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

Tse‐Dinh, Yuk‐Ching

doi:10.4155/fmc.14.157

Cited by 40 publications

(25 citation statements)

References 88 publications

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“…Trapping of the bacterial topoisomerase I covalent complex on cleaved chromosomal DNA has been shown to result in rapid bacterial cell death, validating this class of enzyme as a useful target for novel bactericidal antibiotics 26, 27 . The structure of MtTOP1-704t reported here provides details of the active site and its vicinity that would be useful for the discovery of poison-type inhibitors for trapping of the topoisomerase covalent intermediate.…”

Section: Discussionmentioning

confidence: 99%

Insights from the Structure of Mycobacterium tuberculosis Topoisomerase I with a Novel Protein Fold

Tan

Cao

Cheng

et al. 2016

Journal of Molecular Biology

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The DNA Topoisomerase I enzyme of Mycobacterium tuberculosis (MtTOP1) is essential for the viability of the organism and survival in a murine model. This topoisomerase is being pursued as a novel target for the discovery of new therapeutic agents for the treatment of drug resistant tuberculosis (TB). In this study, we succeeded in obtaining a structure of MtTOP1 by first predicting that the C-terminal region of MtTOP1 contains four repeated domains that do not involve the Zn-binding tetra-cysteine motifs seen in the C-terminal domains of E. coli topoisomerase I. A construct (a.a. A2-T704), MtTOP1-704t, that includes the N-terminal domains (D1-D4) and the first predicted C-terminal domain (D5) of MtTOP1 was expressed and found to retain DNA cleavage-religation activity and catalyze ssDNA catenation. MtTOP1-704t was crystallized, and a structure of 2.52 Å resolution limit was obtained. The structure of the MtTOP1 N-terminal domains has features that have not been observed in the other previously available bacterial topoisomerase I crystal structures. The first C-terminal domain D5 forms a novel protein fold of a four-stranded antiparallel β-sheet stabilized by a crossing-over α-helix. Since there is only one type IA topoisomerase present in Mycobacteriaceae and related Actinobacteria, this subfamily of type IA topoisomerase may be required for multiple functions in DNA replication, transcription, recombination, and repair. The unique structural features observed for MtTOP1 may allow these topoisomerase I enzymes to carry out physiological functions associated with topoisomerase III enzyme in other bacteria.

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Section: Discussionmentioning

confidence: 99%

Insights from the Structure of Mycobacterium tuberculosis Topoisomerase I with a Novel Protein Fold

Tan

Cao

Cheng

et al. 2016

Journal of Molecular Biology

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“…Clinically, topoisomerase enzymes represent attractive and successful targets for anticancer and antibacterial chemotherapy [4, 5]. In contrast, topoisomerase I is underexplored as antibacterial target, thus potent and selective topoisomerase I inhibitors can serve as a promising class of chemotherapeutic agents toward the treatment of problematic bacterial infections [6, 7]. …”

Section: Introductionmentioning

confidence: 99%

Synthesis, evaluation, and CoMFA study of fluoroquinophenoxazine derivatives as bacterial topoisomerase IA inhibitors

Zhang

Annamalai

et al. 2017

European Journal of Medicinal Chemistry

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New antibacterial agents with novel target and mechanism of action are urgently needed to combat problematic bacterial infections and mounting antibiotic resistances. Topoisomerase IA represents an attractive and underexplored antibacterial target, as such, there is a growing interest in developing selective and potent topoisomerase I inhibitors for antibacterial therapy. Based on our initial biological screening, fluoroquinophenoxazine 1 was discovered as a low micromolar inhibitor against E. coli topoisomerase IA. In the literature, fluoroquinophenoxazine analogs have been investigated as antibacterial and anticancer agents, however, their topoisomerase I inhibition was relatively underexplored and there is little structure-activity relationship (SAR) available. The good topoisomerase I inhibitory activity of 1 and the lack of SAR prompted us to design and synthesize a series of fluoroquinophenoxazine analogs to systematically evaluate the SAR and to probe the structural elements of the fluoroquinophenoxazine core toward topoisomerase I enzyme target recognition. In this study, a series of fluoroquinophenoxazine analogs was designed, synthesized, and evaluated as topoisomerase I inhibitors and antibacterial agents. Target-based assays revealed that the fluoroquinophenoxazine derivatives with 9-NH2 and/or 6-substituted amine functionalities generally exhibited good to excellent inhibitory activities against topoisomerase I with IC50s ranging from 0.24–3.9 µM. Notably, 11a bearing the 6-methylpiperazinyl and 9-amino motifs was identified as one of the most potent topoisomerase I inhibitors (IC50 = 0.48 µM), and showed broad spectrum antibacterial activity (MICs = 0.78–7.6 µM) against all the bacteria strains tested. Compound 11g with the 6-bipiperidinyl lipophilic side chain exhibited the most potent antituberculosis activity (MIC = 2.5 µM, SI = 9.8). In addition, CoMFA analysis was performed to investigate the 3D-QSAR of this class of fluoroquinophenoxazine derivatives. The constructed CoMFA model produced reasonable statistics (q2 = 0.688 and r2 = 0.806). The predictive power of the developed model was obtained using a test set of 7 compounds, giving a predictive correlation coefficient r2pred of 0.767. Collectively, these promising data demonstrated that fluoroquinophenoxazine derivatives have the potential to be developed as a new chemotype of potent topoisomerase IA inhibitors with antibacterial therapeutic potential.

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“…There is at least one type IA topoI in each bacterium and a new class of poison inhibitors can be utilized to target these topoisomerases . It is therefore highly desirable to identify the poison inhibitors for type IA topoI for the development of new antibacterial drugs . Development of such new antibacterial drugs requires investigations of topoIccs.…”

Section: Introductionmentioning

confidence: 99%

Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development

et al. 2020

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A topoisomerase‐DNA transient covalent complex can be a druggable target for novel topoisomerase poison inhibitors that represent a new class of antibacterial or anticancer drugs. Herein, we have investigated molecular features of the functionally important Escherichia coli topoisomerase I (EctopoI)‐DNA covalent complex (EctopoIcc) for molecular simulations, which is very useful in the development of new antibacterial drugs. To demonstrate the usefulness of our approach, we used a model small molecule (SM), NSC76027, obtained from virtual screening. We examined the direct binding of NSC76027 to EctopoI as well as inhibition of EctopoI relaxation activity of this SM via experimental techniques. We then performed molecular dynamics (MD) simulations to investigate the dynamics and stability of EctopoIcc and EctopoI‐NSC76027‐DNA ternary complex. Our simulation results show that NSC76027 forms a stable ternary complex with EctopoIcc. EctopoI investigated here also serves as a model system for investigating a complex of topoisomerase and DNA in which DNA is covalently attached to the protein.

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

Cited by 40 publications

References 88 publications

Insights from the Structure of Mycobacterium tuberculosis Topoisomerase I with a Novel Protein Fold

Insights from the Structure of Mycobacterium tuberculosis Topoisomerase I with a Novel Protein Fold

Synthesis, evaluation, and CoMFA study of fluoroquinophenoxazine derivatives as bacterial topoisomerase IA inhibitors

Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development

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