Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases

Basarab, Gregory S.; Kern, Günther; McNulty, John; Mueller, John P.; Lawrence, Kenneth; Vishwanathan, Karthick; Alm, Richard A.; Barvian, Kevin; Doig, P.; Galullo, Vincent; Gardner, Humphrey; Gowravaram, Madhusudhan; Huband, Michael D.; Kimzey, Amy L.; Morningstar, Marshall L.; Kutschke, Amy; Lahiri, S. C.; Perros, Manos; Singh, Rajeev Kumar; Schuck, Virna; Tommasi, Rubén; Walkup, Grant K.; Newman, Joseph V.

doi:10.1038/srep11827

Cited by 92 publications

(118 citation statements)

References 59 publications

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“…This NBTIbinding site is different from the FQ-binding sites, and gepotidacin retains minimum inhibitory concentration (MIC) activity against FQresistant strains (16). The spiropyrimidinetriones, exemplified by ETX0914, also in phase II trials, bind the topoisomerase complex at a site that overlaps with that of FQs, but remains effective against FQ-resistant strains (18,19). In contrast to the FQ, triazaacenaphthylene, and spiropyrimidinetrione classes, which all bind to the DNA gate, the aminocoumarins, represented by novobiocin, target the gyrase ATPase domain.…”

Section: Significancementioning

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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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: Significancementioning

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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“…Despite the now widespread resistance to the quinolones, the type II topoisomerases continue to provide opportunities for antibacterial discovery based on exploiting novel binding interactions between new chemical ligands and the target enzymes in order to bypass mutations associated with quinolone resistance. Selected examples of this strategy are the 2-aminoquinazolinedione (11), the isothiazoloquinolone (12), the spiropyrimidinetrione (13), and the novel tricyclic topoisomerase inhibitor (NTTI) (14) classes.…”

mentioning

confidence: 99%

Novel Bacterial Topoisomerase Inhibitors with Potent Broad-Spectrum Activity against Drug-Resistant Bacteria

Charrier

Salisbury

Savage

et al. 2017

Antimicrob Agents Chemother

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The novel bacterial topoisomerase inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that does not have cross-resistance with the quinolones. Here, we report the evaluation of the in vitro properties of a new series of this type of small molecule. Exemplar compounds selectively and potently inhibited the catalytic activities of Escherichia coli DNA gyrase and topoisomerase IV but did not block the DNA breakage-reunion step. Compounds showed broad-spectrum inhibitory activity against a wide range of Grampositive and Gram-negative pathogens, including biodefence microorganisms and Mycobacterium tuberculosis. No cross-resistance with fluoroquinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC 90 values were 4 and 8 g/ml against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli, respectively. In addition, representative compounds exhibited greater antibacterial potency than the quinolones against obligate anaerobic species. Spontaneous mutation rates were low, with frequencies of resistance typically Ͻ10 Ϫ8 against E. coli and A. baumannii at concentrations equivalent to 4-fold the MIC. Compound-resistant E. coli mutants that were isolated following serial passage were characterized by whole-genome sequencing and carried a single Arg38Leu amino acid substitution in the GyrA subunit of DNA gyrase. Preliminary in vitro safety data indicate that the series shows a promising therapeutic index and potential for low human ether-a-go-go-related gene (hERG) inhibition (50% inhibitory concentration [IC 50 ], Ͼ100 M). In summary, the compounds' distinct mechanism of action relative to the fluoroquinolones, whole-cell potency, low potential for resistance development, and favorable in vitro safety profile warrant their continued investigation as potential broad-spectrum antibacterial agents.

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“…It showed selectivity of acting as a topoisomerase poison inhibitor for Neisseria gonorrhoeae gyrase and topoisomerase IV over human topoisomerase IIα and IIβ [38]. With low spontaneous resistance frequency (1.5 × 10 -8 to <5.2 × 10 -9 at 4 × the MIC) and lack of cross-resistance to pre-existing fluoroquinolone and cephalosporin resistance mechanisms in N. gonorrhoeae [71], AZD0914 is being tested in clinical trials (ClinicalTrials website) to help meet the challenge of untreatable gonorrhea [72].…”

Section: New Inhibitors Interacting Near the Active Site Of Gyrase Thmentioning

confidence: 99%

Targeting Bacterial Topoisomerases: How to Counter Mechanisms of Resistance

Tse‐Dinh

2016

Future Med. Chem.

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DNA gyrase and topoisomerase IV are type IIA bacterial topoisomerases that are targeted by highly effective antibiotics. However, resistance via multiple mechanisms arises to limit the efficacies of these drugs. Continued research on type IIA bacterial topoisomerases has provided novel approaches to counter the most common resistance mechanism for utilization of these proven targets in antibacterial therapy. Bacterial topoisomerase I is being explored as an alternative target that is not expected to show cross-resistance. Dual targeting or combination therapy could be strategies for circumventing the development of resistance to topoisomerase-targeting antibiotics. Bacterial topoisomerases are high-value bactericidal targets that could continue to be exploited for antibacterial therapy, if new tactics to counter resistance can be adopted.

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Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases

Cited by 92 publications

References 59 publications

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

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

Novel Bacterial Topoisomerase Inhibitors with Potent Broad-Spectrum Activity against Drug-Resistant Bacteria

Targeting Bacterial Topoisomerases: How to Counter Mechanisms of Resistance

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