Tyler Olsen and Dr. Paul Savage, Department of Chemistry and Biochemistry
The need for novel antibiotic mechanisms is prevalent. Common antimicrobial medicines such as penicillin, ampicillin and vancomycin have started becoming obsolete as resistant strains of bacteria become more widespread. The main problem with antibiotics is the rapid mutations that bacteria undergo. Eventually one cell will develop resistance, and then have that mutation selected for as patients undergo antibiotic therapy. Bacteria are rapidly changing to combat the many new antibiotic variants that have come out.
One exciting new mechanism for antibiotic treatment is mimicking the effects of antimicrobial peptides. These naturally produced proteins have stayed effective for thousands of years, unlike most synthetic antibiotics. Their resistance to mutation comes from the way that they kill bacteria. Unlike most antibiotics that target one specific organelle, protein or process in a bacterial cell, antimicrobial peptides target the cell overall. Bacterial cell membranes have an overall negative charge. One side of the peptide is positively charged, which is attracted to the cell membrane. The other side of the peptide is attracted to fatty, greasy molecules such as the interior of the cell membrane. Once the positive portion of the peptide interacts with the cell membrane, the fatty portion inserts itself into the membrane. This causes the positive side to pull apart the cell membrane, quickly killing the cell.
CSA-13 is an antimicrobial peptide mimic. We believe that it follows a similar mechanism as the natural peptides. CSA-13 is synthesized from Cholic Acid, which is made in the liver and stored in the gall bladder of most mammals. This allows for a natural and simple way to obtain starting material.
My project dealt with synthesizing and purifying CSA-13, as well as finding ways to optimize the synthetic procedure. While a first synthesis had already been drafted, it never took into account anything other than small laboratory production. Many reactions that were performed in the synthesis either used hazardous materials or were impractical for large scale use. We have been able to design new processes that eliminate these hazards as well as making purification simple. We currently are contracted with an industrial company to produce CSA-13 and other antimicrobial peptide derivatives on large scale.
We have run into problems still however. The final portion of the synthesis involves the transformation of an alcohol into an amine group. While we have toyed with many methods, none are the perfect combination of speed, simplicity and safety. We are still researching how to perform this vital step simply and efficiently. CSA-13 is currently undergoing bacterial reduction tests as well as live animal testing. This is possible due to our improved synthesis. The data currently show high antimicrobial activity.
The future directions of this research are really exciting. We are working on attaching CSA-13 onto metal surfaces. This will allow for metal implants such as hip replacements or plates for broken bones to resist infection from the beginning. Hospital surfaces can also be coated, allowing for much sanitation that lasts much longer than a few minutes. We are also working on placing CSA-13 within contact lenses to have a new medicine delivery system. These contact lenses would be directly applied to the eyes, ensuring targeted medicine delivery.
New antibiotics such as CSA-13 offer many possibilities for the future. While research is still ongoing, we hope to soon apply antimicrobial peptide mimics to many problems in the world. All indications point to the effectiveness of these mimics; the only unresolved issue is the safety and side effects of these compounds. These molecules offer a greater understanding of biology as well as having the potential to save countless lives.