Synthesis and Biological Evaluation of Novel FtsZ‐targeted 3‐arylalkoxy‐2,6‐difluorobenzamides as Potential Antimicrobial Agents

Qiang, Shengsheng; Chang-de, Wang; Venter, Henrietta; Li, Xin; Wang, Yi; Guo, Liwei; Ma, Ruixin; Ma, Shutao

doi:10.1111/cbdd.12658

Cited by 10 publications

(17 citation statements)

References 21 publications

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“…In recent years, a number of small molecule inhibitors of FtsZ have already been revealed to perturb FtsZ polymerization and inhibit bacterial cell division (Bierer et al, 1998; Beuria et al, 2005; Schaffner-Barbero et al, 2012; Li et al, 2015; Haranahalli et al, 2016; Hurley et al, 2016; Qiang et al, 2016; Bi et al, 2017). These studies suggest that the molecules impair bacterial growth through disrupting the dynamic assembly or/and GTP hydrolysis of FtsZ.…”

Section: Introductionmentioning

confidence: 99%

A Thiazole Orange Derivative Targeting the Bacterial Protein FtsZ Shows Potent Antibacterial Activity

Sun

Chan

et al. 2017

Front. Microbiol.

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The prevalence of multidrug resistance among clinically significant bacteria calls for the urgent development of new antibiotics with novel mechanisms of action. In this study, a new small molecule exhibiting excellent inhibition of bacterial cell division with potent antibacterial activity was discovered through cell-based screening. The compound exhibits a broad spectrum of bactericidal activity, including the methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and NDM-1 Escherichia coli. The in vitro and in vivo results suggested that this compound disrupts the dynamic assembly of FtsZ protein and Z-ring formation through stimulating FtsZ polymerization. Moreover, this compound exhibits no activity on mammalian tubulin polymerization and shows low cytotoxicity on mammalian cells. Taken together, these findings could provide a new chemotype for development of antibacterials with FtsZ as the target.

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Section: Introductionmentioning

confidence: 99%

A Thiazole Orange Derivative Targeting the Bacterial Protein FtsZ Shows Potent Antibacterial Activity

Sun

Chan

et al. 2017

Front. Microbiol.

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“…In order to further validate their anti-MRSA Figure 1. Design strategy of the novel 2,6-difluorobenzamide derivatives described previously for compounds MST A9 (1) [23], A12 (2) [23], B8 (3) [24], B9 (4) [24] and C4 (5) [24].…”

Section: Antimicrobial Activity Of Mst Compoundsmentioning

confidence: 99%

“…Previously our group has sought to further probe whether new 2,6-difluorobenzamide derivatives with other non-heterocyclic modifications to the 3-alkyloxy side chain could lead to increased antibacterial activity, broader spectrum of activity and improved on-target potency [23,24]. It was hypothesized that retaining the amide and 2,6-difluoro functions but introducing a series of small hydrophobic side chains such as substituted benzyl, alkyl halides, or a branched alkyl would enhance interactions with the hydrophobic pocket in the interdomain cleft of FtsZ.…”

Section: Introductionmentioning

confidence: 99%

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Antimicrobial Action and Reversal of Resistance in MRSA by Difluorobenzamide Derivatives Targeted at FtsZ

et al. 2020

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The bacterial cell division protein, FtsZ, has been identified as a target for antimicrobial development. Derivatives of 3-methoxybenzamide have shown promising activities as FtsZ inhibitors in Gram-positive bacteria. We sought to characterise the activity of five difluorobenzamide derivatives with non-heterocyclic substituents attached through the 3-oxygen. These compounds exhibited antimicrobial activity against methicillin resistant Staphylococcus aureus (MRSA), with an isopentyloxy-substituted compound showing modest activity against vancomycin resistant Enterococcus faecium (VRE). The compounds were able to reverse resistance to oxacillin in highly resistant clinical MRSA strains at concentrations far below their MICs. Three of the compounds inhibited an Escherichia coli strain lacking the AcrAB components of a drug efflux pump, which suggests the lack of Gram-negative activity can partly be attributed to efflux. The compounds inhibited cell division by targeting S. aureus FtsZ, producing a dose-dependent increase in GTPase rate which increased the rate of FtsZ polymerization and stabilized the FtsZ polymers. These compounds did not affect the polymerization of mammalian tubulin and did not display haemolytic activity or cytotoxicity. These derivatives are therefore promising compounds for further development as antimicrobial agents or as resistance breakers to re-sensitive MRSA to beta-lactam antibiotics.

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“…Today, a number of proteins are considered as promising drug targets for the development of antibiotics to treat staphylococcal infections. After extensive review of the literature for the last three years, the following proteins were considered as potential therapeutic drug targets for the development of antistaphylococcal agents: bacterial enoyl reductase (FabI) [3,4], transglycosylase (TGase) [5,6], sortase A [7][8][9][10][11][12][13], diapophytoene desaturase (CrtN) [14][15][16][17], type II topoisomerase [18][19][20][21], topoisomerase IV [22][23][24][25][26][27], filamentous temperature-sensitive protein Z (FtsZ) [28][29][30], UDP-N-acetylenolpyruvylglucosamine reductase (MurB) [31], lipoteichoic acid synthase (LtaS) [32], biotin protein ligase [33,34], peptide deformylase [35], Ser/Thr protein kinase STK1 [36], pentaerythritol tetranintrate reductase [37], peptide deformylase (PDF) [38,39], NorA efflux pump [40][41][42][43][44]…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of potential membrane-bound molecular drug targets of methicillin-resistant Staphylococcus aureus using in silico approaches

et al. 2019

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Aim. To identify novel putative drug targets of methicillin-resistant S. aureus (MRSA) through subtractive proteome analysis. Methods. Identification of non-homologous proteins in the human proteome, search of MRSA essential genes and evaluation of drug target novelty were performed using a protein BLAST server. Unique metabolic pathways identification was carried out using data and tools from KEGG (Kyoto Encyclopedia of Genes and Genomes). Prediction of sub-cellular proteins localization was performed using combination of PSORT v. 3.0.2, CELLO v. 2.5, iLoc-Gpos, and Pred-Lipo tools. Homology modeling was performed using SWISS-MODEL, Phyre2, I-TASSER web-servers and the MODELLER software. Results. Proteomes of six annotated methicillin-resistant strains : MRSA ATCC BAA-1680, H-EMRSA-15, LA MRSA ST398, MRSA 252, MRSA ST772, UTSW MRSA 55 were initially analyzed. The proteome analysis of the MRSA strains in several consequent steps allowed to identify two molecular targets: diadenylate cyclase and D-alanyl-lipoteichoic acid biosynthesis (DltB) protein which meet the requirements of being essential, membrane-bound, non-homologous to human proteome, involved in unique metabolic pathways and new in terms of not having approved drugs. Using the homology modeling approach, we have built three-dimensional structures of these proteins and predicted their ligand-binding sites. Conclusions. We used classical bioinformatics approaches to identify two molecular targets of MRSA :diadenylate cyclase and DltB which can be used for further rational drug design in order to find novel therapeutic agents for treatment of multidrug resistant staphylococcal infection. K e y w o r d s: molecular drug targets; methicillin-resistant Staphylococcus aureus; MRSA; subtractive proteome analysis.

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Synthesis and Biological Evaluation of Novel FtsZ‐targeted 3‐arylalkoxy‐2,6‐difluorobenzamides as Potential Antimicrobial Agents

Cited by 10 publications

References 21 publications

A Thiazole Orange Derivative Targeting the Bacterial Protein FtsZ Shows Potent Antibacterial Activity

A Thiazole Orange Derivative Targeting the Bacterial Protein FtsZ Shows Potent Antibacterial Activity

Antimicrobial Action and Reversal of Resistance in MRSA by Difluorobenzamide Derivatives Targeted at FtsZ

Identification and characterization of potential membrane-bound molecular drug targets of methicillin-resistant Staphylococcus aureus using in silico approaches

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