| Summary: | Chemistry === Ph.D. === Various organizations, including the Centers for Disease Control and Prevention (CDC), and World Health Organization (WHO) have declared infections caused by multi-drug resistance pathogens as an “emergent global disease” and a “major public health problem.” The reports were issued in response to two seismic developments in 2016. The first report of antibiotic-resistant bacteria addresses the story of the American patient carrying the mcr-1 gene, which confers resistance to the antibiotic colistin, while the second report proclaims the pathetic death of U.S. patient from septic shock attributed to bacterial infection resistant to treatment with 26 antibiotics. Thus, the rapid development of bacterial resistance to antibiotics coupled with marked changes in the pharmaceutical sector has resulted in a global health crisis; so new antibiotics are urgently needed. Approximately two-thirds of all antibiotics are derived from natural products, so the structural modification of natural products-derived antibiotics by either semi- or total synthesis is a highly successful strategy for discovering novel drugs to address bacterial resistance. My Ph.D. research project comprises of analog development for three main classes: macrolides, albocycline, and aminoglycosides. Macrolides in general and ketolides, in particular, have been widely successful in treating various serious infections affecting lungs (e.g., pneumonia) and skin (e.g. cellulitis) over the past decades. My research of macrolides orients towards establishing a structure-activity relationship (SAR) via developing analogs of solithromycin (current-leading ketolide), that can be accessed via Cu (I) combinatorial click chemistry inspired by Sharpless, in which a library of synthesized and commercial alkynes have been clicked at N-11 azide side chain. Alternatively, synthetic approaches have been applied on the macrolide azide, in order to establish novel scaffolds termed as bis-clicked products that possess supplementary binding pockets. Despite the fact that albocycline (macrolactone) shares similar structural scaffolds with macrolides, it still possesses promising activity for treating methicillin-resistant Staphylococcus (MRSA) as well as vancomycin-resistant strains (MIC = 0.5−1.0 μg/mL). My research of albocycline has established a library of albocycline analogs accessed via cultured albocycline that is isolated from Streptomyces maizeus. However, attempts to functionalize various sites of the albocycline core resulted in poor biological activity reflected with high minimum inhibitory concentrations (MICs). Therefore, developing novel analogs with improved properties required a better understanding of the mode of action. Initial reports indicated the possibility of albocycline inhibiting the bacterial cell wall synthesis, particularly the peptidoglycan that involves various downstream enzymes MurA to MurZ. Using biochemical pathways and molecular modeling, we concluded that albocycline has an alternative bacterial target. Current efforts in collaboration with Paul Dunman at The University of Rochester (School of Medicine), initiated a genetic approach to identify the target. In this regard, four albocycline-resistant S. aureus strains have been identified by whole-genome sequencing of both mutant and parent (wild-type) and studied to identify the target of albocycline. Preliminary data suggest that albocycline exerts a direct inhibition to the nicotinate pathway in Bacillus subtilis cells, which indirectly causes the blockage of peptidoglycan biosynthesis. In short, the long-term goal revolves toward delivering new antibiotics to avert a post-antibiotic era after gaining a better understanding of the antibacterial mechanism of action. Typical strategies to antibiotic discovery require chemical synthesis, lead optimization, accompanied by tedious compound characterization followed by biological evaluation. These approaches are time-consuming and expensive in terms of labor, cost of reagents, and solvents. A promising solution to this problem is found in the emerging field of target-guided synthesis (TGS), wherein the bacterial target assembles its own inhibitor following the principles of fragment-based drug design leading to acceleration in the drug discovery process. On this subject, we have developed seven novel analogs of aminoglycoside neomycin via Cu (I) click chemistry and tested their MICs against resistant strain pikR2. MIC results revealed few analogs that share similar potency with neomycin against pikR2, illustrating the potential for expanding this method further with in situ click experiments. The viability of the proposed in situ click is predicted on previous work established by the Andrade lab, which could explore novel analogs addressing resistance concerns. My final research project centers on the recent advances of C–H activation and its tremendous growth as a hot topic in the synthetic field through the application of longifolene. This triggers us to take advantage of 1,5-Hydrogen Atom Transfer (HAT) to afford cyclization of the seven-membered ring of the molecule. Although longifolene has been previously accessed, it presents a challenging synthesis due to the intricate carbon-carbon framework. Innovative methodology relying on a modified Suarez oxidation (oxygen-centered radical) is proposed to accomplish a formal synthesis of longifolene, which can be expanded for much broader applications. === Temple University--Theses
|
|---|
