Targeting Bacterial Topoisomerases: How to Counter Mechanisms of Resistance

Tse‐Dinh, Yuk‐Ching

doi:10.4155/fmc-2016-0042

Cited by 39 publications

(26 citation statements)

References 108 publications

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“…However, they act through the formation of a covalent enzyme-DNA reaction intermediate, which is a potentially toxic lesion itself when stabilized. Indeed, targeting topoisomerase-DNA complexes has been widely explored in the identification and development of antibacterial and anticancer agents [67, 68]. These agents are known as “poison” inhibitors to indicate a mechanism of trapping topoisomerase and consequently forming a covalent enzyme-DNA complex, rather than a classic enzymatic inhibition mechanism, which would signify the lack of DNA binding or cleavage activity by the enzyme [69].…”

Section: Diphenyl Ditelluride Mechanisms Of Antiproliferative Actimentioning

confidence: 99%

Diphenyl Ditelluride: Redox-Modulating and Antiproliferative Properties

Trindade

Juchem

Guecheva

et al. 2019

Oxidative Medicine and Cellular Longevity

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Tellurium is a rare element that has been regarded as a toxic, nonessential element, and its biological role is not clearly established. In addition, the biological effects of elemental tellurium and some of its organic and inorganic derivatives have been studied, leading to a set of interesting and promising applications. Diphenyl ditelluride (DPDT), an organic tellurium derivate, showed antioxidant, antigenotoxic, antimutagenic, and anticancer properties. The antioxidant and prooxidant properties of DPDT are complex and depend on experimental conditions, which may explain the contradictory reports of these properties. In addition, DPDT may exert its effects through different pathways, including distinct ones to those responsible for chemotherapy resistance phenotypes: transcription factors, membrane receptors, adhesion, structural molecules, cell cycle regulatory components, and apoptosis pathways. This review aims to present recent advances in our understanding of the biological effects, therapeutic potential, and safety of DPDT treatment. Moreover, original results demonstrating the cytotoxic effects of DPDT in different mammalian cell lines and systems biology analysis are included, and emerging approaches for possible future applications are inferred.

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Section: Diphenyl Ditelluride Mechanisms Of Antiproliferative Actimentioning

confidence: 99%

Diphenyl Ditelluride: Redox-Modulating and Antiproliferative Properties

Trindade

Juchem

Guecheva

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…For readers interested in a broader and historical overview of GyrB inhibitor discovery, we recommend the review of Bisacchi and Manchester that covers the 50 years of effort towards ATPase inhibitors of DNA gyrase and topoisomerase IV [16], along with the review of Meyer [41]. For strategies relating to how to counter mechanisms of resistance by targeting bacterial topoisomerases, we suggest the review of Tse-Dinh that covers GyrA and GyrB [42]. For readers interested in developing antituberculotic agents through targeting topoisomerases from Mycobacterium tuberculosis, we recommend the recent review of Nagaraja [43].…”

Section: Novel Synthetic Classes Of Gyrase Inhibitorsmentioning

confidence: 99%

Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors

2018

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New antibacterials that modulate less explored targets are needed to fight the emerging bacterial resistance. DNA gyrase and topoisomerase IV are attractive targets in this search. These are both type II topoisomerases that can cleave both DNA strands, and can thus alter DNA topology during replication or similar processes. Currently, there are no ATP-competitive inhibitors of these two enzymes on the market, as the only aminocoumarin representative, novobiocin, was withdrawn due to safety concerns. The search for novel ATP-competitive inhibitors is a focus of ongoing industrial and academical research. This review summarizes the recent efforts in the design, synthesis and evaluation of GyrB/ParE inhibitors. The various approaches to achieve improved antibacterial activities are described, with particular reference to Gram-negative bacteria.

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“…In contrast to the Type II enzymes, Type I topoisomerases have been very sparsely explored for antibiotic drug discovery. These enzymes, which cause single-stranded nicks in relaxing the DNA, perform an essential function in remodeling the chromosome for various processes including DNA replication and recombination, RNA transcription, and condensation and therefore represent an attractive target (Tse-Dinh, 2016 ). For this reason, Sridevi et al conducted virtual screens of two chemical libraries for the capacity to dock with M. tuberculosis TopA (Sridevi et al, 2015 ).…”

Section: The Mycobacterial Dna Replication Machinerymentioning

confidence: 99%

Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis

Reiche

Warner

Mizrahi

2017

Front. Mol. Biosci.

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Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), an infectious disease which results in approximately 10 million incident cases and 1.4 million deaths globally each year, making it the leading cause of mortality from infection. An effective frontline combination chemotherapy exists for TB; however, this regimen requires the administration of four drugs in a 2 month long intensive phase followed by a continuation phase of a further 4 months with two of the original drugs, and is only effective for the treatment of drug-sensitive TB. The emergence and global spread of multidrug-resistant (MDR) as well as extensively drug-resistant (XDR) strains of M. tuberculosis, and the complications posed by co-infection with the human immunodeficiency virus (HIV) and other co-morbidities such as diabetes, have prompted urgent efforts to develop shorter regimens comprising new compounds with novel mechanisms of action. This demands that researchers re-visit cellular pathways and functions that are essential to M. tuberculosis survival and replication in the host but which are inadequately represented amongst the targets of current anti-mycobacterial agents. Here, we consider the DNA replication and repair machinery as a source of new targets for anti-TB drug development. Like most bacteria, M. tuberculosis encodes a complex array of proteins which ensure faithful and accurate replication and repair of the chromosomal DNA. Many of these are essential; so, too, are enzymes in the ancillary pathways of nucleotide biosynthesis, salvage, and re-cycling, suggesting the potential to inhibit replication and repair functions at multiple stages. To this end, we provide an update on the state of chemotherapeutic inhibition of DNA synthesis and related pathways in M. tuberculosis. Given the established links between genotoxicity and mutagenesis, we also consider the potential implications of targeting DNA metabolic pathways implicated in the development of drug resistance in M. tuberculosis, an organism which is unusual in relying exclusively on de novo mutations and chromosomal rearrangements for evolution, including the acquisition of drug resistance. In that context, we conclude by discussing the feasibility of targeting mutagenic pathways in an ancillary, “anti-evolution” strategy aimed at protecting existing and future TB drugs.

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Targeting Bacterial Topoisomerases: How to Counter Mechanisms of Resistance

Cited by 39 publications

References 108 publications

Diphenyl Ditelluride: Redox-Modulating and Antiproliferative Properties

Diphenyl Ditelluride: Redox-Modulating and Antiproliferative Properties

Recent Progress in the Discovery and Development of DNA Gyrase B Inhibitors

Targeting DNA Replication and Repair for the Development of Novel Therapeutics against Tuberculosis

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