Overview

Agile Sciences is a Research Triangle, NC based company dedicated to solving problems caused by bacterial biofilms with novel compounds capable of inhibiting and disrupting film formation <ref> Richards, J.J.; Huigens, R.W.; Ballard, T.E.; Basso, A.; Cavanagh, J., and Melander, C. "Inhibition and Dispersion of Proteobacterial Biofilms." Chemical Communications. 2008, 14, 1698 - 1700.</ref> . Founded in 2007 by Professors Christian Melander and John Cavanagh of North Carolina State University (NCSU), Agile’s compounds have been to shown to be effective across order, class and phylum, making it a technology capable of broad action inhibition and disruption of biofilms <ref> Rogers, S.A. and Melander, C. "Construction and Screening of a 2-Aminoimidazole Library Accessed by [3 2] Click Chemistry Identifies a Small Molecule Capable of Inhibiting and Dispersing Bacterial Biofilms Across Order, Class and Phylum." Angewandte Chemie International Edition, In press. </ref>.

The Agile compounds do not kill bacteria; instead, they force bacteria to remain in or revert to a planktonic phenotype. Such activity is especially interesting if used as an adjuvant to existing bactericides which can be orders of magnitude more efficient against planktonic bacteria than those in biofilms.

The compounds were derived from investigation of chemicals created on the surface of marine sponges known to remain clean of fouling despite heavy growth in their surroundings <ref> Huigens, R.W.; Richards, J.J.; Parise, G.; Ballard, T.E.; Zeng, W.; Deora, R., and Melander, C. "Inhibition of Pseudomonas aeruginosa Biofilm Formation with Bromoageliferin Analogues." Journal of the American Chemical Society. 2007, 129 (22), 6966-6967.</ref> . From an initial active molecule, Agile's founders have isolated an optimized broad spectrum compound as well as analogues particularly suited to specific varieties of bacteria <ref> Richards, J.J. and Melander, C. "Synthesis of a 2-Aminoimidazole Library for Anti-Biofilm Screening Utilizing the Sonogashira Reaction." Journal of Organic Chemistry, In Press. </ref>.

Applications

Biofilms are accepted to be responsible for a wide range of serious problems <ref> “Introduction to Biofilms: Negative and Positive Effects.” http://www.erc.montana.edu/biofilmbook/MODULE_01/Mod01_Blue/Mod01_S03_Blue.htm. Center for Biofilm Engineering. </ref> . Their effect is perhaps most visible in industrial settings where they accumulate on the surfaces of pipelines and equipment and contribute to both product contamination and corrosion of infrastructure <ref> “How do Biofilms Impact Our World.” Montana State University Center for Biofilm Engineering. http://www.erc.montana.edu/biofilmbook/MODULE_01/Mod01_Blue/Mod01_S03_Blue.htm </ref>. Often chemical biocides and cleaners are ineffective and the only recourse is to halt activity and mechanically clean surfaces, which can be costly and impractical <ref> Ludensky, Michael. Control and Monitoring of Biofilms in Industrial Applications. International Biodeterioration & Biodegradation. Volume 51, Issue 4, June 2003, Pages 255-263 </ref>. In processes such as reverse osmosis membranes, paper mills, fuel storage, ship hull protection, and many others biofouling is a problem managed but not solved. Agile’s compounds potentially represent a powerful new technique for preventing and treating this contamination.


Beyond industrial settings, biofilms have also been implicated as contributors to chronic diseases of both plants and humans <ref> Ludensky, Michael. Control and Monitoring of Biofilms in Industrial Applications. International Biodeterioration & Biodegradation. Volume 51, Issue 4, June 2003, Pages 255-263 </ref>. Bacterial diseases of crops can be devastating as seen in recent years with outbreaks of Citrus Greening in Florida <ref> Dorell, Oren. “Disease threatens Fla. citrus industry.” USA Today. October 2nd, 2007. </ref> and Pierce’s disease in California’s Napa Valley<ref> “California Agriculture Research Priorities: Pierce’s Disease.” Board on Agriculture and Natural Resource. 0-309-09289-2. http://www.nap.edu/catalog.php?record_id=11060. 2004</ref>. Current techniques for controlling these infections include direct treatment by antibiotics, disinfectants, and copper sprays or indirectly through insecticides to eliminate pests who serve as vectors for the diseases. All of these methods are often ineffective in curing the disease and carry risks of environmental contamination. Concern is also present regarding the use of antibiotics which may remain present in food or soil and contribute toward the development of resistant bacteria dangerous to humans<ref> McManus, P. S., and Stockwell, V. O. 2001. Antibiotic use for plant disease management in the United States. Online. Plant Health Progress doi:10.1094/PHP-2001-0327-01-RV.</ref>. A compound which directly prevents film growth has the potential to dramatically increase the effectiveness of existing crop disease solutions at smaller doses by destroying the biofilms contributing to resistance. Lower biocide doses can help to reduce the negative environmental effects often associated with biocides such as copper which can both accumulate to degrade soil quality and pose an occupational hazard to farm employees <ref> “Copper.” ToxFAQS. Agency for Toxic Substances and Disease: Department of Health and Human Services. http://www.atsdr.cdc.gov/tfacts132.html. September 2004.</ref>.
The impact of a biofilm dispersant could be even greater in human medicine. Each year in the US alone close to two million patients are afflicted by hospital acquired infections such as MRSA, VRE, and CDAD. Over 100,000 of these individuals die from the infection or associated complications, making this the fourth leading cause of death in the United States behind heart disease, cancer, and stroke according to the CDC <ref> Barens, Michael. “Preventable Hospital Infections Becoming a Deadly Epidemic.” L.A. Times. July 21, 2002</ref> . A common source of such infection is indwelling medical devices such as catheters which become colonized by thick films of pathogenic bacteria <ref> Barbara W. Trautner and, Rabih O. Darouiche. “Role of biofilm in catheter-associated urinary tract infection.” American Journal of Infection Control, Volume 32, Issue 3, May 2004, Pages 177-183 </ref>. This growth is an even greater problem when it occurs on surfaces implanted in the body. Infection of pacemakers, joint replacements, and other implanted devices can require removal of the device and puts the patient at risk for life-threatening systemic infection <ref> Gilbert, Peter, Andrew J. McBain, Alexander H. Rickard, and Sarah R. Schooling. “Control of Biofilms Associated with Implanted Medical Devices.” Medical Biofilms. Copyright © 2003 John Wiley & Sons, Ltd 9780471988670. 25 Feb 2005 </ref>. An antibiofilm compound used as a coating for medical devices has the potential to prevent colonization in the first place.


In addition to preventing hospital Infection, the ability to disperse established biofilms means that these compounds are a possible treatment for existing chronic infections. Bacteria in biofilms are orders of magnitude more resistant than when they are individuals so dispersion of these films leaves bacteria more vulnerable to both natural immune responses and traditional antibiotics <ref> Philip S Stewart, J William Costerton, “Antibiotic resistance of bacteria in biofilms”, The Lancet Volume 358, Issue 9276, , 14 July 2001, Pages 135-138.</ref>. If used as an adjuvant to existing antibiotics the compound could allow these drugs to be effective at lower doses or even allow for use of drugs not considered viable today due to resistance. Targeted delivery of the compound could allow for novel therapeutics against diseases recognized to be caused by biofilms ranging from Cystic Fibrosis <ref> Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, Greenberg EP. Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 407: 762-4, 2000.</ref>, an incurable hereditary disease of the lungs to Otitis Media (ear infections), which afflict most US children by age three and are often recurring as existing antibiotics can only kill surface bacteria without disrupting the underlying biofilm <ref “Direct Detection of Bacterial Biofilms on the Middle-Ear Mucosa of Children With Chronic Otitis Media” Journal of the American Medical Association. 2006;296:202-211 </ref>.