Antibiotics

Biology

Gene

Topoisomerase

Efflux

Multiple drug resistance

Biochemistry

Pharmacology

Topoisomerase IV

Escherichia coli

DNA gyrase

Chemistry

Topoisomerase inhibitor

Microbiology

Journal of Medicinal Chemistry

The rise of multidrug resistant (MDR) Gram-negative (GN) pathogens and the decline of available antibiotics that can effectively treat these severe infections are a major threat to modern medicine. Developing novel antibiotics against MDR GN pathogens is particularly difficult as compounds have to permeate the GN double membrane, which has very different physicochemical properties, and have to circumvent a plethora of resistance mechanisms such as multiple efflux pumps and target modifications. The bacterial type II topoisomerases DNA gyrase (GyrA2B2) and Topoisomerase IV (ParC2E2) are highly conserved targets across all bacterial species and validated in the clinic by the fluoroquinolones. Dual inhibitors targeting the ATPase domains (GyrB/ParE) of type II topoisomerases can overcome target-based fluoroquinolone resistance. However, few ATPase inhibitors are active against GN pathogens. In this study, we demonstrated a successful strategy to convert a 2-carboxamide substituted azaindole chemical scaffold wit...

Discovery of Pyrido[2,3-<i>b</i>]indole Derivatives with Gram-Negative Activity Targeting Both DNA Gyrase and Topoisomerase IV

Discovery of Pyrido[2,3-b]indole Derivatives with Gram-Negative Activity Targeting Both DNA Gyrase and Topoisomerase IV