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DNA-Minor Groove as a Molecular Target for the Design of Highly-Effective Anti-Tubercular Agents | SciTechnol

Endocrinology & Diabetes Research.ISSN: 2470-7570

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Short Communication, Endocrinol Diabetes Res Vol: 7 Issue: 7

DNA-Minor Groove as a Molecular Target for the Design of Highly-Effective Anti-Tubercular Agents

  

Abstract

Tuberculosis (TB) is one of the top ten killers worldwide and remains
the leading cause of death among infectious diseases. There is still
a limited number of validated TB targets and it is crucial to identify
novel, or re-purpose existing, molecular targets to generate new
anti-tubercular drugs to fight the tuberculosis pandemic. To this
end, the well-characterised DNA-minor groove might be used to
develop highly-effective anti-tubercular probes with a mechanism
of action, i.e., DNA-binding, different from that of current TB
drugs. DNA-minor groove binding agents can recognise discrete
DNA sequence, modulate the activity of transcription factors and
ultimately cause cell death. Libraries of distamycin analogues
and pyrrolobenzodiazepine(PBD)-C8-polyamide conjugates were
synthesized and screened against slow-growing, pathogenic
Mycobacterium tuberculosis H37Rv and Mycobacterium bovis
BCG strains, and evaluated for DNA-binding activity using DNase
I footprinting experiments. The compounds were also tested using
the in vitro Wayne model of hypoxia-induced dormancy at pH
5.8 and 7.3 to reproduce environments of cellular and caseous
granulomas. The PBD-conjugates possessed significant antitubercular
properties with minimum inhibitory concentration (MIC)
values ranging from 0.04 – 5.19 μg/mL against M. tuberculosis and
M. bovis, although showing some degree of cytotoxicity. H37Rvactive
pyrrole(Py)-pyrrole(Py)-thiazole(Thz)-PBD bound with high
affinity to discrete sequences (6-8 nucleobases) of a DNA duplex
and showed growth inhibitory activity at 5.1 μg/mL against hypoxic,
non-replicating (NR) M. tuberculosis cultures and aerobic cells at
pH 7.3. DNA-minor groove binding agents are remarkable chemical
tools with significant anti-tubercular activity that represent promising
leads against aerobic and NR, dormant M. tuberculosis

Keywords: Endocrinology & Diabetes Research

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