Non-quinolone Topoisomerase Inhibitors

Maxwell, Anthony; Bush, Natassja G.; Germe, Thomas; McKie, Shannon J

doi:10.1007/978-3-319-78538-7_19

Cited by 3 publications

(2 citation statements)

References 136 publications

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“…The ability of compounds to stabilize DNA gyrase-DNA cleavage complexes is dubbed “poisoning” as it converts an essential enzyme into a deleterious lesion. These have, to date, been much more successful in the clinic than the “catalytic” ATPase inhibitors [50]. The mechanism described above for the allosteric hinge binders reflects general features of the mechanism of poisoning by a variety of compounds binding to a variety of pockets.…”

Section: General Mechanistic and Energetic Features Of Dna Gyrase Poimentioning

confidence: 99%

DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion

Bax

Murshudov

Maxwell

et al. 2019

Journal of Molecular Biology

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131

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Type II topoisomerases regulate DNA topology by making a double-stranded break in one DNA duplex, transporting another DNA segment through this break and then resealing it. Bacterial type IIA topoisomerase inhibitors, such as fluoroquinolones and novel bacterial topoisomerase inhibitors, can trap DNA cleavage complexes with double- or single-stranded cleaved DNA. To study the mode of action of such compounds, 21 crystal structures of a “gyrase CORE ” fusion truncate of Staphyloccocus aureus DNA gyrase complexed with DNA and diverse inhibitors have been published, as well as 4 structures lacking inhibitors. These structures have the DNA in various cleavage states and appear to track trajectories along the catalytic paths of the DNA cleavage/religation steps. The various conformations sampled by these multiple “gyrase CORE ” structures show rigid body movements of the catalytic GyrA WHD and GyrB TOPRIM domains across the dimer interface. Conformational changes common to all compound-bound structures suggest common mechanisms for DNA cleavage-stabilizing compounds. The structures suggest that S. aureus gyrase uses a single moving-metal ion for cleavage and that the central four base pairs need to be stretched between the two catalytic sites, in order for a scissile phosphate to attract a metal ion to the A-site to catalyze cleavage, after which it is “stored” in another coordination configuration (B-site) in the vicinity. We present a simplified model for the catalytic cycle in which capture of the transported DNA segment causes conformational changes in the ATPase domain that push the DNA gate open, resulting in stretching and cleaving the gate-DNA in two steps.

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Section: General Mechanistic and Energetic Features Of Dna Gyrase Poimentioning

confidence: 99%

DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion

Bax

Murshudov

Maxwell

et al. 2019

Journal of Molecular Biology

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131

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“…The more established sites on the topoisomerases for the interaction of inhibitors are associated with their DNA- and ATP-binding sites. 6,11 In the case of the fluoroquinolones, these drugs bind to the enzyme-DNA complex and effectively “trap” the bound DNA within the enzyme by forming key interactions within the DNA-binding site via a water-metal ion bridge. 12 However, despite the success of dual-targeting agents such as the fluoroquinolones, as well as the relatively slow rate at which bacterial resistance to these drugs has occurred, resistance within the clinic is growing.…”

Section: Introductionmentioning

confidence: 99%

De novo design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region

et al. 2022

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The pentapeptide-repeat protein, MfpA, interacts with mycobacterial DNA gyrase as a DNA T-segment mimic

Feng

Mundy

Stevenson

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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DNA gyrase, a type II topoisomerase, introduces negative supercoils into DNA using ATP hydrolysis. The highly effective gyrase-targeted drugs, fluoroquinolones (FQs), interrupt gyrase by stabilizing a DNA-cleavage complex, a transient intermediate in the supercoiling cycle, leading to double-stranded DNA breaks. MfpA, a pentapeptide-repeat protein in mycobacteria, protects gyrase from FQs, but its molecular mechanism remains unknown. Here, we show that Mycobacterium smegmatis MfpA (MsMfpA) inhibits negative supercoiling by M. smegmatis gyrase (Msgyrase) in the absence of FQs, while in their presence, MsMfpA decreases FQ-induced DNA cleavage, protecting the enzyme from these drugs. MsMfpA stimulates the ATPase activity of Msgyrase by directly interacting with the ATPase domain (MsGyrB47), which was confirmed through X-ray crystallography of the MsMfpA–MsGyrB47 complex, and mutational analysis, demonstrating that MsMfpA mimics a T (transported) DNA segment. These data reveal the molecular mechanism whereby MfpA modulates the activity of gyrase and may provide a general molecular basis for the action of other pentapeptide-repeat proteins.

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Non-quinolone Topoisomerase Inhibitors

Cited by 3 publications

References 136 publications

DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion

DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion

De novo design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region

The pentapeptide-repeat protein, MfpA, interacts with mycobacterial DNA gyrase as a DNA T-segment mimic

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