Title:
Synthesis and Evaluation of Guanidinium-Based Antibiotic-Adjuvant Hybrids and Their Anitbiotic Properties
Author(s):
Kyle Handy
Author Email:
khandy@unca.edu
Department:
CHEMISTRY & BIOCHEMISTRY
Faculty Mentor(s):
Amanda Wolfe
Abstract / Summary:
Antibiotic resistance is becoming an increasing threat to our livelihood, and the CDC estimated in its 2019 annual threat report that by 2050, there will be over 10 million deaths due to antibiotic-resistant bacteria. Novel antibiotics effective against Gram-positive (G+) bacteria are not effective against Gram-negative (G-) bacteria due to their additional outer membrane (OM). Research done by Hergenrother et. al. proved that adding nitrogenous groups to antibiotics that are effective against G+ bacteria increased their accumulation in G- bacteria. From this data, they developed the rules of eNTRy, which outline the requirements for a small molecule to penetrate the OM of a G- cell. Previous research has shown that addition of guanidinium functionality to novel antibiotics effective against G+ bacteria increase their effectiveness against G- bacteria by allowing them to penetrate the OM. For this research, we synthesized a phenyl-guanidine base adjuvant and explored linking conditions in two synthetic routes to synthesize antibiotic-adjuvant hybrids bonded together by a carbonyl-based cleavable linker molecule, all following the aforementioned rules of eNTRy. The adjuvant was successfully linked to ampicillin, sulfadiazine, and trimethoprim in synthetic route 1 with low conversion rates determined by mass spectroscopy. Successful linkage was also observed with sulfadiazine and sulfamethoxazole in synthetic route 2, with high conversion rates and lower yields calculated by mass. Future work will involve testing more combinations of antibiotics and carbonyl linkers with the developed phenyl-guanidine molecule, as well as increasing yields in both routes and testing them against pathogenic bacteria to study inhibitory effects.
Publication Date:
May-14-2024
Documents: