In response to the above claim, the past three decades of work in biomaterials has involved augmentation of the surface of medical implants to grant anti-infection properties during and immediately after implantation. The two most common approaches are (1) the slow release of antibiotics from a pre-filled well and (2) the conjugation of anti-infection agents, such as silver coatings or antibiotic surfacing, onto the implant’s interfacial surfaces. Unfortunately, both of these techniques are inadequate. The supply of soluble antibiotics will eventually run out in the pre-filled well and, near the end of depletion, the sub-lethal concentrations of antibiotic potentially increases the volume of ...view middle of the document...
The increased exposure suggests an increased efficacy of the host immune system and any treatment requiring a surface interaction with the bacteria.
This project aims to develop novel amyloid-inhibiting peptides to block the aggregation process of biofilm formation. An amyloid-inhibiting peptide will function by blocking the polymerization of amyloid fibrils that provide the fundamental structural framework of certain biofilms (Figure 1). Thus, if this peptide therapeutic is introduced to the body before medical device implantation, biofilm formation can be prevented before it begins. If the design is successful, the effects will be significant: not only will bacteria become more exposed to the host immune system, but supplied treatment or antibiotics will have greater efficacy in eliminating the infection before immunity to treatment is developed. Computational protein engineering provides an iterative in silico method to design novel peptides that have a high affinity to prevent the aggregation of amyloid fibrils. The proposed project will involve (1) the design of the amino acid sequence and conformation of peptides that imitate the alpha-sheet structure of amyloid proteins, (2) the testing and scoring of these designed peptides with molecular dynamics simulation using the software package in lucem molecular mechanics, (3) peptide synthesis and solubility testing of high-scoring designs, and (4) in vitro testing of amyloid aggregation inhibition of the amyloid protein involved in biofilm synthesis. Analysis of the molecular dynamics simulations and in vivo aggregation tests will provide key insights into the viability of the designed peptides and their potential to inhibit the amyloid-mechanism of biofilm formation. The amino acid sequence and structural conformation of successful designs will be evaluated and implemented in subsequent generations of peptides. The final outcome of this project will consist of multiple peptide designs that have shown a high affinity for inhibiting biofilm amyloid protein aggregation and have shown potential in preventing bacterial biofilm formation.
Evaluation of Alternative Approaches
In response to the global concern of multi-drug resistant (MDR) bacteria strains, there has been a push in the medical community to avoid all bacterial therapies and treatments that involve the killing of bacteria to reduce the risk of developing MDR strains.14-18 As a result, alternatives to traditional antibiotic treatments are entering the international spotlight. Some examples of these new techniques include (1) the enhancement of macrophage phagocytosis, (2) disruption of iron-dependent metabolism, and (3) bacterial adhesion prevention. Each approach will be discussed and compared with the proposed amyloid-inhibiting approach. In most situations, a combination of these new approaches and the amyloid-inhibiting approach would work well in tandem,
Enhancement of Macrophage Phagocytosis
For a macrophage to consume a...