Paratek publishes crystal structure of E. coli MarR protein
MarR contributes to multiple antibiotic resistance
Paratek Pharmaceuticals, Inc. announced today that, in collaboration with a team of structural biologists led by James Head, Ph.D. at the Boston University School of Medicine, it published a completed crystal structure for the E. coli MarR protein in the August issue of Nature Structural Biology. MarR and other closely related proteins regulate a plethora of bacterial functions, including resistance to multiple antibiotics, a mounting global public health threat. Completing the crystal structure represents a major milestone in Paratek's novel drug discovery efforts.
"If you can imagine a bacterial cell as a medieval fort, the MarR protein acts as a sentry and is responsible for alerting the cell to trouble, for example when a microbe confronts an antibiotic," said Dr. Michael Alekshun, manager of Paratek's multiple antibiotic resistance (MAR) program and lead author of the manuscript. "Completing the crystal structure of MarR moves us further along toward understanding what triggers this response and toward designing drugs to keep the bacterial fort vulnerable."
To complete the structure, Paratek researchers inserted genetic material responsible for producing excess MarR proteins into E. coli cells. These proteins were purified and coaxed to form crystals that were then examined. The E. coli structure is the first to be completed for the very large MarR family of proteins, which exists in a variety of bacteria. When E. coli bacteria are threatened, by antibiotics, other pharmaceuticals, such as acetyl salicylate (aspirin) and clofibric (a protypical agent used to treat hypertrigliceridemia) and ethacrynic (a diuretic) acids, and natural phenomena, MarR is inactivated. This results in the production of MarA, which activates the bacterial defenses. In E. coli, Paratek and others have identified more than 80 distinct genes that are regulated by MarA. By developing compounds that bind to MarR, Paratek aims to block chemical signals that inactivate the protein.
"What we are developing in our MAR program are not antibiotics - they are anti-infectives," says Dr. Alekshun. "Rather than killing the bacteria outright (and sounding the alarms that allow the cells to defend themselves), we want MarR to remain active to keep the bacteria in check. Similar strategies could be applied to other members of the MarR family, and these drugs would be of great value to immuno-compromised patients."
In addition to protecting people with weak immune responses, Paratek's goal is to use their MAR products to resuscitate antibiotic efficacy that has otherwise been compromised by bacterial resistance.
Paratek's Vice President of Research & Development Dr. S. Ken Tanaka said, "The bottom line from what we found is that these proteins are relatively easy to produce and purify, which means we have abundant screening resources." Tanaka added, "Additionally, the structure gives us plenty of potential binding sites to work with in developing products targeted to MarR and MarR- family members. We are very pleased."
Paratek is a privately-held specialty pharmaceuticals company, headquartered in Boston, Mass., which is engaged in the discovery and commercialization of novel therapeutics that treat life-threatening infectious disease agents, including those that have become resistant to existing antibiotic treatments. Paratek was founded in 1996 by Dr. Stuart B. Levy, Professor of Molecular Biology and Microbiology and of Medicine at Tufts University School of Medicine, and by Dr. Walter Gilbert, the Nobel Prize- winning Professor at Harvard University. Paratek was created to harness the 20 years of research and discovery in mechanisms of antibiotic resistance and tetracycline chemistry by Dr. Levy and his scientific team at Tufts University School of Medicine. In 1999, the Company announced a research collaboration with GlaxoSmithKline plc (formerly Glaxo Wellcome plc) for the development of novel Tetracyclines.
Source: Paratek Pharmaceuticals, Inc.