Effects of quinolone derivatives on eukaryotic topoisomerase II. A novel mechanism for enhancement of enzyme-mediated DNA cleavage

Robinson, Megan J.; Martin, Barbara A.; Gootz, Thomas D.; McGuirk, Paul R.; Moynihan, Melinda S.; Sutcliffe, J.A.; Osheroff, Neil

doi:10.1016/s0021-9258(18)98726-0

Cited by 147 publications

(51 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Levels of cleavage complexes generated by the enzyme on relaxed DNA were between those generated on positively and negatively supercoiled plasmid. Gyrase also maintained the distinction between over and underwound DNA in the presence of ciprofloxacin or levofloxacin, two other clinically relevant quinolones; CP-115,953, a quinolone that displays high activity against both bacterial and eukaryotic type II topoisomerases; − and two quinolone-derived drugs, 8-methyl-moxifloxacin and 3′-(AM)P-dione, which overcome quinolone resistance caused by mutations in M. tuberculosis gyrase , (Figure ). These results suggest that, although gyrase in M. tuberculosis has adapted to perform some of the functions of topoisomerase IV, it still retains the characteristics that make gyrase a safe enzyme to function ahead of replication forks and other DNA tracking systems such as RNA polymerase.…”

Section: Resultsmentioning

confidence: 98%

Recognition of DNA Supercoil Geometry byMycobacterium tuberculosisGyrase

Ashley¹,

Blower

Osheroff

2017

Biochemistry

View full text Add to dashboard Cite

Mycobacterium tuberculosis encodes only a single type II topoisomerase, gyrase. As a result, this enzyme likely carries out the cellular functions normally performed by canonical gyrase and topoisomerase IV, both in front of and behind the replication fork. In addition, it is the sole target for quinolone antibacterials in this species. Because quinolone-induced DNA strand breaks generated on positively supercoiled DNA ahead of replication forks and transcription complexes are most likely to result in permanent genomic damage, the actions of M. tuberculosis gyrase on positively supercoiled DNA were investigated. Results indicate that the enzyme acts rapidly on overwound DNA and removes positive supercoils much faster than it introduces negative supercoils into relaxed DNA. Canonical gyrase and topoisomerase IV distinguish supercoil handedness differently during the DNA cleavage reaction: while gyrase maintains lower levels of cleavage complexes on overwound DNA, topoisomerase IV maintains similar levels of cleavage complexes on both over- and underwound substrates. M. tuberculosis gyrase maintained lower levels of cleavage complexes on positively supercoiled DNA in the absence and presence of quinolone-based drugs. By retaining this important feature of canonical gyrase, the dual function M. tuberculosis type II enzyme remains a safe enzyme to act in front of replication forks and transcription complexes. Finally, the N-terminal gate region of the enzyme appears to be necessary to distinguish supercoil handedness during DNA cleavage, suggesting that the capture of the transport segment may influence how gyrase maintains cleavage complexes on substrates with different topological states.

show abstract

Section: Resultsmentioning

confidence: 98%

Recognition of DNA Supercoil Geometry byMycobacterium tuberculosisGyrase

Ashley¹,

Blower

Osheroff

2017

Biochemistry

View full text Add to dashboard Cite

show abstract

“…DNA ligation assays were carried out in the absence or presence of GSK000 or moxifloxacin following the procedure of Robinson and Osheroff. 66 Reaction mixtures (20 μL) contained 100 nM wild-type M. tuberculosis gyrase and 10 nM negatively supercoiled pBR322 in cleavage buffer. In experiments carried out in the absence of drug, MgCl 2 in the cleavage buffer was replaced with 6 mM CaCl 2 to increase baseline levels of DNA cleavage.…”

Section: ■ Methodsmentioning

confidence: 99%

“…DNA ligation assays were carried out in the absence or presence of GSK000 or moxifloxacin following the procedure of Robinson and Osheroff . Reaction mixtures (20 μL) contained 100 nM wild-type M.…”

Section: Methodsmentioning

confidence: 99%

Mechanism of Action of Mycobacterium tuberculosis Gyrase Inhibitors: A Novel Class of Gyrase Poisons

et al. 2018

View full text Add to dashboard Cite

Tuberculosis is one of the leading causes of morbidity worldwide, and the incidences of drug resistance and intolerance are prevalent. Thus, there is a desperate need for the development of new antitubercular drugs. Mycobacterium tuberculosis gyrase inhibitors (MGIs) are napthyridone/aminopiperidine-based drugs that display activity against M. tuberculosis cells and tuberculosis in mouse models [Blanco, D., et al. (2015) Antimicrob. Agents Chemother. 59, 1868-1875]. Genetic and mutagenesis studies suggest that gyrase, which is the target for fluoroquinolone antibacterials, is also the target for MGIs. However, little is known regarding the interaction of these drugs with the bacterial type II enzyme. Therefore, we examined the effects of two MGIs, GSK000 and GSK325, on M. tuberculosis gyrase. MGIs greatly enhanced DNA cleavage mediated by the bacterial enzyme. In contrast to fluoroquinolones (which induce primarily double-stranded breaks), MGIs induced only single-stranded DNA breaks under a variety of conditions. MGIs work by stabilizing covalent gyrase-cleaved DNA complexes and appear to suppress the ability of the enzyme to induce double-stranded breaks. The drugs displayed little activity against type II topoisomerases from several other bacterial species, suggesting that these drugs display specificity for M. tuberculosis gyrase. Furthermore, MGIs maintained activity against M. tuberuclosis gyrase enzymes that contained the three most common fluoroquinolone resistance mutations seen in the clinic and displayed no activity against human topoisomerase IIα. These findings suggest that MGIs have potential as antitubercular drugs, especially in the case of fluoroquinolone-resistant disease.

show abstract

“…Position 1: The N atom at this is necessary for activity, the changing of N-1 substituent ethyl group to cyclopropyl group at this position was found to increase the antiproliferative activity and produce better quinolones interference with Topo II than with Gyrase. Also, phenyl and thiazolyl moieties at this site were found to be valuable [64,67]. Position 2 and 3: Substitution at these positions should be coplanar with the main quinolone nucleus and does not disturb the coplanarity of the quinolone nucleus [68].…”

Section: Structure Activity Relationships (Sar) Of Cytotoxic Quinolonesmentioning

confidence: 99%

Recent Strategies in Design of Antitumor and Antibacterial Fluoroquinolones

Samir

Ramadan

Hamed

et al. 2021

Journal of advanced Biomedical and Pharmaceutical Sciences

View full text Add to dashboard Cite

Fluoroquinolones are known widely used synthetic antibacterial agents. Generally, there were some obstacles associated with their therapeutic use. Moreover, many research studies all over the world proved the variable biological effects of fluoroquinolones such as antituberculosis, anticancer, or even antiviral activities. The current review is focused on modifications that occurred in the fluoroquinolone scaffold for their repositioning from antibacterial into anticancer agents especially modifications at C-7 or at the carboxylic C-3 groups. In addition, it includes the recent research studies carried out to improve the potency, spectrum of activity, or pharmacokinetics of antibacterial fluoroquinolones. Hence, this review may be useful for researchers in the design and synthesis of new fluoroquinolones with improved biological activities.

show abstract

Effects of quinolone derivatives on eukaryotic topoisomerase II. A novel mechanism for enhancement of enzyme-mediated DNA cleavage

Cited by 147 publications

References 49 publications

Recognition of DNA Supercoil Geometry byMycobacterium tuberculosisGyrase

Recognition of DNA Supercoil Geometry byMycobacterium tuberculosisGyrase

Mechanism of Action of Mycobacterium tuberculosis Gyrase Inhibitors: A Novel Class of Gyrase Poisons

Recent Strategies in Design of Antitumor and Antibacterial Fluoroquinolones

Contact Info

Product

Resources

About