Multidrug resistance (MDR) among various pathogenic microbes is emerging as a serious concern and has led to the ineffectiveness of several antibiotics. Thus, novel antimicrobial drugs with a distinct mechanism of action are needed urgently. In this context, 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), is a key metalloenzyme that has been found to be essential for the survival of many pathogenic bacteria including <i>Mycobacterium tuberculosis</i> and <i>Plasmodium falciparum</i>. Existing DXR inhibitors, such as Fosmidomycin, possess high polarity resulting in limited cellular uptake. In addition, the presence of hydroxamate as a metal-binding group (MBG) results in the generation of toxic metabolites. To overcome these challenges, we designed hydrophobic DXR inhibitors based on non-hydroxamate MBGs. Since dioxygen moiety forms an important motif for metal chelation, several lipophilic fragments containing such functionalities were selected as potential MBGs. Molecular docking studies of a few fragments with DXR exhibited necessary metal chelation with the metal ion in the active site. Some of these fragments demonstrated significant DXR inhibition at 100 μM and therefore serve as the useful starting point for the design of lipophilic non-hydroxamate DXR inhibitors.

Towards the design of non-hydroxamate lipophilic DXR inhibitors as potential antimicrobials

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.