheres called liposomes. The researchers were able to create liposomes with a higher concentration of cholesterol than normal mammalian cells. Because the cholesterol-dependent cytolysins are indeed “cholesterol-dependent,” the engineered liposomes were very effective at grabbing and neutralizing toxins. In fact, the paper found that their high-cholesterol liposomes were—to certain toxins—more than 1000 times more attractive than mammalian cells.
To test their system in a living model, the researchers established severe infections in mice using S. aureus and S. pneumoniae. The mice that were subsequently administered liposomes were much more likely to survive their infections. Additionally, combination of the liposome therapy with low doses of antibiotics provided “complete protection” against S. aureus infection.
The research team points to a number of mechanisms to explain the effectiveness of the liposome treatment. First: sequestering the toxins prevents cell death, thereby preventing tissue damage. This has obvious benefits in that healthy tissues tend to be preferable. That’s not the whole story, however. Cell death results in the release of cytokines and other “alarm” signals from the dying cell – these signals spread systemically through the blood and cause wild, unproductive, damaging immune responses called “cytokine storms.” Thus, preventing the lethal action of bacterial toxins not only protects infected tissues, but it also protects the entire body by preventing aberrant immune function.
Another advantage of liposome treatment is that the liposomes themselves pose no threat to the bacteria. Though they reduce that ability of the microbes to cause disease, the liposomes do not attempt to directly harm the organisms themselves. This eases the possibility of the bacteria developing resistance to the treatment, as there is no strong selective pressure to drive their evolution in that direction. Essentially, as long as the bacteria continue to produce the same toxins, the liposomes will continue to be effective.
In order to regain the upper hand on bacterial diseases, medical science needs innovative ideas. Engineered liposomes are certainly an example of this sort of “outside the box” thinking, and they have clear potential for application in the near future.
