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Title:Development of predictive guidelines for compound accumulation in gram-negative bacteria
Author(s):Richter, Michelle F
Director of Research:Hergenrother, Paul J
Doctoral Committee Chair(s):Hergenrother, Paul J
Doctoral Committee Member(s):Burke, Martin D; van der Donk, Wilfred A; Mitchell, Douglas A
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Gram-negative bacteria
Accumulation
Complex natural product-like compounds
Abstract:New antibiotics to combat drug-resistant Gram-negative pathogens are urgently needed. Most small molecules are unable to rapidly traverse the outer membrane of Gram-negative bacteria and accumulate inside these cells, making the discovery of drugs against these pathogens challenging. Current understanding of the physicochemical properties that dictate small molecule accumulation in Gram-negative bacteria is largely based on retrospective analyses of antibacterial agents, which suggest that polarity and molecular weight are key factors. A few compound accumulation studies in whole cells have been performed. These accumulation studies support the retrospective studies, but broad conclusions cannot be drawn from these small data sets (10–20 compounds and all within a single structural class). Both the retrospective studies and the accumulation studies have major limitations, and the canonical view about the importance of polarity and molecular weight for Gram-negative activity has not led to general strategies to discover new broad-spectrum antibiotics. With the goal of developing predictive guidelines for compound accumulation in Gram-negative bacteria, here we assess the ability of over 180 diverse compounds to accumulate in Escherichia coli. Most of the compounds were synthesized using the Complexity-to-Diversity method to rapidly obtain a diverse collection of natural product-like compounds. The CtD collection allowed us to be successful where others were not due to unique features of the collection, particularly in that the CtD library has significantly more compounds with contiguous and/or overlapping ring systems than standard commercially available libraries. Structure-activity relationship studies and computational analyses of the accumulation results reveal that small molecules are most likely to accumulate if they contain an amine, are amphiphilic and rigid, and have low globularity. These guidelines were then applied to convert deoxynybomycin, a natural product that is active only against Gram-positive organisms, into an antibiotic with activity against a diverse panel of multi-drug-resistant Gram-negative pathogens. In addition, with the compound collection, assay conditions, and machine learning method in hand, we are performing mechanistic studies to understand how different bacterial components contribute to accumulation, and we are studying accumulation in other Gram-negative pathogens. We anticipate that these findings will aid in the discovery and development of antibiotics against Gram-negative bacteria.
Issue Date:2017-10-04
Type:Text
URI:http://hdl.handle.net/2142/99183
Rights Information:Copyright 2017 Michelle Richter
Date Available in IDEALS:2018-03-13
Date Deposited:2017-12


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