FtsZ inhibition and redox modulation with one chemical scaffold: Potential use of dihydroquinolines against mycobacteria

Duggirala, Sridevi; Napoleon, John Victor; Nankar, Rakesh P.; Adeeba, V. Senu; Manheri, Muraleedharan K.; Doble, Mukesh

doi:10.1016/j.ejmech.2016.07.058

Cited by 16 publications

(8 citation statements)

References 59 publications

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“…Protein was expressed in E. coli BL21 (DE3) Rosetta cells. MtbFtsZ is a soluble protein and it was expressed by induction of IPTG, and purified by Ni-NTA column chromatography (Chen et al, 2007; Duggirala et al, 2016). The protein was analyzed on SDS-PAGE and its purity was determined to be >95%.…”

Section: Methodsmentioning

confidence: 99%

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Mutation at G103 of MtbFtsZ Altered their Sensitivity to Coumarins

et al. 2017

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Coumarins are natural polyphenol lactones comprising of fused rings of benzene and α-pyrone. The current study demonstrates the inhibitory effect of coumarins with various substitutions on Mycobacterium smegmatis mc2 155. We also demonstrate the effect of pomegranate (Punica granatum) extract containing ellagic acid, on M. smegmatis as well as their affect on MtbFtsZ (FtsZ from Mycobacterium tuberculosis). The ellagic acid extracts from pomegranate peels inhibit mycobacteria with a MIC of 25 μM and 0.3 to 3.5 mg/mL, respectively, but failed to inhibit the polymerization of MtbFtsZ. However, the coumarins were shown to inhibit the polymerization and GTPase activity of the protein as well as have an inhibitory affect on M. smegmatis mc2 155. Docking of the most active coumarin (7-Dimethyl-4-methyl coumarin with MIC of 38.7 μM) to the GTP binding site suggests that it interacted with the G103 residue. Based on the docking results two mutants of varying activity (G103S and G103A) were constructed to elucidate the interaction of MtbFtsZ and coumarins. Mutation of G103 with Serine (a bulky group) results in an inactive mutant and substitution with alanine produces a variant that retains most of the activity of the wild type. There is a disruption of the protofilament formation of the MtbFtsZ upon interaction with coumarins as demonstrated by TEM. The coumarins increase the length of Mycobacteria five times and MtbFtsZ localization is disturbed. The mutant proteins altered the GTPase and polymerization activity of coumarins as compared to wild type protein. The results here support that coumarins inhibit proliferation of Mycobacteria by targeting the assembly of MtbFtsZ and provide the possible binding site of coumarins on MtbFtsZ. This study may aid in the design of natural products as anti-mycobacterial agents. The currently reported GTP analogs for FtsZ are toxic to the human cell lines; natural coumarins targeting the GTP binding site of MtbFtsZ may hold promise as an important drug lead for tuberculosis treatment.

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Section: Methodsmentioning

confidence: 99%

“…They inhibit Mycobacteria by targeting the MtbFtsZ protein (Mathew et al, 2011). Recently we reported the role of dihydroquinolines in inhibiting Mycobacteria by targeting MtbFtsZ (Duggirala et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Mutation at G103 of MtbFtsZ Altered their Sensitivity to Coumarins

et al. 2017

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“…Hence, in vitro assays were further performed to visualize the effect of the compounds on Mtb FtsZ protein. [ ]…”

Section: Resultsmentioning

confidence: 99%

“…The inhibitory effect of the compounds directly on the Mtb FtsZ protein was studied by analysing the GTP hydrolysing capacity of the protein in the presence and absence of the compounds. [ ] Mtb FtsZ was incubated with 100 μM of the compounds and free inorganic phosphate was measured using BIOMOL green assay and the results were represented as percentage inhibition by comparing the GTPase activity of the protein in the presence of the inhibitor with that of the control (absence of inhibitor) and were listed in Table .…”

Section: Resultsmentioning

confidence: 99%

An efficient and facile green synthesis of bisindole methanes as potential Mtb FtsZ inhibitors

et al. 2018

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The rising multidrug-resistant Mycobacterium tuberculosis (Mtb) strain made current anti-TB drug therapy ineffective and became a major health concern globally; hence it is crucial to develop new molecules against vital targets with a novel mechanism. Mtb Filamenting temperature sensitive protein Z (FtsZ), a tubulin homolog plays a major role in bacterial cell division, in the presence of GTP recruiting essential proteins for cell division and considered to be a potential target for drug discovery. Most of MtbFtsZ inhibitors known are of antibiotics from natural resources and suffer from cellular uptake, specificity. In the present study, we demonstrated for the first time bisindole derivatives as potential MtbFtsZ inhibitors. The synthesis of bisindole derivatives has been carried out using green synthetic approach by applying ammonium molybdate as a catalyst under Ultrasonic condition. Among the synthesized bisindole derivative, I16 and I5 showed 62.29% and 56.86% inhibition of GTPase activity of MtbFtsZ and increased the length of Mycobacterium smegmatis and Bacillus subtilis by two folds. Further compound I16 inhibited Mtb growth with a MIC of 37.5 μg/ml. To explain these interactions, detailed Molecular docking studies have been carried out and found to be supportive to the biological activity.

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“…The development of novel therapeutic agents against Mycobacterium tuberculosis that interfere with its cytokinesis process has also caught the attention of research groups around the world. Taking anti-tubercular drug bedaquiline (Figure 7, (37)) as a lead, Duggirala and co-workers reported the synthesis and biological evaluation against mycobacteria of a collection of 1,2-dihydroquinolines [59]. The most promising compounds, i.e., 38 and 39 (Figure 7), were able to inhibit the growth of Mycobacterium smegmatis with MICs ranging from 2.58-22.30 µM (Table 5).…”

Section: Dihydroquinolinesmentioning

confidence: 99%

Recent Progress in the Development of Small-Molecule FtsZ Inhibitors as Chemical Tools for the Development of Novel Antibiotics

Carro

2019

Antibiotics

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Antibiotics are potent pharmacological weapons against bacterial pathogens, nevertheless their efficacy is becoming compromised due to the worldwide emergence and spread of multidrug-resistant bacteria or “superbugs”. Antibiotic resistance is rising to such dangerous levels that the treatment of bacterial infections is becoming a clinical challenge. Therefore, urgent action is needed to develop new generations of antibiotics that will help tackle this increasing and serious public health problem. Due to its essential role in bacterial cell division, the tubulin-like protein FtsZ has emerged as a promising target for the development of novel antibiotics with new mechanisms of action. This review highlights the medicinal chemistry efforts towards the identification of small-molecule FtsZ inhibitors with antibacterial activity in the last three years.

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FtsZ inhibition and redox modulation with one chemical scaffold: Potential use of dihydroquinolines against mycobacteria

Cited by 16 publications

References 59 publications

Mutation at G103 of MtbFtsZ Altered their Sensitivity to Coumarins

Mutation at G103 of MtbFtsZ Altered their Sensitivity to Coumarins

An efficient and facile green synthesis of bisindole methanes as potential Mtb FtsZ inhibitors

Recent Progress in the Development of Small-Molecule FtsZ Inhibitors as Chemical Tools for the Development of Novel Antibiotics

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