The Golden Treatment: Staying One Step Ahead of Drug Resistance
03/23/2011
Today, drug resistance continues to be one of the most deadly threats we face.
In the 1930s, a common disease called childbed fever went from killing 3 out of every 4 women who contracted it during childbirth to less than 1 in 20. This miraculous shift in the trajectory of an infectious disease resulted from Gerhard Domagk's 1931 discovery and isolation of the first safe antibiotic drug called prontosil. A few years later, penicillin was isolated, and the remarkable success of both of these drugs prompted many scientists and doctors worldwide to proclaim the end of all infectious disease.
Their enthusiasm was short-lived. By 1942, bacteria began developing resistance to antibiotics, and the effectiveness of prontosil dropped from 90% to 25%. Today, drug resistance continues to be one of the most deadly threats we face. For example, some forms of tuberculosis (TB) - a disease we've known how to treat for over 60 years - are now resistant to almost all antibiotics currently available. Resistance can turn back the clock on many of our greatest public health achievements and render our best medicines useless.
The Size of the Molecule Matters
One of the reasons pathogens are able to become resistant to treatment is because most drugs we use today are "small molecule drugs." Less than one nanometer in size, they typically work by binding to specific protein enzymes within a pathogen or infectious agent and inhibiting reactions critical to that pathogen's survival. Penicillin, for example, blocks an enzyme that helps build and maintain strong cell walls, causing the bacteria to burst.
These interactions, however, frequently occur only at a single contact point. With only one option, the point of contact must be very strong for the drug to work, and drug resistance can develop when a target mutates. Imagine trying to catch a baseball with one finger. You could do it if the contact between the ball and your finger was very sticky. However, if something happened to the ball to make it even slightly less sticky - if it in fact mutated - the ball would probably bounce right off you.
Now imagine there was a drug that could bind to a target at multiple points of contact - a "multivalent drug." This would be like catching a baseball with five fingers - a much easier task, even if each finger only contacts the ball weakly. And you could probably still catch the ball even if one finger did not make contact at all.
Most interactions in biology are, in fact, multivalent. Bacteria and viruses invade cells by making multiple points of contact to a cell membrane. Our immune systems then respond by producing antibodies that make multivalent contacts with pathogens.
Several years ago, my colleague Christian Melander and I asked ourselves, "Why not develop drugs that resemble interactions in nature?" Then, if one point of contact is rendered useless or weakened, there would still be several other points of contact that could potentially circumvent drug resistance. Now we are trying to do just that.
The Making of Multivalency
Making a multivalent drug requires a platform that allows us to bring several small molecules onto a core particle, forming what is known as a "nanoparticle." Gold particles are an ideal core because molecules can be easily attached, and you can change the size of the nanoparticle depending on your target. With over two hundred commercially available molecules - and many more that are easily synthesized - the diversity of nanoparticles that can be assembled on gold particles and tested as drugs is unlimited.
Creating gold nanoparticles, however, is not enough. For nanoparticles to have any impact on global health, they have to have biological activity. And initial tests suggest that they do. In a recent experiment, we showed that when multiple copies of penicillin are attached to gold nanoparticles, they can inhibit the growth of a strain of Staphylococcus aureus that is typically resistant to penicillin. In a second experiment, we found that different types of small molecules attached to gold nanoparticles could inhibit the growth of E.coli.
Together, these two experiments suggest that it could be possible to "reactivate" antibiotics - like penicillin or prontosil - by attaching multiple copies to a gold nanoparticle. Additionally, it may be possible to create entirely new antibiotics that will be less susceptible to resistance.
These preliminary results - and the results of many other labs working on nanometer-sized therapeutics - have inspired us to think about nanoparticle-based drug design in new ways. Could the charge of a group of molecules attached to a nanoparticle help guide a particle toward the enzyme of interest while avoiding unwanted targets? Are there combinations of molecules that when displayed on a nanoparticle surface could breach the most impenetrable of pathogens such as TB? Can the spacing between molecules attached to a nanoparticle be tuned to match the spikes on HIV, and could this "distance-matching" lead to better therapeutics?
We are only at the beginning of what we expect will be a long journey filled with many dead ends. However, thanks to Gerhard Domagk and the many early pioneers of modern pharmaceutical chemistry, we know that success is not impossible.
Learn More
Read the other blogs in the Grand Challenges in Global Health Series
Bill Gates, Bill & Melinda Gates Foundation, Great Ideas From Unexpected Places
Chris Wilson, Global Health Discovery Program, Bill & Melinda Gates Foundation, Engaging the Best Minds to Tackle Global Health Challenges
Keith Jerome, University of Washington, Slicing HIV DNA from Infected Human Cells
Dr. Szabolcs Márka, Columbia University, From Black Holes to Malaria
Dan Feldheim is a Professor of Chemistry and Biochemistry at the University of Colorado, Boulder. He is grateful to the Bill and Melinda Gates family and foundation for their inspiration and research support.
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