Antibiotic resistance is growing to dangerously high levels and poses a serious threat to global public health. The emergence and spread of resistance mechanisms to all antibiotics introduced into the clinic jeopardize the effectiveness of current treatments. Traditionally, antibiotics were designed to inhibit bacterial viability or impair their growth, which induce a strong selection pressure for resistance development. A promising approach to control pathogenic bacteria is to disarm their virulence, which potentially delays the emergence of resistance.
In this project, we target the thiol-disulfide oxidoreductase enzyme DsbA which catalyzes disulfide bond formation in the periplasm of Gram-negative bacteria. DsbA facilitates folding of multiple virulent factors and acts as a major facilitator of bacterial virulence. Bacteria lacking a functional DsbA displays reduced virulence, increased sensitivity to antibiotics and diminished capacity to cause infection in many Gram-negative pathogens.
Previously we carried out a drug screening campaign against Escherichia coli DsbA using a library of “fragments” (compound MW<300 Da) and identified the first inhibitors that bind to the catalytic site of DsbA and inhibit DsbA activity in vitro and cell-based assays. By exploiting an array of biophysical/biochemical tools (NMR, SPR, X-ray crystallography and in vitro assays), we are optimising these DsbA inhibitors from fragment hits to high-affinity leads. Herein we report our current efforts in developing DsbA inhibitors that belong to two different chemical classes, the diaryl ether and phenythiazole series. The goal of this work is to develop a new generation of antimicrobials with a novel mode of action that could be used alone or in combination with existing drugs to treat multi-drug resistant infections.