Hlaka, Lerato, Rosslee, Michael-Jon, Ozturk, Mumin, Kumar, Santosh, Parihar, Suraj P., Brombacher, Frank, Khalaf, Abedawn I., Carter, Katharine C., Scott, Fraser J., Suckling, Colin J. and Guler, Reto (2017) Evaluation of Minor Groove Binders (MGBs) as novel anti-mycobacterial agents, and the effect of using non-ionic surfactant vesicles as a delivery system to improve their efficacy. Journal of Antimicrobial Chemotherapy. ISSN 0305-7453

Objectives: The slow development of major advances in drug discovery for the treatment of
Mycobacterium tuberculosis (Mtb) infection have led to a compelling need for evaluation of
more effective drug therapies against tuberculosis. New classes of drugs are constantly being evaluated for anti-mycobacterial activity with currently a very limited number of new drugs approved for TB treatment. Minor Groove Binders (MGBs) have previously revealed promising anti-microbial activity against various infectious agents; however have not yet been screened against Mtb.
Methods: Mycobactericidal activity of MGB compounds against Mtb was determined using H37Rv-GFP microplate assay. MGB hits were screened for their intracellular mycobactericidal efficacy against clinical Beijing Mtb strain HN878 in bone marrow-derived
macrophages using standard colony-forming unit counting. Cell viability was assessed by
CellTiter-Blue assays. Selected MGB were encapsulated into non-ionic surfactant vesicles
(NIVs) for drug delivery system evaluation.
Results: H37Rv-GFP screening yielded a hitlist of 7 compounds at an MIC99 between 0.39
and 1.56 μM. MGB-362 and MGB-364 displayed intracellular mycobactericidal activity
against Mtb HN878 at MIC50 of 4.09 μM and 4.19 μM respectively, whilst being non-toxic.
Subsequent encapsulation into NIVs demonstrated a 1.6 and 2.1-fold increased intracellular
mycobacterial activity, similar to that of rifampicin when compared to MGB alone formulation
Conclusions: MGBs anti-mycobacterial activities together with non-toxic properties indicate
that MGB compounds constitute an important new class of drug/chemical entity, which holds
promise in future anti-TB therapy. Furthermore, NIVs ability to better deliver entrapped MGB
compounds to an intracellular Mtb infection has provided merit for further preclinical

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