Presentation Title

Synthesis, Characterization, and Antibiotic Efficacy of Pterin-based Inhibitors of Dihydropteroate Synthase

Faculty Mentor

Edward Njoo

Start Date

23-11-2019 8:00 AM

End Date

23-11-2019 8:45 AM

Location

195

Session

poster 1

Type of Presentation

Poster

Subject Area

interdisciplinary

Abstract

Antibiotic resistance evolution is a rapidly growing problem in pharmaceutical development; in the United States alone, antibiotic-resistant bacterial infections cause an estimated 23,000 deaths annually (Centers for Disease Control and Prevention). A target for further pharmaceutical development is the enzyme Dihydropteroate Synthase (DHPS), which plays a key role in bacterial biosynthesis of folic acid. A class of drugs called sulphonamides, including drugs Sulfamethoxazole and Sulfatrim, bind and act as competitive substrates to p-aminobenzoic acid, but are limited by their numerous side effects on the human body and bacterial resistance mutations that block larger molecules from entering the binding pocket. The evolution of new resistant strains necessitates the continued development of new compounds. Here, we report the design, combinatorial synthesis, and antibacterial properties of a library of novel biaryl small molecules mimicking folic acid to target the pABA and pterin binding pocket. Compounds were first screened in silico via docking to the binding pocket in DHPS. Antibiotic efficacy of these compounds was then tested on four strains of bacteria related to human pathogens through a MIC assay. A folic acid rescue assay and ELISA were utilized to verify the mode of action as acting on DHPS in the biosynthetic pathway. Synthesized compounds were shown to be water-soluble unlike past compounds targeting the pterin pocket, and computational results confirmed high binding affinity of the compounds to the enzyme in silico. These results establish a definitive structure-activity relationship for the compounds studied, and provide a basis for future development of antibiotics targeting DHPS.

This document is currently not available here.

Share

COinS
 
Nov 23rd, 8:00 AM Nov 23rd, 8:45 AM

Synthesis, Characterization, and Antibiotic Efficacy of Pterin-based Inhibitors of Dihydropteroate Synthase

195

Antibiotic resistance evolution is a rapidly growing problem in pharmaceutical development; in the United States alone, antibiotic-resistant bacterial infections cause an estimated 23,000 deaths annually (Centers for Disease Control and Prevention). A target for further pharmaceutical development is the enzyme Dihydropteroate Synthase (DHPS), which plays a key role in bacterial biosynthesis of folic acid. A class of drugs called sulphonamides, including drugs Sulfamethoxazole and Sulfatrim, bind and act as competitive substrates to p-aminobenzoic acid, but are limited by their numerous side effects on the human body and bacterial resistance mutations that block larger molecules from entering the binding pocket. The evolution of new resistant strains necessitates the continued development of new compounds. Here, we report the design, combinatorial synthesis, and antibacterial properties of a library of novel biaryl small molecules mimicking folic acid to target the pABA and pterin binding pocket. Compounds were first screened in silico via docking to the binding pocket in DHPS. Antibiotic efficacy of these compounds was then tested on four strains of bacteria related to human pathogens through a MIC assay. A folic acid rescue assay and ELISA were utilized to verify the mode of action as acting on DHPS in the biosynthetic pathway. Synthesized compounds were shown to be water-soluble unlike past compounds targeting the pterin pocket, and computational results confirmed high binding affinity of the compounds to the enzyme in silico. These results establish a definitive structure-activity relationship for the compounds studied, and provide a basis for future development of antibiotics targeting DHPS.