title: Antimycobacterial activity of DNA intercalator inhibitors of Mycobacterium tuberculosis primase DnaG.
abstract: Owing to the rise in drug resistance in tuberculosis combined with the global spread of its causative pathogen, Mycobacterium tuberculosis (Mtb), innovative anti mycobacterial agents are urgently needed. Recently, we developed a novel primase-pyrophosphatase assay and used it to discover inhibitors of an essential Mtb enzyme, primase DnaG (Mtb DnaG), a promising and unexplored potential target for novel antituberculosis chemotherapeutics. Doxorubicin, an anthracycline antibiotic used as an anticancer drug, was found to be a potent inhibitor of Mtb DnaG. In this study, we investigated both inhibition of Mtb DnaG and the inhibitory activity against in vitro growth of Mtb and M. smegmatis (Msm) by other anthracyclines, daunorubicin and idarubicin, as well as by less cytotoxic DNA intercalators: aloe-emodin, rhein and a mitoxantrone derivative. Generally, low-μM inhibition of Mtb DnaG by the anthracyclines was correlated with their low-μM minimum inhibitory concentrations. Aloe-emodin displayed threefold weaker potency than doxorubicin against Mtb DnaG and similar inhibition of Msm (but not Mtb) in the mid-μM range, whereas rhein (a close analog of aloe-emodin) and a di-glucosylated mitoxantrone derivative did not show significant inhibition of Mtb DnaG or antimycobacterial activity. Taken together, these observations strongly suggest that several clinically used anthracyclines and aloe-emodin target mycobacterial primase, setting the stage for a more extensive exploration of this enzyme as an antibacterial target.
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Chathurada
authors.initials: C
authors.lastname: Gajadeera
authors.affiliation: Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Melisa J
authors.initials: MJ
authors.lastname: Willby
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.affiliation: School of Chemistry, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Pazit
authors.initials: P
authors.lastname: Shaul
authors.affiliation: School of Chemistry, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Micha
authors.initials: M
authors.lastname: Fridman
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
authors.affiliation: Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Posey
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Tsodikov
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D019915:DNA Primase / Q000037:antagonists & inhibitors*; D007364:Intercalating Agents / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development
chemical_list: D000995:Antitubercular Agents; D007364:Intercalating Agents; D019915:DNA Primase