zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva 
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  • ||||||||||  ciprofloxacin oral / Generic mfg., zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva
    Preclinical, Journal:  In vitro evolution of ciprofloxacin resistance in Neisseria commensals and derived mutation population dynamics in natural Neisseria populations. (Pubmed Central) -  Jan 28, 2025   
    Finally, to interrogate the likelihood of experimentally derived mutations emerging and contributing to resistance in natural Neisseria, we used a population-based approach and identified GyrA 91I as a substitution circulating within commensal Neisseria populations and ParC 85C in a single gonococcal isolate. A small cluster of gonococcal isolates shared commensal alleles at parE, suggesting recent cross-species recombination events.
  • ||||||||||  zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva
    Journal:  Recommendations for the optimal introduction of novel antibiotics to treat uncomplicated gonorrhoea in the face of increasing antimicrobial resistance: a case study with zoliflodacin. (Pubmed Central) -  Dec 17, 2024   
    Recommendations from the expert group included: the generation of evidence for the role of a drug like zoliflodacin in clinical treatment failures; the need for additional antimicrobial resistance surveillance; investigation of the role of novel diagnostic approaches, such as point-of-care tests, to improve stewardship; study of preferences and values among the population in need; and modelling of the emergence of N. gonorrhoeae resistance and transmission in different scenarios. Forthcoming World Health Organization (WHO) global guidelines could outline recommendations for a new oral antibiotic like zoliflodacin based on existing evidence, and rational approaches for certain populations or use cases, while the evidence base is further strengthened.
  • ||||||||||  Invanz (ertapenem) / Merck (MSD), gepotidacin (GSK2140944) / GSK, zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva
    Review, Journal:  Alternative drugs for the treatment of gonococcal infections: old and new. (Pubmed Central) -  Nov 28, 2024   
    New oral drugs zoliflodacin and gepotidacin are in late clinical development, but there are concerns regarding their effectiveness for extragenital infections and the development of resistance...Among older antibiotics, ertapenem shows the most potential as an alternative but shares the same administrative drawbacks as ceftriaxone...Phase 3 trial results have not been made available except through press releases, which perpetuates concerns. Understanding pharmacokinetic and pharmacodynamic profiles of antibiotics will be key in optimizing future treatment recommendations.
  • ||||||||||  ceftriaxone / Generic mfg.
    Preclinical, Journal:  Assessing novel partner antimicrobials to protect ceftriaxone against gonococcal resistance: An in vitro evaluation. (Pubmed Central) -  Sep 3, 2024   
    Understanding pharmacokinetic and pharmacodynamic profiles of antibiotics will be key in optimizing future treatment recommendations. The low MICs of zoliflodacin and pristinamycin for the three ceftriaxone-resistant strains suggest that these antimicrobials could be used as partner drugs with ceftriaxone to reduce the probability of ceftriaxone resistance spreading in areas with a high prevalence of ceftriaxone resistance.
  • ||||||||||  zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva
    Journal:  Interactions between Zoliflodacin and Neisseria gonorrhoeae Gyrase and Topoisomerase IV: Enzymological Basis for Cellular Targeting. (Pubmed Central) -  Jul 31, 2024   
    Finally, when compared to zoliflodacin, the novel SPT H3D-005722 induced more balanced double-stranded DNA cleavage with gyrase and topoisomerase IV from N. gonorrhoeae, Escherichia coli, and Bacillus anthracis. This finding suggests that further development of the SPT class could yield compounds with a more balanced targeting against clinically important bacterial infections.
  • ||||||||||  zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva
    Trial completion, Head-to-Head:  Zoliflodacin in Uncomplicated Gonorrhoea (clinicaltrials.gov) -  Jul 25, 2024   
    P3,  N=1011, Completed, 
    Small clusters of gonococcal isolates had commensal-like alleles at parC and parE , indicating recent cross-species recombination events. Active, not recruiting --> Completed
  • ||||||||||  gepotidacin (GSK2140944) / GSK, zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva
    Review, Journal:  Management of Neisseria gonorrhoeae infection: from drug resistance to drug repurposing. (Pubmed Central) -  Jun 10, 2024   
    Presently, only expanded spectrum cephalosporins (ceftriaxone and cefixime) and azithromycin remain useful for its management...By exploiting different subunits from the gyrase/topoisomerase IV as well as new chemotypes, two new antibiotics reached Phase II/III clinical trials, zoliflodacin and gepotidacin...Acetazolamide and similar CA inhibitors might be thus repurposed as antiinfectives. The scientific/patent literature has been searched for on PubMed, ScienceDirect, Espacenet, and PatentGuru, from 2016 to 2024.
  • ||||||||||  zoliflodacin (ETX0914) / Entasis Therap, Global Antibiotic Research and Development Partnership
    Preclinical, Journal:  Evaluating the potency of zoliflodacin against Helicobacter pylori: In (Pubmed Central) -  Apr 21, 2024   
    Enhanced gonococcal AMR surveillance, including WGS, is imperative in Brazil and other Latin American and Caribbean countries. These findings support the potential of zoliflodacin as a promising candidate for H. pylori treatment, warranting further development and evaluation.
  • ||||||||||  gepotidacin (GSK2140944) / GSK, zoliflodacin (ETX0914) / Entasis Therap, Global Antibiotic Research and Development Partnership
    Review, Journal:  Gyrase and Topoisomerase IV: Recycling Old Targets for New Antibacterials to Combat Fluoroquinolone Resistance. (Pubmed Central) -  Apr 15, 2024   
    Phase III clinical trials that utilized two members of these classes, gepotidacin (triazaacenaphthylene) and zoliflodacin (spiropyrimidinetrione), have been completed with positive outcomes, underscoring the potential of these compounds to become the first new classes of antibacterials introduced into the clinic in decades. Because gyrase and topoisomerase IV are validated targets for established and emerging antibacterials, this review will describe the catalytic mechanism and cellular activities of the bacterial type II topoisomerases, their interactions with fluoroquinolones, the mechanism of target-mediated fluoroquinolone resistance, and the actions of novel antibacterials against wild-type and fluoroquinolone-resistant gyrase and topoisomerase IV.
  • ||||||||||  gepotidacin (GSK2140944) / GSK, zoliflodacin (ETX0914) / Entasis Therap, Global Antibiotic Research and Development Partnership
    Review, Journal:  Neisseria gonorrhoeae Antimicrobial Resistance: The Future of Antibiotic Therapy. (Pubmed Central) -  Dec 23, 2023   
    Notably, gonorrhea has been included in the "WHO Priority Pathogens List for Research and Development of New Antibiotics". In conclusion, the urgent need for innovative treatment strategies is underscored by the rising threat of antibiotic resistance in N. gonorrhoeae; collaboration among researchers, industries, and healthcare authorities is therefore essential.
  • ||||||||||  zoliflodacin (ETX0914) / Entasis Therap, Global Antibiotic Research and Development Partnership
    Clinical, PK/PD data, Journal, Combination therapy:  Pharmacodynamics of zoliflodacin plus doxycycline combination therapy against Neisseria gonorrhoeae in a gonococcal hollow-fiber infection model. (Pubmed Central) -  Dec 22, 2023   
    P3
    The first in class zoliflodacin (spiropyrimidinetrione, DNA Gyrase B inhibitor) is a promising novel antimicrobial in late-stage clinical development for gonorrhea treatment, i.e., the phase III randomized controlled clinical trial (ClinicalTrials.gov Identifier: NCT03959527) was recently finalized, and zoliflodacin showed non-inferiority compared to the recommended ceftriaxone plus azithromycin dual therapy...In a previous static in vitro study, it was indicated that doxycycline/tetracycline inhibited the gonococcal killing of zoliflodacin in 6-h time-kill curve analysis...The present study shows the high efficacy of zoliflodacin plus doxycycline combination therapy using a dynamic HFIM that more accurately and comprehensively simulate gonococcal infection and their treatment, i.e., compared to static in vitro models, such as short-time checkerboard experiments or time-kill curve analysis. Based on our dynamic in vitro HFIM work, zoliflodacin plus doxycycline for the treatment of both gonorrhea and chlamydia can be an effective combination.
  • ||||||||||  gepotidacin (GSK2140944) / GSK, zoliflodacin (ETX0914) / Entasis Therap, Global Antibiotic Research and Development Partnership
    Review, Journal:  Treatment of bacterial sexually transmitted infections in Europe: gonorrhoea, Mycoplasma genitalium, and syphilis. (Pubmed Central) -  Nov 6, 2023   
    Furthermore, we address the challenges posed by syphilis, where the primary treatment consists of penicillin or doxycycline, with challenges arising in neurosyphilis, allergy, pregnancy, and supply shortages and discuss the ongoing evaluation of alternative antimicrobials (e.g., ceftriaxone, cefixime, linezolid). Our findings identify priority actions and provide concrete solutions for long-term effective management of STIs and antimicrobial resistance mitigation.
  • ||||||||||  zoliflodacin (ETX0914) / Entasis Therap, Global Antibiotic Research and Development Partnership
    Journal:  An Erythrocyte Membrane-Derived Nanosystem for Efficient Reversal of Endothelial Injury in Sepsis. (Pubmed Central) -  Oct 26, 2023   
    Then, zoliflodacin was loaded into Ca-MOF (CMZ) to sterilize, and nanoscale erythrocyte membrane vesicles were prepared by modification with a ?3 peptide on the surface (?3-RM) for precise targeting...Moreover, our findings revealed for the first time that the bactericidal drug zoliflodacin also had anti-inflammatory effects in vivo and in vitro. Therefore, the novel nanosystem (?3-RCMZ) provides a new nanotherapy strategy for sepsis treatment.
  • ||||||||||  zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva
    Enrollment closed, Trial completion date, Head-to-Head:  Zoliflodacin in Uncomplicated Gonorrhoea (clinicaltrials.gov) -  May 12, 2023   
    P3,  N=1092, Active, not recruiting, 
    In conclusion, administration of single 3 and 4 Recruiting --> Active, not recruiting | Trial completion date: Jul 2023 --> Dec 2023
  • ||||||||||  Review, Journal:  Antibiotics with novel mode of action as new weapons to fight antimicrobial resistance. (Pubmed Central) -  May 7, 2023   
    Today, the pipeline of potential new treatments with these characteristics includes promising compounds such as gepotidacin, zoliflodacin, ibezapolstat, MGB-BP-3, CRS-3123, afabicin and TXA-709, which are currently in clinical trials, and lefamulin, which has been recently approved by FDA and EMA. In this review, we report the chemical synthesis, mode of action, structure-activity relationships, in vitro and in vivo activities as well as clinical data of these eight small molecules listed above.
  • ||||||||||  zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva
    Trial completion:  Zoliflodacin Bioequivalence and Drug-Drug Interaction Study (clinicaltrials.gov) -  Mar 1, 2023   
    P1,  N=50, Completed, 
    These approaches enable us to stay one step ahead of adaptive bacteria and safeguard the efficacy of our existing antibiotics. Recruiting --> Completed
  • ||||||||||  zoliflodacin (ETX0914) / Entasis Therap, Global Antibiotic Research and Development Partnership
    Journal:  A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase. (Pubmed Central) -  Jan 22, 2023   
    Zoliflodacin, together with the unrelated novel bacterial topoisomerase inhibitor gepotidacin, is likely to become the first entirely novel chemical entities approved against Gram-negative bacteria in the 21st century. Zoliflodacin may also become the progenitor of a new safer class of antibacterial drugs against other problematic Gram-negative bacteria.
  • ||||||||||  zoliflodacin (ETX0914) / Global Antibiotic Research and Development Partnership, Innoviva
    New P1 trial:  Zoliflodacin Bioequivalence and Drug-Drug Interaction Study (clinicaltrials.gov) -  Dec 2, 2022   
    P1,  N=50, Recruiting, 
  • ||||||||||  zoliflodacin (ETX0914) / Entasis Therap, Global Antibiotic Research and Development Partnership
    Journal:  Impact of Alternative Growth Supplements on Antimicrobial Susceptibility Testing of Neisseria gonorrhoeae. (Pubmed Central) -  Sep 29, 2022   
    The overall MIC results of using hemoglobin as a growth supplement were higher than those of sheep blood and Vitox in the susceptibility testing of these three antibiotics. Compared with the expected results, sheep blood may be considered for the use as an alternative material for N. gonorrhoeae antibiotics susceptibility surveillance, while hemoglobin may not be suitable for supplement to antimicrobial-containing medium.
  • ||||||||||  gepotidacin (GSK2140944) / GSK, zoliflodacin (ETX0914) / Entasis Therap, Global Antibiotic Research and Development Partnership
    Journal:  Europe-wide expansion and eradication of multidrug-resistant Neisseria gonorrhoeae lineages: a genomic surveillance study. (Pubmed Central) -  Jun 8, 2022   
    In the EU and EEA, increasing low-level azithromycin resistance could threaten the recommended ceftriaxone-azithromycin dual therapy, and an evidence-based clinical azithromycin resistance breakpoint is needed. Nevertheless, increasing ceftriaxone susceptibility, declining cefixime resistance, and absence of known resistance mutations for new treatments (zoliflodacin, gepotidacin) are promising.
  • ||||||||||  Journal:  Discovery and Development of Antibacterial Agents: Fortuitous and Designed. (Pubmed Central) -  May 26, 2022   
    This article aims to review the investigational and recently approved antibacterials with a focus on their structure, mechanisms of action/resistance, and spectrum of activity. Delving deep, their success or otherwise in various phases of clinical trials is also discussed while attributing the same to various causal factors.
  • ||||||||||  zoliflodacin (ETX0914) / Entasis Therap, Global Antibiotic Research and Development Partnership
    Journal:  Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity. (Pubmed Central) -  May 18, 2022   
    While the clinical candidate zoliflodacin has progressed to phase 3 trials for the treatment of gonorrhea, compounds herein demonstrated higher inhibitory potency against Mtb DNA gyrase (e.g., compound 42 with IC = 2.0) and lower Mtb minimum inhibitor concentrations (0.49 μM for 42)...DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA, while on-target activity was supported by hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs with Mtb DNA gyrase was developed, and a structural hypothesis was built for structure-activity relationship expansion.
  • ||||||||||  Zyclara (imiquimod) / Mochida, Viatris, Bausch Health, zoliflodacin (ETX0914) / Entasis Therap, Global Antibiotic Research and Development Partnership
    Review, Journal:  Fascinating Molecular and Immune Escape Mechanisms in the Treatment of STIs (Syphilis, Gonorrhea, Chlamydia, and Herpes Simplex). (Pubmed Central) -  Apr 19, 2022   
    Novel drugs can overcome these challenges while nanocarriers enhance their potency, particularly in mucosal areas. This review summarizes the most recent and valuable discoveries regarding the immunopathogenic mechanisms of these sexually transmitted infections and discusses the challenges and opportunities of the novel molecules and nanomaterials.