Reversion of antibiotic resistance in by spiroisoxazoline SMARt-420.

Science 2017 Mar 16;355(6330):1206-1211. Epub 2017 Mar 16.

Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France.

Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. We have developed drug-like molecules that activate a cryptic alternative bioactivation pathway of ethionamide in , circumventing the classic activation pathway in which resistance mutations have now been observed. The first-of-its-kind molecule, named SMARt-420 (Small Molecule Aborting Resistance), not only fully reverses ethionamide-acquired resistance and clears ethionamide-resistant infection in mice, it also increases the basal sensitivity of bacteria to ethionamide.

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.aag1006DOI Listing
March 2017
41 Reads

Publication Analysis

Top Keywords

antibiotic resistance
8
resistance
6
circumventing classic
4
ethionamide circumventing
4
classic activation
4
bioactivation pathway
4
pathway ethionamide
4
pathway resistance
4
mutations observed
4
resistance mutations
4
alternative bioactivation
4
activation pathway
4
activate cryptic
4
pathway required
4
enzymatic pathway
4
bacterial enzymatic
4
mutations bacterial
4
required bioactivation
4
bioactivation developed
4
observed first-of-its-kind
4

References

(Supplied by CrossRef)

Similar Publications