Delving into the Latest Updates on Irresistin-16 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target-

Mechanism-

Therapeutic Areas

Infectious DiseasesUrogenital Diseases

Active Indication-

Inactive Indication

GonorrheaVaginal Diseases

Originator Organization

Princeton University

Active Organization-

Inactive Organization

Princeton University

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

Structure

Molecular FormulaC23H19N5

InChIKeyCKQXMSDRDDHCOR-UHFFFAOYSA-N

CAS Registry2624247-60-3

AbstractPseudomonas aeruginosa is a leading cause of hospital-acquired infections for which the development of antibiotics is urgently needed. Unlike most enteric bacteria, P. aeruginosa lacks enzymes required to scavenge exogenous thymine. An appealing strategy to selectively target P. aeruginosa is to disrupt thymidine synthesis while providing exogenous thymine. However, known antibiotics that perturb thymidine synthesis are largely inactive against P. aeruginosa.Here we characterize fluorofolin, a dihydrofolate reductase (DHFR) inhibitor derived from Irresistin-16, that exhibits significant activity against P. aeruginosa in culture and in a mouse thigh infection model. Fluorofolin is active against a wide range of clinical P. aeruginosa isolates resistant to known antibiotics. Metabolomics and in vitro assays using purified folA confirm that fluorofolin inhibits P. aeruginosa DHFR. Importantly, in the presence of thymine supplementation, fluorofolin activity is selective for P. aeruginosa. Resistance to fluorofolin can emerge through overexpression of the efflux pumps MexCD-OprJ and MexEF-OprN, but these mutants also decrease pathogenesis. Our findings demonstrate how understanding species-specific genetic differences can enable selective targeting of important pathogens while revealing trade-offs between resistance and pathogenesis.

100 Deals associated with Irresistin-16

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