Rational Design of Berberine-Based FtsZ Inhibitors with Broad-Spectrum Antibacterial Activity

Sun, Ning; Chan, Fung‐Yi; Lu, Yu‐Jing; Neves, Marco A. C.; Lui, Hok-Kiu; Wang, Yong; Chow, Ka-Yan; Chan, Kin‐Fai; Yan, Siu‐Cheong; Leung, Yun Chung; Abagyan, Ruben; Chan, T.C.L.; Wong, Kwok Yin

doi:10.1371/journal.pone.0097514

Cited by 93 publications

(102 citation statements)

References 47 publications

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“…Transmission electron microscopy (TEM) images of Sa -FtsZ with compound 1 , revealed that it significantly reduced the thickness and size of FtsZ polymers, as well as the bundling of FtsZ protofilaments. 55 …”

Section: Ftsz Inhibitorsmentioning

confidence: 99%

Recent advances in the discovery and development of antibacterial agents targeting the cell-division protein FtsZ

Haranahalli

Tong

Ojima

2016

Bioorganic & Medicinal Chemistry

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With the emergence of multidrug-resistant bacterial strains, there is a dire need for new drug targets for antibacterial drug discovery and development. Filamentous temperature sensitive protein Z (FtsZ), is a GTP-dependent prokaryotic cell division protein, sharing less than 10% sequence identity with the eukaryotic cell division protein, tubulin. FtsZ forms a dynamic Z-ring in the middle of the cell, leading to septation and subsequent cell division. Inhibition of the Z-ring blocks cell division, thus making FtsZ a highly attractive target. Various groups have been working on natural products and synthetic small molecules as inhibitors of FtsZ. This review summarizes the recent advances in the development of FtsZ inhibtors, focusing on those in the last 5 years, but also includes significant findings in previous years.

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Section: Ftsz Inhibitorsmentioning

confidence: 99%

Recent advances in the discovery and development of antibacterial agents targeting the cell-division protein FtsZ

Haranahalli

Tong

Ojima

2016

Bioorganic & Medicinal Chemistry

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“…Drug discovery studies that focussed on scaffolds such as naphthalenes, benzimidazoles, and pyrimidopyrazines targeting FtsZ were reasonably successful (Jaiswal et al, 2007). Quinoloines and taxanes were reported to specifically inhibit MtbFtsZ (Sun et al, 2014). Screening of known tubulin inhibitors against M. tuberculosis identified derivatives of pyridopyrazine and pteridine.…”

Section: Introductionmentioning

confidence: 99%

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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“…In addition, several research groups have reported that bacterial cell division process is one of the exciting targets for the development of next-generation antibiotics due to its conserved nature among the prokaryotes. In recent years, many natural compounds, which can perturb the bacterial cell division, have been studied extensively as potential microbial agents ( Jaiswal et al, 2007;Rai et al, 2008;Sun et al, 2014).…”

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confidence: 99%

Proteomics Analyses ofBacillus subtilisafter Treatment with Plumbagin, a Plant-Derived Naphthoquinone

Reddy

Sathe

et al. 2015

OMICS: A Journal of Integrative Biology

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Infectious diseases and increasing antibiotic resistance among diverse classes of microbes are global health concerns and a prime focus of omics systems science applications in novel drug discovery. Plumbagin is a plant-derived naphthoquinone, a natural product that exhibits antibacterial activity against gram-positive bacteria. In the present study, we investigated the antimicrobial effects of plumbagin against Bacillus subtilis using two complementary proteomics techniques: two-dimensional electrophoresis (2-DE) and isobaric tag for relative and absolute quantification (iTRAQ). Comparative quantitative proteomics analysis of plumbagin treated and untreated control samples identified differential expression of 230 proteins (1% FDR, 1.5 fold-change and ‡ 2 peptides) in B. subtilis after plumbagin treatment. Pathway analysis involving the differentially expressed proteins suggested that plumbagin effectively increases heme and protein biosynthesis, whereas fatty acid synthesis was significantly reduced. Gene expression and metabolic activity assays further corroborated the proteomics findings. We anticipate that plumbagin blocks the cell division by altering the membrane permeability required for energy generation. This is the first report, to the best of our knowledge, offering new insights, at proteome level, for the putative mode(s) of action of plumbagin and attendant cellular targets in B. subtilis. The findings also suggest new ways forward for the modern omics-guided drug target discovery, building on traditional plant medicine.

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Rational Design of Berberine-Based FtsZ Inhibitors with Broad-Spectrum Antibacterial Activity

Cited by 93 publications

References 47 publications

Recent advances in the discovery and development of antibacterial agents targeting the cell-division protein FtsZ

Recent advances in the discovery and development of antibacterial agents targeting the cell-division protein FtsZ

Mutation at G103 of MtbFtsZ Altered their Sensitivity to Coumarins

Proteomics Analyses ofBacillus subtilisafter Treatment with Plumbagin, a Plant-Derived Naphthoquinone

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