Old class but new dimethoxy analogue of benzimidazole: a bacterial topoisomerase I inhibitor

Bansal, Sandhya; Tawar, Urmila; Singh, Manish Kumar; Nikravesh, Abbas; Good, Liam; Tandon, Vibha

doi:10.1016/j.ijantimicag.2009.07.018

Cited by 20 publications

(15 citation statements)

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“…12 The MIC 50 value of DMA was 8 mM and a PAE of .24 h was obtained for E. coli K-12. 12 These results have driven us to undertake a detailed systematic study of bis-benzimidazole ligands as antibacterial agents (Table 1). The lowest MIC 50 value of DMA determined for clinical strains of E. coli was 3.74 mg/L (8 mM).…”

Section: Effect Of Bis-benzimidazoles On Growth Of E Colimentioning

confidence: 96%

“…10 - 12 Recently, we have evaluated a new bisbenzimidazole, 2-(3,4-dimethoxyphenyl)-5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2yl]-1H-benzimidazole (DMA), a synthetic analogue of Hoechst 33342, which is less cytotoxic and does not affect cell viability in mammalian cells up to a concentration of 100 mM, but inhibits growth of E. coli cultures even at a concentration of 2 mM when grown in co-culture with human cells. 13 We have synthesized several analogues of Hoechst 33342 with dichloro {DCA, 2-(2,4-dichlorophenyl)-5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-benzimidazole} and difluoro {DFA, 2-(2,4-difluorophenyl)-5-[5-(4-methylpiperazinyl)-1H-benzimidazol-2-yl]-1H-benzimidazole} substitutions on the phenyl ring and evaluated their activity against HuTOPI (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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3,4-Dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I

Bansal¹,

Sinha²,

Singh³

et al. 2012

Journal of Antimicrobial Chemotherapy

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Objectives: Antibiotic resistance in bacterial pathogens is a serious clinical problem. Novel targets are needed to combat increasing drug resistance in Escherichia coli. Our objective is to demonstrate that 2-(3,4-dimethoxyphenyl)-5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2yl]-1H-benzimidazole (DMA) inhibits E. coli DNA topoisomerase I more strongly than human topoisomerase I. In addition, DMA is non-toxic to mammalian cells at antibiotic dosage level. Methods:In the present study, we have established DMA as an antibacterial compound by determining MICs, post-antibiotic effects (PAEs) and MBCs for different standard as well as clinical strains of E. coli. We have described the differential catalytic inhibitory mechanism of bis-benzimidazole, DMA, for human and E. coli topoisomerase I and topoisomerase II by performing different assays, including relaxation assays, cleavage -religation assays, DNA unwinding assays, ethidium bromide displacement assays, decatenation assays and DNA gyrase supercoiling assays.Results: DMA significantly inhibited bacterial growth at a very low concentration, but did not affect human cell viability at higher concentrations. Activity assays showed that it preferentially targeted E. coli topoisomerase I over human topoisomerase I, topoisomerase II and gyrase. Cleavage-religation assays confirmed DMA as a poison inhibitor of E. coli topoisomerase I. This study illuminates new properties of DMA, which may be further modified to develop an efficient topoisomerase inhibitor that is selective towards bacterial topoisomerase I.Conclusions: This is the first report of a bis-benzimidazole acting as an E. coli topoisomerase I inhibitor. DMA is a safe, non-cytotoxic molecule to human cells at concentrations that are needed for antibacterial activity.

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Section: Effect Of Bis-benzimidazoles On Growth Of E Colimentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

3,4-Dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I

Bansal¹,

Sinha²,

Singh³

et al. 2012

Journal of Antimicrobial Chemotherapy

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“…There was evidence that DMA can act as a poison inhibitor for E. coli topoisomerase I, increasing the level of DNA cleavage products [70]. DMA was effective for growth inhibition of clinical isolates of E. coli , with no apparent cytotoxic effect on mammalian cells [70,71]. The antibacterial activity of DMA increased slightly when E. coli topoisomerase I is overexpressed, consistent with cell killing initiated by trapping of the topoisomerase I covalent complex [70].…”

Section: Newly Identified Bacterial Topoisomerase I Inhibitorsmentioning

confidence: 99%

“…New bisbenzimidazole analogues of these Hoechst dyes that can selectively target bacterial DNA topoisomerase I over human topoisomerases have been synthesized and characterized [70–73]. 3,4-Dimethoxyphenyl bisbenzimidazole [70,71] (DMA, Compound 5 in Figure 3) as well as DPA 153 [72] with a terminal alkyne substitution (Compound 6 in Figure 3) represent independently discovered bisbenzimidazole analogues that inhibit E. coli topoisomerase I much more strongly than E. coli DNA gyrase, human topoisomerase I and human topoisomerase IIα. The IC 50 for E. coli topoisomerase I inhibition by DMA was found to be 3.8 μM [70], very similar to the IC 50 value of 2.5 μM for DPA 153 [72].…”

Section: Newly Identified Bacterial Topoisomerase I Inhibitorsmentioning

confidence: 99%

Targeting Bacterial Topoisomerase I to Meet the Challenge of Finding New Antibiotics

Tse‐Dinh

2015

Future Med. Chem.

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Resistance of bacterial pathogens to current antibiotics has grown to be an urgent crisis. Approaches to overcome this challenge include identification of novel targets for discovery of new antibiotics. Bacterial topoisomerase I is present in all bacterial pathogens as a potential target for bactericidal topoisomerase poison inhibitors. Recent efforts have identified inhibitors of bacterial topoisomerase I with antibacterial activity. Additional research on the mode of action and binding site of these inhibitors would provide further validation of the target and establish that bacterial topoisomerase I is druggable. Bacterial topoisomerase I is a potentially high value target for discovery of new antibiotics. Demonstration of topoisomerase I as the cellular target of an antibacterial compound would provide proof-of-concept validation.

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“…Bacterial DNA gyrase and topoisomerase IV are both targeted by antibiotic classes, for example, (fluoro)quinolones and aminocoumarins, effective against bacteria at low minimal inhibitory concentrations . It is also noteworthy that recent studies have shown the potential of bacterial topoisomerase IA as an attractive target for developing new antibiotics …”

Section: Introductionmentioning

confidence: 99%

Topoisomerases: Resistance versus Sensitivity, How Far We Can Go?

Bansal

Bajaj

Pandey

et al. 2016

Medicinal Research Reviews

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DNA topoisomerases are ubiquitously present remarkable molecular machines that help in altering topology of DNA in living cells. The crucial role played by these nucleases during DNA replication, transcription, and recombination vis-à-vis less sequence similarity among different species makes topoisomerases unique and attractive targets for different anticancer and antibacterial drugs. However, druggability of topoisomerases by the existing class of molecules is increasingly becoming questationable due to resistance development predominated by mutations in the corresponding genes. The current scenario facing a decline in the development of new molecules further comprises an important factor that may challenge topoisomerase-targeting therapy. Thus, it is imperative to wisely use the existing inhibitors lest with this rapid rate of losing grip over the target we may not go too far. Furthermore, it is important not only to design new molecules but also to develop new approaches that may avoid obstacles in therapies due to multiple resistance mechanisms. This review provides a succinct account of different classes of topoisomerase inhibitors, focuses on resistance acquired by mutations in topoisomerases, and discusses the various approaches to increase the efficacy of topoisomerase inhibitors. In a later section, we also suggest the possibility of using bisbenzimidazoles along with efflux pump inhibitors for synergistic bactericidal effects.

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Old class but new dimethoxy analogue of benzimidazole: a bacterial topoisomerase I inhibitor

Cited by 20 publications

References 10 publications

3,4-Dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I

3,4-Dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I

Targeting Bacterial Topoisomerase I to Meet the Challenge of Finding New Antibiotics

Topoisomerases: Resistance versus Sensitivity, How Far We Can Go?

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