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Title:The influence of positively charged nitrogen species on compound accumulation and activity in gram-negative bacteria
Author(s):Perlmutter, Sarah Jacqueline
Director of Research:Hergenrother, Paul J
Doctoral Committee Chair(s):Hergenrother, Paul J
Doctoral Committee Member(s):Chan, Jerrerson; van der Donk, Wilfred A; White, M Christina
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Gram-negative accumulation
antibiotic drug design
Abstract:Multidrug resistant Gram-negative bacterial infections are on the rise, and with no FDA approvals for new classes of broad-spectrum antibiotics in over 50 years, these infections constitute a major threat to human health. A significant challenge is the inability of most compounds to accumulate in Gram-negative bacteria. Recently developed predictive guidelines called the eNTRy rules show that appending a primary amine to an appropriately shaped compound can enhance Gram-negative accumulation and antibacterial activity. However, in certain cases addition of a primary amine resulted in the disruption of target engagement. Therefore, it would be advantageous to have alternate functional groups that facilitate accumulation in Gram-negative bacteria but offer different interactions with a given target protein. Here we report that other positively charged nitrogen functional groups, namely N-alkyl guanidiniums and pyridiniums, can also facilitate compound uptake into Gram-negative bacteria. Accumulation of a set of 60 non-antibiotic compounds, consisting of 20 primary amines derived from the Complexity-to-Diversity strategy and their corresponding guanidiniums and pyridiniums, was assessed in Escherichia coli. We also installed these alternate functional groups onto six antibiotic scaffolds and assessed their accumulation and antibacterial activity in Gram-negative bacteria. In addition, computational studies were performed to predict whether additional charged functional groups will be able to facilitate Gram-negative uptake. The results suggest that other positively charged, nitrogen-containing functional groups should be considered when designing antibiotics with Gram-negative activity. Finally, retrospective analysis of commercial screening libraries showed a lack of compounds containing primary amines. This is likely a major reason for the failures within the pharmaceutical industry to find lead compounds with whole cell activity from high throughput screening campaigns. Here strategies for addressing this problem through efficient amine installation strategies are discussed and applied to compounds from the CtD collection and their antimicrobial activity assessed.
Issue Date:2020-11-25
Rights Information:Copyright 2020 Sarah Perlmutter
Date Available in IDEALS:2021-03-05
Date Deposited:2020-12

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