Pathogens’ protein structures offer blueprint for new drugs

Washington - Scientists say that they have reached a significant milestone by determining 1,000 protein structures from infectious disease organisms.

The knowledge gained from these structures should lead to new interventions for the deadly diseases caused by these pathogens.

The breakthrough study was carried out by investigators at the Center for Structural Genomics of Infectious Diseases (CSGID) and the Seattle Structural Genomics Center for Infectious Disease (SSGCID).

Since 2007, the SSGCID, headed by Dr. Peter J. Myler of Seattle Biomedical Research Institute (Seattle BioMed), and the CSGID, headed Dr. Wayne Anderson, Molecular Pharmacology and Biological Chemistry at the Northwestern University Feinberg School of Medicine, have been funded by five-year contracts from the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the National Institutes of Health (NIH).

Researchers in both centers use X-ray crystallography and nuclear magnetic resonance to examine the atomic details of proteins from more than 40 human pathogens, including those responsible for the plague, anthrax, salmonellosis, cholera, tuberculosis (TB), leprosy, amoebic dysentery and influenza.

The proteins are selected for their biomedical relevance, as well as potential therapeutic and diagnostic benefits, with one-third being direct requests from the infectious disease research community.

 â€œWe are laying the groundwork for drug discovery. Determining protein structures can help researchers find potential targets for new drugs, essential enzymes, and possible vaccine candidates,” Anderson said.

One of the major challenges in medicine today is fighting bacteria that have become drug-resistant.

Methicillin-resistant Staphylococcus aureus, commonly known as MRSA, is incredibly difficult to treat because it has developed a resistance to antibiotics, including penicillin and cephalosporins.

“By determining the structure of proteins targeted by these drugs, we can now look at how the atoms are arranged in space and how they interact with one another,” Anderson stated.

“Then researchers can determine how the bacterium developed resistance and figure out what to change in the drug so that the bacteria will not recognize it,” he explained.

Dr. Lance Stewart, co-PI of the SSGCID, continued, “The emergence of multi-drug resistant strains of Mycobacterium tuberculosis (MDR-TB), is also an important global health concern, with the most recent cases of TB emerging from India being considered extensively drug resistant (XDR-TB).”

The World Health Organization (WHO) and other global health authorities have called for a concerted effort to identify new therapeutic agents for new and better drugs to combat TB, especially medications directed at treating drug resistant strains of the disease.

The SSGCID has solved 22 structures from M. tuberculosis and an additional 126 closely related targets from other Mycobacterium species, which cause diseases such as leprosy, Buruli ulcer, and lung infections in AIDS patients. These structures will aid in the understanding of these deadly diseases, as well as providing a blueprint for development of new drugs.