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Dual‐Acting Small‐Molecule Inhibitors Targeting Mycobacterial DNA Replication
Author(s) -
Singh Meenakshi,
Ilic Stefan,
Tam Benjamin,
BenIshay Yesmin,
Sherf Dror,
Pappo Doron,
Akabayov Barak
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202001725
Subject(s) - dna gyrase , primase , mycobacterium tuberculosis , dnag , dna , biology , replisome , dna replication , mycobacterium smegmatis , microbiology and biotechnology , tuberculosis , chemistry , escherichia coli , biochemistry , circular bacterial chromosome , polymerase chain reaction , medicine , reverse transcriptase , gene , pathology
Mycobacterium tuberculosis ( Mtb ) is a pathogenic bacterium and a causative agent of tuberculosis (TB), a disease 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 small‐molecule inhibitors that target two DNA replication enzymes of Mtb , namely DnaG primase and DNA gyrase (Gyr), which share a conserved TOPRIM fold near the inhibitors’ binding site. The molecules were developed on the basis of previously reported inhibitors for T7 DNA primase that bind near the TOPRIM fold. To improve the physicochemical properties of the molecules as well as their inhibitory effect on primase and gyrase, 49 novel compounds have been synthesized as potential drug candidates in three stages of optimization. The last stage of chemical optimization yielded two novel inhibitors for both Mtb DnaG and Gyr that also showed inhibitory activity toward the fast‐growing non‐pathogenic model Mycobacterium smegmatis ( Msmg ).