SAVING LIVES in an antibiotic-resistant world by Julie O Connor 16 Imagine this scenario. At a metro Detroit hospital emergency room, a four-year old girl with a severe case of vomiting, diarrhea, fever and dehydration is given intravenous fluids and antibiotics, and is admitted to the hospital. The next day, lab tests reveal the young girl has an E. coli infection. In this case, the girl s illness is caused by a superbug that is resistant to all of antibiotics typically used to treat this type of infection. On the third day, the young girl dies. On the same day of the young girl s death, an expectant mother in her 15th week in Ohio goes to her local ER complaining of fever, chills, vomiting and diarrhea. She is diagnosed with a gastrointestinal infection and is given an antibiotic and is sent home. The next day, she returns to the ER because of worsening symptoms and bleeding.
Dr. Phillip Cunningham, associate professor, Department of Biological Sciences, College of Liberal Arts and Sciences. Our technology takes advantage of the bugs natural adaptability to identify new drug targets and to isolate all of the target mutations that might lead to drug resistance. Dr. Phillip Cunningham 17
The members of the Cunnigham Lab include students from the Biological Sciences and Chemistry departments who are learning multidisciplinary approaches to solving important scientific problems. Doctors discover she has miscarried because of the infection. Three days later, the would-be mother dies. Two days later, over 500 people are dead from similar symptoms. Tens of thousands of others wait impatiently in hospitals across the Great Lakes states complaining of similar symptoms. By the end of the week, thousands are dead and the epidemic spreads across the U.S. and Canada. Could this really happen? Years ago, such strains of E.coli and other diseasecausing bacteria were rarely drug-resistant. Today, infections caused by bacteria such as E. coli, Salmonella, and others are reaching super-bug status resulting in strains of these diseases becoming more and more antibiotic resistant. In addition, there is good evidence that some of the most deadly human pathogens were genetically engineered to be antibioticresistant superbugs during the Cold War. Thus, the growing risk of bioterrorism also increases the risk of catastrophes caused by antibiotic-resistant microorganisms. Adding to this threat of super-bug, drug resistant infections is the decrease in developing new antibiotics. In the future, seriously ill patients may not have new and effective antibiotics to treat their symptoms or even save their lives. A growing need for R & D Approximately 13 million people throughout the world lose their lives every year because infectious diseases have become resistant to antibiotics. In fact, this is the greatest cause of death in children and young adults worldwide. This year alone, antibiotic-resistant strains will account for approximately 70 percent of the 90,000 Americans who will die from infectious diseases. Unfortunately, large pharmaceutical companies have slowed the development of new antibiotics and focused their attention on more profitable drugs such as those aimed at improving our lifestyle or treating high cholesterol. It is estimated that only five of over 500 drugs currently in the 18
research and development channel and at the human testing stage are antibiotics. The few antibiotics being developed today are primarily broad-spectrum, meaning that they are designed to be effective against virtually all bacteria. Studies have shown that this type of antibiotic is the most likely to lead to antibiotic resistance. The team approach allows the WSU drugdiscovery group to study aspects of antibiotic development ranging from the whole organism to minute molecular details. Instant evolution technology A team led by Dr. Philip R. Cunningham, a microbial geneticist in the Department of Biological Sciences in the College of Liberal Arts and Sciences, has been studying one of the most important antibiotic targets, the bacterial ribosome, for nearly 15 years. Ribosomes are the proteinmaking machines in all cells. Dr. Cunningham has developed several new bacterial genetic mutation technologies that allow rapid identification of any mutation in antibiotic drug targets that might produce an antibiotic resistant bacterial strain. This technology short-circuits the evolutionary mutation process that would normally produce an antibiotic-resistant strain only after an antibiotic began to be used to treat infections. Instead, Dr. Cunningham s instant evolution genetic technology allows the immediate identification of all of the mutations in a ribosomal drug target that might lead to resistance even before the new antibiotic has been developed. Since the average antibiotic currently costs about $800 million to develop for the market, this technology offers a very costeffective way to anticipate the development of drug resistance and to use this knowledge to engineer new antibiotics that are not affected by target mutations. This instant evolution technology can also be used to identify and target genetic sequences unique to a particular bacterial species or subgroup of bacteria. Through Dr. Cunningham s efforts, he and his multidisciplinary team of scientists and students are isolating new antibiotic leads for the development of new antibiotics that specifically affect only disease-causing bacteria without harming beneficial bacteria, thereby reducing the side-effects of antibiotic therapy. Dr. Cunningham explained, For an antibiotic to work, it must bind to a part of the cell that is absolutely required for that cell to carry out its normal metabolic processes. These targets are much like the moving parts of a machine if you somehow stop the parts from moving correctly, you stop the machine. The difference is that the moving parts of bacterial machines are able to change (mutate) so that the antibiotic can no longer bind and this allows the machine to keep working even if the antibiotic is present. For every bacterial machine, there are several antibiotic-resistant replacement parts that bacteria can call on when needed. The problem is we had no way of finding out what these replacement parts looked like until now. Dr. Cunningham s technology can possibly change this and play a major role in combating antibiotic-resistant bacteria. According to Dr. Cunningham, The technology we have developed allows us to do two very important things that were previously impossible. First, it allows us to identify the parts of the machine that are absolutely essential to the bug. These 19
essential parts will be targets for new antibiotics. Second, it allows us to uncover all of the mutations or replacement parts for the new target that the bug may have at its disposal. Knowing all of the mutations that the bug can throw at us before we begin the drug development process is allowing us to develop new antibiotics that are much less likely to be susceptible to antibiotic resistance. Because of their remarkable powers of genetic adaptation, bacteria have been able to mutate and become resistant to every antibiotic currently in use, stated Dr. Cunningham. Our technology takes advantage of the bugs natural adaptability to identify new drug targets and to isolate all of the target mutations that might lead to drug resistance. These new antibiotics will therefore be pre-selected to remain active in the presence of any mutation that the microbe might develop. Spinning out the technology Working with Wayne State s Office of Technology Transfer, Dr. Cunningham s technology has one patent application pending, and others being prepared. From his technologies, a spin-out company known as RiboNovix, Inc. has been formed which has an exclusive license for commercialization of the intellectual property encompassing the technology. RiboNovix, Inc. was founded by Dr. Cunningham and Alison Taunton-Rigby, Ph.D., O.B.E. Dr. Taunton- Rigby, chief executive officer, was president of Aquila Biopharmaceuticals, Inc., a life sciences company that merged with Antigenics, Inc. Prior to this, she served as President and CEO of Cambridge Biotech, and of Miotix, Inc., now merged with GPC Biotech. She has held other senior management positions at several other corporations as well. The Office of the Vice President for Research has promoted interdisciplinary research for some time now, and this approach has created some creative bonds across campus resulting in new technologies that once were not possible, said John P. Oliver, WSU s Vice President for Research. RiboNovix s genetic technology is an excellent example of using an interdisciplinary approach to lead to new ideas. Their platform technology integrates genomics, bioinformatics, structural biology, combinatorial chemistry, high through-put screening and rational drug design. This clearly crosses many boundaries across our campus, which has led to an exciting technology that will affect the lives of millions. Through this new antibiotic development technology, Dr. Cunningham, his scientific team at Wayne State University and RiboNovix, Inc. aim to make significant advancements in drug development in the field of anti-infectives. RiboNovix s new drugs may provide alternative therapies for infections resistant to current antibiotics, new therapies for the treatment of infections for which current therapies are insufficient, and its products will potentially have Marny Waddington and Srividya Pattabiraman (left) prepare bacterial cultures for instant evolution experiments. Kris Ann Baker and Jennifer Stroka isolate mutated ribosomes from the Cunningham E. coli strain. Ashesh Saraiya loads samples on the automated DNA sequences. 20
longer therapeutic lifetimes. The anticipated result would be less people losing their lives to infectious diseases once resistant to antibiotics. Reaching out to developing countries The technology developed by Dr. Cunningham's group could play a major role in targeting antibiotic-resistant diseases that pose a threat to human health around the globe. This team, which consists of WSU researchers Dr. Christine Chow, professor of Chemistry, Dr. John Montgomery, professor of Chemistry, Dr. John Santa Lucia, associate professor of Chemistry, and Dr. Mark Spaller, assistant professor of Chemistry are collaborating to develop solutions to critical scientific and technological problems that, if solved, could lead to important advances against diseases of the developing world. Each member of the multidisciplinary Cunningham team has contributed novel technology for the creation of innovative and affordable solutions to health problems in developing countries. Through their development of new synthetic antimicrobials that are not susceptible to resistance, morbidity and mortality due to infectious diseases such as tuberculosis caused by drug resistant Mycobacterium tuberculosis that run rapid in developing countries, may be significantly reduced. The members of the team are also training students and postdoctoral fellows who will be uniquely prepared to take on future scientific challenges through their interactions with the multidisciplinary members of this outstanding group. This team of researchers may one day save many lives in our ever-growing antibiotic-resistant world. DR. PHILIP R. CUNNINGHAM BIOGRAPHY NS/2005 Dr. Philip R. Cunningham earned his bachelor s degree in Biology from Murray State University in Murray, Kentucky, and his Ph.D. in microbiology from Southern Illinois University in Carbondale, Illinois. He was a post-doctoral fellow at the Roche Institute of Molecular Biology in Nutley, NJ where he first began his studies on ribosomes. He joined Wayne State University s Department of Biological Sciences in the College of Liberal Arts and Sciences in 1991 where he is currently an associate professor. The WSU team working to develop new types of antibiotics that are less susceptible to the development of resistance. From top left, Dr. Mark Spaller, Dr. Philip Cunningham, Dr. John Santa Lucia, Jr., Dr. Christine Chow. 21