Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases

Miles, Timothy J.; Hennessy, Alan J.; Bax, Benjamin; Brooks, Gerald; Brown, Barry S.; Brown, Pamela; Cailleau, Nathalie; Chen, Dongzhao; Dabbs, Steven; Davies, David T.; Esken, Joel M.; Giordano, Ilaria; Hoover, Jennifer L.; Huang, Jianzhong; Jones, Graham; Sukmar, Senthill K. Kusalakumari; Spitzfaden, Claus; Markwell, Roger E.; Minthorn, Elisabeth A.; Rittenhouse, Steve; Gwynn, Michael N.; Pearson, Neil D.

doi:10.1016/j.bmcl.2013.07.013

Cited by 61 publications

(56 citation statements)

References 27 publications

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“…The structure contains one complex in the asymmetric with two molecules of compound 2 bound, and one GSK945237 sitting on the internal twofold axis of the complex. The central four base pairs of DNA, between the two DNA-cleavage sites, were well-ordered, with the left-hand side of GSK945237 sitting between the central bases of the DNA as in other NBTI structures (15,40). Tyr-639 from the GyrB subunit was displaced from the thiophene-hinge pocket by the binding of compound 2.…”

Section: Methodsmentioning

confidence: 86%

“…Compound 2 (soaked into GSK945237 cocrystal). In all our previous complex structures of S. aureus DNA gyrase with DNA and a variety of DNA-gate inhibitors (15,19,40), the thiophene class inhibitor-binding pocket was present. Therefore, a soakable crystal system for determining thiophene crystal structures was developed by cocrystallizing with an NBTI (namely, GSK945237) (41) and then soaking in compound 2.…”

Section: Methodsmentioning

confidence: 99%

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Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Chan

Germe

Bax

et al. 2017

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

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A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase–DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.

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Section: Methodsmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Chan

Germe

Bax

et al. 2017

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

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“…We have previously described the use of a fusion truncate of the C-terminus of Staphylococcus aureus GyrB and the N-terminus of S. aureus GyrA to determine high-resolution structures with novel bacterial topoisomerase inhibitors (Bax et al, 2010;Miles et al, 2013). An S. aureus GyrB-GyrA fusion truncate (GyrB27-A56/Y123F) gave a 3.5 Å resolution structure with an NBTI and uncleaved DNA.…”

Section: Introductionmentioning

confidence: 99%

“…DNA sequences used in successful crystallization experiments. DNAs are self-complementary and form 20-base-pair homoduplexes, except for 20-23, which forms a heteroduplex with 20-23comp (Miles et al, 2013). DNAs which are cleaved by the enzyme form a covalent bond with Tyr123 from GyrA (indicated by a superscript Y).…”

Section: Introductionmentioning

confidence: 99%

“…The 20-12p-8 DNA duplex has an artificial nick in the DNA at each cleavage site, and the 5 0 nucleotide of the 12-mer includes a 5 0 phosphate (indicated by a superscript P). The 20-20 and 20-23 DNAs were not used in the crystals described in this paper, but as uncleaved DNA (the uncleaved link between the À1 and +1 nucleotides is underlined in purple) in crystal structures with the NBTIs GSK299423, GSK966587 and the Y123F mutant (PDB entries 2xcs, 2xcr and 4bul; Bax et al, 2010;Miles et al, 2013). Nucleotides coloured in red have their phosphates bound by GyrB and those in blue by GyrA.…”

Section: Introductionmentioning

confidence: 99%

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Crystallization and initial crystallographic analysis of covalent DNA-cleavage complexes of Staphyloccocus aureus DNA gyrase with QPT-1, moxifloxacin and etoposide

Srikannathasan

Wohlkonig

Shillings

et al. 2015

Acta Crystallogr F Struct Biol Commun

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Fluoroquinolone drugs such as moxifloxacin kill bacteria by stabilizing the normally transient double-stranded DNA breaks created by bacterial type IIA topoisomerases. Previous crystal structures of Staphylococcus aureus DNA gyrase with asymmetric DNAs have had static disorder (with the DNA duplex observed in two orientations related by the pseudo-twofold axis of the complex). Here, 20-base-pair DNA homoduplexes were used to obtain crystals of covalent DNA-cleavage complexes of S. aureus DNA gyrase. Crystals with QPT-1, moxifloxacin or etoposide diffracted to between 2.45 and 3.15 Å resolution. A G/T mismatch introduced at the ends of the DNA duplexes facilitated the crystallization of slightly asymmetric complexes of the inherently flexible DNAcleavage complexes.

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Antibiotics

Surivet

Panchaud

2017

Methods and Principles in Medicinal Chemistry

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Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases

Cited by 61 publications

References 27 publications

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Crystallization and initial crystallographic analysis of covalent DNA-cleavage complexes of Staphyloccocus aureus DNA gyrase with QPT-1, moxifloxacin and etoposide

Antibiotics

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