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MDR-TB challenges researchers
Before Andrew Speaker made his front page debut in 2007, most Americans had not heard of extensively drug-resistant tuberculosis (XDR-TB), but the ensuing media storm would soon guarantee almost everyone with a newspaper, radio, television, or Internet access was about to get pretty familiar with XDR-TB as well as Speaker’s travel itinerary.
Speaker was the personal injury attorney who, at first, was diagnosed with multi drug-resistant tuberculosis (MDR-TB) and discouraged from traveling by the Centers for Disease Control. Nonetheless, Speaker traveled to Europe for his wedding and honeymoon, during which time further lab tests changed the diagnosis to XDR-TB, which is far more difficult to treat. Speaker was placed on a no-fly list. Upon his return to the United States, authorities put him in involuntary isolation and he was transferred to National Jewish Medical and Research Center in Denver where his diagnosis reverted back to MDR-TB, and he received the appropriate medical treatment.
While MDR-TB and XDR-TB were new acronyms to most, researchers at the Mycobacteria Research Laboratories (MRL) were well versed in the challenges presented by these particularly tenacious mycobacterial diseases and the concerns they were raising in the global health community. The fear awakened in the Speaker case simply brought to the public forum what researchers had been focusing on for years – new drugs were needed to treat drug-resistant bacterial diseases.
“If we just look at tuberculosis, there have been no new drugs developed for first-line treatment in probably 30 years,” said Dr. Richard Slayden, an Associate Professor in the Department of Microbiology, Immunology and Pathology, and member of the MRL team. “The appearance of drug-resistant tuberculosis, and other drug-resistant diseases, is driving new drug discovery forward as we seek to provide better drug options to doctors and their patients, as well as global health programs looking to prevent and treat publicly important diseases such as TB.”
Tuberculosis, caused by Mycobacterium tuberculosis, is an airborne infectious disease. The World Health Organization estimated 1.5 million people died from TB in 2006, mostly in developing countries with poor sanitation and restricted access to medical care. In addition, another 200,000 people with HIV died from HIV-associated TB. WHO is working to dramatically reduce the burden of TB, and halve TB deaths and prevalence by 2015, through its Stop TB Strategy and supporting the Global Plan to Stop TB. The development of new drug therapies is critical to that goal. Relatively new strategies in the drug discovery process to assist researchers in the development of novel chemotherapeutics are the use of computational biology and structural genomics.
Computational biology and structural genomics are interdisciplinary fields that apply the techniques of computer science, applied mathematics and statistics to address biological problems. Together, computational biology and structural genomics are used to identify new protein drug targets and to systematically produce accurate structural three-dimensional protein structures, which allows researchers to sort through seemingly endless possibilities of drug-protein combinations to find subsets of best candidates to progress further along the drug discovery process.
“We are examining the coding capacity of genomes of different pathogenic bacteria looking for unexploited targets, particularly unique metabolic processes in bacteria that allow them to survive, cause disease, tolerate treatment, and persist,” said Dr. Slayden. “The push is to develop novel broad-spectrum antibiotics with novel modes of action that will be effective against a diversity of bacterial illnesses.”
There are historical observations in TB drug discovery that potency of a drug does not always correlate well with treatment efficacy. How a bacterium interacts with its host affects drug performance so understanding host-pathogen interaction is an important aspect of developing the “next-generation” drugs. Researchers are studying how drug potency correlates with effectiveness in animal models of infection by molecular modeling and investigating, protein-drug residence time (how long a drug binds the target protein), drug-protein affinity, drug mode of action, and physiochemical characteristics.
MRL researchers work cooperatively with colleagues at Stony Brook University and with the Rocky Mountain Regional Center of Excellence Genomics Proteomics Core and Animal Models Core, and the Center for BioInformatics at Colorado State University. Starting with genomic data from more than 1,000 pathogens, researchers first identify drug targets of interest. Then, via virtual screening, identify molecules that interact with the target (from a library of 8.5 million compounds) cutting off the data set at 1,000. Another analysis strategy is then applied, and the number of potential drug structures is reduced to between 15 and 20 representatives. A reiterative process of sensitivity testing and medicinal chemistry refines the compounds to a final candidate. Efficacy testing in animal models of infection is incorporated where appropriate. This comprehensive process optimizes the total number of compounds being investigated, thus streamlining the process and reducing the need for animals in early-stage development programs.
“With this collaboration, we are able to expand our capabilities, tap into more expertise, and split the responsibilities as well,” said Dr. Slayden. “Stony Brook has a team of 30 to 40 people, so we can build on each other’s experiences – both successes and failures – to move forward more quickly with drug development. We’ll be able to deliver the molecules we want that have a higher likelihood of effectiveness against the target diseases caused by bacteria.”
Pre-clinical evaluation of compounds is coordinated and contracted through the Rocky Mountain Regional Center of Excellence at Colorado State University, and through a grant from the National Institutes of Health.