| Who: | Ryan Marshall in collaboration with Professor Paul Savage and students at Brigham Young University's Department of Chemistry & Biochemistry. |
| What: | Journal of the American Chemical Society publication citation: "Synthesis of Lipid A Derivatives and Their Interactions with Polymyxin B and Polymyxin B Nonapeptide", Ning, Y.; Marshall, R. L.; Matheson, S.; Savage, P.B. J. Am. Chem. Soc. 2003, 125, 2426. |
| When: | Published on March 5, 2003 for research conducted 1997-2002. |
Sepsis is a life-threatening condition resulting from bacterial infection and release of an endotoxin or poison called lipid A. Lipid A is the primary constituent of the outer membrane of gram-negative bacteria. As the poison is released, patients suffer from low blood pressure induced shock. Patients who enter suffer septic shock reportedly experience a 50-60% mortality rate.
Sepsis treatment usually includes antibiotics directed to removing the toxin-producing bacteria. However, antibiotic treatment of bacteria can result in additional toxin released from the bacterial membrane. Polymyxin B ("PMB") and its relative polymyxin B nonapeptide ("PMBN") are antibiotics present in topical antibiotics such as Neosporin® and are known to bind lipid A. Unfortunately, their oral and intravenous administration is often as toxic to humans as the poison from the bacteria. Understanding the binding affinity between the polymyxin antibiotics and lipid A may lead to therapeutic agents for treatment of sepsis with antibiotic activity.
Mr. Marshall and co-workers describe their research regarding lipid A binding in the Journal of the American Chemical Society ("JACS"). The JACS paper describes the synthesis of compounds that structurally mimic lipid A and a systematic study to understand the mechanisms that drive association of lipid A with cationic peptide binding agents. Their study answers a long standing debate about whether ionic or hydrophobic interactions dominate the binding mechanism. Furthermore, their study system and measurements reveal that binding stoichiometry is less than one and determined by the number of ionic groups on the binding partners. Because PMB and PMBN can bind more than one lipid A molecule, the strength of the interactions appears to be influenced by the aggregation state of the toxin. Finally, their studies also reveal what structural characteristics contribution to binding.
The results of Mr. Marshall's research should contribute to further development of lipid A binding agents and potential therapeutic techniques for treatment of sepsis.