The Hybrid Barrel Mechanism of Outer Membrane Protein Folding by the Bam Complex and Its Inhibition
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Kuo, Katie M.
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Abstract
Antibiotic resistance is a growing and pressing societal issue, with a projected mortality rate of 50 million/year by the year 2050. In particular, Gram-negative bacteria are inherently resistant to antibiotics. The presence of the inner and outer membrane makes it difficult for antibiotics to permeate and enter the cell, in addition to the other mechanisms of resistance that have developed. The protein, the BAM complex, is an attractive target to develop antibiotics against. By understanding the mechanism behind its function, outer membrane protein (OMP) biogenesis, antibiotics can be developed to target BamA and inhibit bacterial infections by Gram-negative species. The first aim focuses on modeling and simulating sequential hybrid-barrel intermediates of BamA-EspP and determining the biophysical features. The second aim details the cryo-EM structures of the hybrid-barrel intermediates and the subsequent simulations of the structures. The third aim identifies the crucial interactions between two potential antibiotics and the target protein BamA as well as the mechanism of action targeted. Investigating these three aspects of the BamA will facilitate antibiotic development and mitigate current and projected mortality rates due to antibiotic resistance.
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2023-12-05
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Text
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Dissertation