Keeping Ahead of MRSA


Keeping Ahead of MRSA
January 20, 2015

Whether you have gotten sick, had surgery or put some Neosporin on a cut, chances are you’ve used antibiotics. Doctors and pharmacists dispensed about 1.4 billion of these bacteria-fighting drugs between 2000 and 2010.

These drugs can prevent and fight infections, but so-called “superbugs” resistant to antibiotics are becoming more common. Even though the rates of these resistant infections are dropping, more than 2 million people in the United States contract resistant infections every year. Of those, 23,000 die from their infection.

Bacteria can develop resistance within years of being exposed to a new drug, and drug developers are constantly playing catch-up. But a team of biologists and computer scientists from Duke University and the University of Connecticut may have found a way to get ahead.

MRSAUsing computers and genomic data, the researchers, led by Bruce Donald, were able to predict the exact changes MRSA (methicillin resistant staphylococcus aureus) cells could make to its DNA to resist certain drugs.

When Donald and his team tested the drugs on MRSA cells, they began to develop the resistance mutations the computers predicted within days.

These findings, published in the Proceedings of the National Academy of Sciences, could potentially allow drug developers to anticipate how bacteria would respond to new drugs and begin planning for that while the drug is still in development.

Antibiotic resistance is a problem of evolution: both the evolution of the bacteria themselves, but also of medicine. Until the 1800s doctors did not even realize that bacteria caused infections. Tuberculosis, the Bubonic Plague, cholera and others killed millions before anyone could figure out what they actually were and any sort of surgery was an invitation to infection.

Doctors as far back as 10,000 BC knew that certain substances could prevent and, in rare cases, fight off an infection. The Sumerians poured beer into wounds, while the Greeks used wine-soaked bandages to patch them up. Onions, rum, moldy bread and similar remedies dominated until the time of Lister and Pasteur, who introduced the ideas of germs and sterilization. Scientists then knew these ingredients had antibacterial – or antibiotic – properties.

Physician Alexander Fleming, however, produced the first antibiotic — penicillin in 1928. By the end of World War II, penicillin had firmly taken hold in the military and had begun to spread to common use.

Fleming won a Nobel Prize in 1945 for his discovery. The compound he isolated from mold was hailed as a medical miracle: a molecule that attacked the bacteria making people sick but left the human cells alone. They made surgery safer and helped crush diseases responsible for millions of deaths in the past.

But in the decades that followed, bacteria began to respond to this antibiotic onslaught.

Evolution is a story very much like the three little pigs. A population makes their home in an area, and genetic diversity makes each organism slightly different than its neighbors. A brick house versus a stick house versus a straw house.

But one day an outside stressor comes to town and whether it is drought, medication or the Big Bad Wolf, it spells trouble for that population. One by one, that stressor starts blowing down houses and eating piggies. But there are almost always a select few, who out of pure happenstance, built their houses out of brick. Those pigs survive, thrive and teach their kids to build their houses out of bricks. After a few generations, all the pigs are building brick houses and when the Big Bad Wolf comes to town, he can huff and puff all he wants and it will not make a bit of difference.

MRSAAntibiotics are molecular Big Bad Wolves. The wolf’s only trick is blowing houses down while antibiotics find a specific place on a specific protein to attack. But all it takes is one change, a single amino acid swap that twists the protein just a little and that antibiotic doesn’t work how it is supposed to work. A new generation of bacteria can be born in seconds and those very few bacteria that survive the antibiotics give rise to a whole population of resistant cells. When the first antibiotic stops working, scientists have to develop a new one that attacks a different protein and the Big Bad Wolf needs to learn how to jimmy a window.

This cycle has repeated and repeated and repeated and now there are many strains of resistant bacteria. Donald’s research makes use of the specific nature of antibiotics and resistance. Because antibiotics attack a single protein at a single spot, the computers can narrow where they have to look for resistant mutations. Once the computers figure out what mutations are possible, they can map what the mutated protein would look like to show which mutations offer the best resistance.

In their study of MRSA, Donald’s team isolated several possible mutations and the one that offered the best resistance – making the antibiotic 38 times less effective – began to appear within a few generations.

While this study serves more as a “proof of principle” than a major change in the pharmaceutical industry, the ability to map a bacteria’s genetic future provides a fascinating avenue for research and treatment of infectious diseases.

— Daniel Lane

Daniel Lane covers science, engineering, medicine and the environment in North Carolina.