Determination of Disk Diffusion and MIC Quality Control Guidelines for GSK2140944, a Novel Bacterial Type II Topoisomerase Inhibitor Antimicrobial Agent

Ross, James E.; Scangarella-Oman, Nicole; Flamm, Robert K.; Jones, Ronald N.

doi:10.1128/jcm.00656-14

Cited by 31 publications

(24 citation statements)

References 2 publications

(1 reference statement)

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“…The antibacterial activity of GSK2140944 was assessed against a global collection of relevant clinical isolates. The minimum inhibitory concentration (MIC) to inhibit 90% of the tested S. aureus isolates, MIC 90 , was in the range of < 0.06 - 1 µg/ml [6, 7]. Target binding of GSK2140944 differs from that of fluoroquinolones by a distinct modus of binding to the type II topoisomerase, resulting in a lack of cross-resistance to fluoroquinolones [6].…”

Section: Investigational Antibiotics Against Mrsamentioning

confidence: 99%

“…The minimum inhibitory concentration (MIC) to inhibit 90% of the tested S. aureus isolates, MIC 90 , was in the range of < 0.06 - 1 µg/ml [6, 7]. Target binding of GSK2140944 differs from that of fluoroquinolones by a distinct modus of binding to the type II topoisomerase, resulting in a lack of cross-resistance to fluoroquinolones [6]. Seven phase I studies were conducted to investigate the bioavailability of two formulations (oral and parenteral), safety, tolerability, pharmacokinetic profiles, and cardiac safety.…”

Section: Investigational Antibiotics Against Mrsamentioning

confidence: 99%

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Investigational drugs to treat methicillin-resistantStaphylococcus aureus

Vuong

Yeh

Cheung

et al. 2015

Expert Opinion on Investigational Drugs

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Introduction Staphylococcus aureus remains one of the leading causes of morbidity and mortality worldwide. This is to a large extent due to antibiotic-resistant strains, in particular methicillin-resistant S. aureus (MRSA). While the toll of invasive MRSA infections appears to decrease in U.S. hospitals, the rate of community-associated MRSA infections remains constant and there is a surge of MRSA in many other countries. This situation calls for continuing if not increased efforts to find novel strategies to combat MRSA infections. Areas covered This review will provide an overview of current investigational antibiotics in clinical development (up to phase II), and of therapeutic antibodies and alternative drugs against S. aureus in preclinical and clinical development, including a short description of the mechanism of action and a presentation of microbiological and clinical data. Expert opinion Increased recent antibiotic development efforts and results from pathogenesis research have led to several new antibiotics and alternative drugs, as well as a more informed selection of targets for vaccination efforts against MRSA. This developing portfolio of novel anti-staphylococcal drugs will hopefully provide us with additional and more efficient ways to combat MRSA infections in the near future and prevent us from running out of treatment options, even if new resistances arise.

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Section: Investigational Antibiotics Against Mrsamentioning

confidence: 99%

Section: Investigational Antibiotics Against Mrsamentioning

confidence: 99%

Investigational drugs to treat methicillin-resistantStaphylococcus aureus

Vuong

Yeh

Cheung

et al. 2015

Expert Opinion on Investigational Drugs

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“…Ridinilazole (36) showed good results in a hamster model of CDI. 225 Gepotidacin (37) (GSK-2140944) is a bacterial Type II topoisomerase inhibitor226,227 being investigated by GlaxoSmithKline (London, UK) that has completed multiple phase-I clinical trials (NCT01706315, NCT01615796, NCT01934205, NCT02000765, NCT02045849, NCT02202187 and NCT02257398), with both oral and IV dosing. A phase-II study investigating gepotidacin (37) with IV/oral switch therapy in G+ve ABSSSI was completed in June 2015 (NCT02045797), with a second phase-II study treating uncomplicated urogenital gonorrhea caused by N. gonorrhoeae initiated in April 2015 London, UK) that is in a phase-II clinical trial that was initiated in November 2014 (NCT02257918) to investigate efficacy in treating uncomplicated gonorrhea.…”

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confidence: 99%

Antibiotics in the clinical pipeline at the end of 2015

2016

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There is growing global recognition that the continued emergence of multidrug-resistant bacteria poses a serious threat to human health. Action plans released by the World Health Organization and governments of the UK and USA in particular recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics. This review lists the 30 antibiotics and two β-lactamase/β-lactam combinations first launched since 2000, and analyzes in depth seven new antibiotics and two new β-lactam/β-lactamase inhibitor combinations launched since 2013. The development status, mode of action, spectra of activity and genesis (natural product, natural product-derived, synthetic or protein/mammalian peptide) of the 37 compounds and six β-lactamase/β-lactam combinations being evaluated in clinical trials between 2013 and 2015 are discussed. Compounds discontinued from clinical development since 2013 and new antibacterial pharmacophores are also reviewed.

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“…A second class of topoisomerase inhibitors known as NBTIs (novel bacterial topoisomerase inhibitors) have not, as of yet, been approved for therapeutic use, but there are three compounds (including compound 3 of Fig. 1 ) that have entered Phase 1 clinical trials and have the potential to circumvent cross-resistance 18 19 20 . The third class of inhibitors compete with ATP in the GyrB/ParE subunits and represent a third mode-of-inhibition relative to fluoroquinolones and NBTIs.…”

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confidence: 99%

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

Kern

McNulty

et al. 2015

Sci Rep

108

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With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.

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Determination of Disk Diffusion and MIC Quality Control Guidelines for GSK2140944, a Novel Bacterial Type II Topoisomerase Inhibitor Antimicrobial Agent

Cited by 31 publications

References 2 publications

Investigational drugs to treat methicillin-resistantStaphylococcus aureus

Investigational drugs to treat methicillin-resistantStaphylococcus aureus

Antibiotics in the clinical pipeline at the end of 2015

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

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