Abstract
Mycobacterium tuberculosis is one of most pathogenic microorganisms in the world. Previously, the bifunctional enzyme GlmU with glucosamine-1-phosphate acetyltransferase activity and N-acetylglucosamine-1-phosphate uridyltransferase activity has been suggested as a potential drug target; therefore, discovering compounds targeting GlmU acetyltransferase is necessary. The natural products were tested for inhibition of GlmU acetyltransferase activity. We found that dicumarol exhibited inhibitory effects on GlmU acetyltransferase, with a concentration achieving a 50% inhibition (IC50) value of 4.608 μg/ml (13.7 μM). The inhibition kinetics indicated that dicumarol uncompetitively inhibited acetyl CoA and showed mixed-type inhibition for glucosamine-1-phosphate (GlcN-1-P). The activity of dicumarol against M. tuberculosis H37Ra was evaluated with a minimum inhibitory concentration (MIC) value of 6.25 μg/ml (18.55 μM) in the Alamar blue assay. Dicumarol also exhibited inhibitory effects on several clinically sensitive M. tuberculosis strains and drug-resistant strains, with a range of MIC value of 6.25 to >100 μg/ml. Dicumarol increased the sensitivity of anti-tuberculosis drugs (isoniazid and rifampicin) when dicumarol was present at a low concentration. The transcriptome and proteome data of M. tuberculosis H37Ra treated by dicumarol showed that the affected genes were associated with cell wall synthesis, DNA damage and repair, metabolic processes, and signal transduction. These results provided the mechanism of dicumarol inhibition against GlmU acetyltransferase and M. tuberculosis and also suggested that dicumarol is a potential candidate for TB treatment.
Highlights
Natural products have a long history of use in the treatment of different diseases in China
We attempted to screen inhibitors of M. tuberculosis GlmU acetyltransferase from the compounds isolated from E. fischeriana and other herbs using a colorimetric assay for GlmU acetyltransferase, which was established in our laboratory (Zhou et al, 2011)
The natural compounds were tested for inhibition of M. tuberculosis GlmU acetyltransferase activity using the 5,5 -dithiobis-(2-nitrobenzoic acid) (DTNB) colorimetric assay
Summary
Natural products have a long history of use in the treatment of different diseases in China. Scientists working with herbs have isolated and identified many active components, which can explain many of their claimed therapeutic effects. An important source of medicines, have been reported to possess anti-Mycobacterium tuberculosis activity (Cragg et al, 1997; Newton et al, 2000; Bunalema et al, 2017) due to their potential bioavailability and biopermeability (Copp and Pearce, 2007; Dashti et al, 2014; Jyoti et al, 2015; Mehra et al, 2016). Inhibition of Dicumarol on GlmU for the treatment of pulmonary tuberculosis. We have not identified compounds from E. fischeriana targeting M. tuberculosis GlmU so far
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