Development of Cleavable Antibiotic-Adjuvant Hybrid Compounds for Increased Accumulation in Gram-Negative Bacteria

Bryce Pugh

Chemistry/Biochemistry

Amanda Wolfe

For decades antibiotics have been synthesized and modified as we try to evade their inevitable loss of efficacy due to the increasingly severe health crisis of antibiotic resistance. Developing new methods of overcoming resistance mechanisms in bacteria is an essential approach to combatting this crisis. Gram-negative bacteria are specifically difficult to treat, one reason being that they contain a negatively charged lipopolysaccharide outer membrane (OM),. The OM has low permeability and often prevents antibiotics from accumulating within the bacteria. This research uses a novel approach with adjuvants and cleavable linkers to allow for selective release of unaltered antibiotics while improving accumulation. Here, we describe the synthesis and evaluation of a series of antibiotic-adjuvant hybrid compounds for their ability to act as antibiotics against wild-type Escherichia coli (EC), and Pseudomonas aeruginosa (PA),. Previous work in the Wolfe lab has generated a series of novel adjuvants capable of potentiating various antibiotics in wild-type EC and PA and will be used for the hybrid synthesis. The hybrids are being synthesized using a cleavable carbamate or urea linker which will be cleaved via esterase hydrolysis in the periplasm. Upon synthesis, the antibiotic-adjuvant hybrid compounds will be evaluated in vitro using a variety of assays including cell death and accumulation assays. The findings of this research are expected to lead to a lower dosage of antibiotics needed to achieve the same level of cell death, renewed activity among antibiotics facing resistance, and progress towards a novel method of antibiotic development.

Jan-9-2024