RT Journal Article
SR Electronic
T1 Dual acting small-Molecule inhibitors targeting Mycobacterial DNA replication
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 561506
DO 10.1101/561506
A1 Meenakshi Singh
A1 Stefan Ilic
A1 Benjamin Tam
A1 Yasmin Ben-Ishay
A1 Doron Pappo
A1 Barak Akabayov
YR 2020
UL http://biorxiv.org/content/early/2020/02/03/561506.abstract
AB Mycobacterium Tuberculosis (Mtb) is a pathogenic bacterium and a causative agent of tuberculosis (TB) that kills more than 1.5 million people worldwide annually. One of the main reasons for this high mortality rate is the evolution of new Mtb strains that are resistant to available antibiotics. Therefore, new therapeutics for TB are in constant demand. Here we report the development of such inhibitors that target two DNA replication enzymes of Mtb, namely DnaG primase and DNA gyrase, which share a conserved TOPRIM fold near the inhibitors’ binding site. The molecules were developed on the basis of inhibitors for T7 primase that bind to the TOPRIM fold. In order to improve the physicochemical properties of the molecules and inhibition of these two enzymes, 49 novel compounds were synthesized as potential drug candidates in three stages of optimization. The last stage of chemical optimization yielded two novel inhibitors for the fast-growing nonpathogenic model Mycobacterium smegmatis (Msmg).