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The Development of Peptide-Based Alternative Approaches to Combat Antibiotic-Resistant Bacterial Infections
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The rapid spread of antibiotic resistance among clinical pathogens and members of the human microbiota has grown to a severe global healthcare issue over the past two decades. Last resort antibiotics exist to treat many of these pathogens, including bacteria exhibiting multi-drug resistance. However, alternative approaches are needed to mitigate selective pressure on both pathogens and commensals to preserve the effectiveness of these critical antibiotics. In an effort to develop new therapeutics that circumvent traditional bacterial resistance mechanisms without contributing to selective pressure, the work described here explored the use of peptides to fill this therapeutic niche. More specifically, novel peptide-based therapeutics were developed with the ability to sequester antibiotics, which undergo undesired accumulation, preventing selective pressure on commensal bacteria. Alternatively, peptides were employed to modulate bacterial phenotypes involved in the uptake of antibiotic resistance genes or extermination of pathogenic commensals.The second chapter describes the use of tripeptide bacterial cell wall mimics to selectively trap the important last resort antibiotic vancomycin, preventing it from exerting selective pressure on members of the colonic microflora following treatment. Several tripeptides were synthesized that display a higher degree of vancomycin antagonism than the native scaffold, several of which were found to covalently bind vancomycin. Additionally, these lead compounds exhibit low oral bioavailability and the ability to prevent vancomycin associated selective pressure in mixed cultures of resistant and susceptible bacteria over a weeklong period. The third chapter explored the role of the Streptococcus oligofermentans competence regulon in phenotypic expression and sought to develop competence stimulating peptide (CSP) derivatives with the ability to modulate quorum sensing (QS). A comprehensive phenotypic analysis was conducted to gain a deeper understanding of the role of the S. oligofermentans competence regulon identifying several key phenotypes that are under QS control. Additionally, a comprehensive structure activity relationship analysis of the CSP was performed. This analysis revealed several structural motifs that are critical for ComD receptor binding and activation and allowed for the development of the first modulators of the S. oligofermentans competence regulon.