Publication in: Spring 2023 Issue

Synthesis of antibiotic/ guanidine adjuvant hybrids capable of crossing the outer membrane of Gram-negative bacteria
Dhruvi Parmar
Faculty Mentor(s):
Amanda Wolfe
Abstract / Summary:
The rise of multidrug antibiotic resistance (MDR), has been a prevalent issue since the 1980s with over 2.8 million infections per year in the US alone. Additionally, there has been a steady decline in the production of new antibiotics leading to the need for novel approaches to overcome MDR. Gram-negative bacteria, such as Pseudomonas aeruginosa (PA),, and Escherichia coli (EC),, have displayed an increasing resistance to existing antibiotics due to their additional outer membrane (OM), and numerous efflux pumps preventing accumulation inside the cell. A way to overcome this resistance is by using adjuvants capable of permeating the OM. Adjuvants designed to be capable of permeating through the OM have proven useful in potentiating antibiotics against Gram-negative bacteria such as PA. Previous studies have designed adjuvants to increase accumulation of antibiotics in EC with nitrogenous groups like guanidinium. This work evaluates the use of 1-(4-(hydroxymethyl),phenyl), guanidine for cleavable inert adjuvant/antibiotic hybrids to improve the antibiotic activity of antibiotics such as ampicillin, trimethoprim, and sulfamethoxazole against EC and PA. These hybrids create carbamate or carbonate groups that are enzymatically cleaved in the periplasm by promiscuous carboxylesterases to release the antibiotic. Future work is focused on altering the conditions for linkage to increase the yield of product. Current and future hybrids are tested via cell death, accumulation, and periplasmic cleavage assays using EC and PA.
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