Novel bacterial topoisomerase inhibitors with potent broad-spectrum activity against drug-resistant bacteria

Cédric Charrier, Anne-Marie Salisbury, Victoria J Savage, Thomas Duffy, Emmanuel Moyo, Nathan Chaffer-Malam, Nicola Ooi, Rebecca Newman, Jonathan Cheung, Richard Metzger, David McGarry, Mark Pichowicz, Ralph Sigerson, Ian R Cooper, Gary Nelson, Hayley S Butler, Mark Craighead, Andrew J Ratcliffe, Stuart A Best, Neil R Stokes

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The Novel Bacterial Topoisomerase Inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that do 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 molecules. 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 Gram-positive and Gram-negative pathogens, including biodefence microorganisms, and Mycobacterium tuberculosis No cross-resistance with quinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC90 values were 4 and 8 μg/mL against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli 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 <10(-8) against E. coli and A. baumannii at concentrations equivalent to four-fold the MIC. Compound-resistant Ecoli mutants isolated following serial passage were characterised 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 hERG inhibition (IC50 >100 μM). 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.

LanguageEnglish
JournalAntimicrobial Agents and Chemotherapy
Early online date21 Feb 2017
DOIs
Publication statusE-pub ahead of print - 21 Feb 2017

Fingerprint

Topoisomerase Inhibitors
Quinolones
DNA Topoisomerase IV
Escherichia coli
Bacteria
Reunion
Pharmaceutical Preparations
DNA Gyrase
Acinetobacter baumannii
Fluoroquinolones
Mutation Rate
Mycobacterium tuberculosis
Staphylococcus aureus
Anti-Bacterial Agents
Safety
DNA
In Vitro Techniques

Keywords

  • topoisomerase
  • DNA gyrase
  • antibiotic
  • ESKAPE pathogens
  • antibacterial inhibitors
  • quinolones
  • drug-resistance

Cite this

Charrier, Cédric ; Salisbury, Anne-Marie ; Savage, Victoria J ; Duffy, Thomas ; Moyo, Emmanuel ; Chaffer-Malam, Nathan ; Ooi, Nicola ; Newman, Rebecca ; Cheung, Jonathan ; Metzger, Richard ; McGarry, David ; Pichowicz, Mark ; Sigerson, Ralph ; Cooper, Ian R ; Nelson, Gary ; Butler, Hayley S ; Craighead, Mark ; Ratcliffe, Andrew J ; Best, Stuart A ; Stokes, Neil R. / Novel bacterial topoisomerase inhibitors with potent broad-spectrum activity against drug-resistant bacteria. In: Antimicrobial Agents and Chemotherapy . 2017.
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abstract = "The Novel Bacterial Topoisomerase Inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that do 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 molecules. 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 Gram-positive and Gram-negative pathogens, including biodefence microorganisms, and Mycobacterium tuberculosis No cross-resistance with quinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC90 values were 4 and 8 μg/mL against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli 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 <10(-8) against E. coli and A. baumannii at concentrations equivalent to four-fold the MIC. Compound-resistant Ecoli mutants isolated following serial passage were characterised 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 hERG inhibition (IC50 >100 μM). 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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Charrier, C, Salisbury, A-M, Savage, VJ, Duffy, T, Moyo, E, Chaffer-Malam, N, Ooi, N, Newman, R, Cheung, J, Metzger, R, McGarry, D, Pichowicz, M, Sigerson, R, Cooper, IR, Nelson, G, Butler, HS, Craighead, M, Ratcliffe, AJ, Best, SA & Stokes, NR 2017, 'Novel bacterial topoisomerase inhibitors with potent broad-spectrum activity against drug-resistant bacteria' Antimicrobial Agents and Chemotherapy . https://doi.org/10.1128/AAC.02100-16

Novel bacterial topoisomerase inhibitors with potent broad-spectrum activity against drug-resistant bacteria. / Charrier, Cédric; Salisbury, Anne-Marie; Savage, Victoria J; Duffy, Thomas; Moyo, Emmanuel; Chaffer-Malam, Nathan; Ooi, Nicola; Newman, Rebecca; Cheung, Jonathan; Metzger, Richard; McGarry, David; Pichowicz, Mark; Sigerson, Ralph; Cooper, Ian R; Nelson, Gary; Butler, Hayley S; Craighead, Mark; Ratcliffe, Andrew J; Best, Stuart A; Stokes, Neil R.

In: Antimicrobial Agents and Chemotherapy , 21.02.2017.

Research output: Contribution to journalArticle

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AU - Charrier, Cédric

AU - Salisbury, Anne-Marie

AU - Savage, Victoria J

AU - Duffy, Thomas

AU - Moyo, Emmanuel

AU - Chaffer-Malam, Nathan

AU - Ooi, Nicola

AU - Newman, Rebecca

AU - Cheung, Jonathan

AU - Metzger, Richard

AU - McGarry, David

AU - Pichowicz, Mark

AU - Sigerson, Ralph

AU - Cooper, Ian R

AU - Nelson, Gary

AU - Butler, Hayley S

AU - Craighead, Mark

AU - Ratcliffe, Andrew J

AU - Best, Stuart A

AU - Stokes, Neil R

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N2 - The Novel Bacterial Topoisomerase Inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that do 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 molecules. 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 Gram-positive and Gram-negative pathogens, including biodefence microorganisms, and Mycobacterium tuberculosis No cross-resistance with quinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC90 values were 4 and 8 μg/mL against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli 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 <10(-8) against E. coli and A. baumannii at concentrations equivalent to four-fold the MIC. Compound-resistant Ecoli mutants isolated following serial passage were characterised 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 hERG inhibition (IC50 >100 μM). 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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KW - topoisomerase

KW - DNA gyrase

KW - antibiotic

KW - ESKAPE pathogens

KW - antibacterial inhibitors

KW - quinolones

KW - drug-resistance

U2 - 10.1128/AAC.02100-16

DO - 10.1128/AAC.02100-16

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