Characterization of the Novel DNA Gyrase Inhibitor AZD0914: Low Resistance Potential and Lack of Cross-Resistance in Neisseria gonorrhoeae

Alm, Richard A.; Lahiri, S. C.; Kutschke, Amy; Otterson, Linda G.; McLaughlin, Robert E.; Whiteaker, James; Lewis, Lisa A.; Su, Xiaohong; Huband, Michael D.; Gardner, Humphrey; Mueller, John P.

doi:10.1128/aac.04456-14

Cited by 80 publications

(147 citation statements)

References 30 publications

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“…Notably, several antimicrobials or other compounds, using new targets or mechanisms, were recently developed, and several have shown high in vitro activities against gonococcal isolates. These include novel inhibitors of protein synthesis, e.g., pleuromutilin BC-3781 (318,319) and the boron-containing inhibitor AN3365 (320,321); novel inhibitors of bacterial topoisomerases that target regions different from the fluoroquinolone-binding sites (322,323), such as VT12-008911 (324) and AZD0914 (323,325,326); FabI inhibitors, such as MUT056399 (327,328); noncytotoxic nanomaterials (329); inhibitors of efflux pumps, particularly coadministered with appropriate antimicrobials, that increase the susceptibility to certain antimicrobials, the innate host defense, and toxic metabolites (234,260,330); LpxC inhibitors (331); molecules mimicking host defensins; host defense peptides, such as LL-37 (multifunctional cathelicidin peptide) (332); and IL-12 NanoCap, which is a biodegradable sustained-release formulation of human interleukin 12 that aims to be a therapeutic vaccine against N. gonorrhoeae (TherapyX Inc.). Several of these novel antimicrobials or other types of compounds deserve further attention for their potential use as future treatments for gonorrhea.…”

Section: Future Perspectives For Treatmentmentioning

confidence: 99%

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

2014

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SUMMARY Neisseria gonorrhoeae is evolving into a superbug with resistance to previously and currently recommended antimicrobials for treatment of gonorrhea, which is a major public health concern globally. Given the global nature of gonorrhea, the high rate of usage of antimicrobials, suboptimal control and monitoring of antimicrobial resistance (AMR) and treatment failures, slow update of treatment guidelines in most geographical settings, and the extraordinary capacity of the gonococci to develop and retain AMR, it is likely that the global problem of gonococcal AMR will worsen in the foreseeable future and that the severe complications of gonorrhea will emerge as a silent epidemic. By understanding the evolution, emergence, and spread of AMR in N. gonorrhoeae , including its molecular and phenotypic mechanisms, resistance to antimicrobials used clinically can be anticipated, future methods for genetic testing for AMR might permit region-specific and tailor-made antimicrobial therapy, and the design of novel antimicrobials to circumvent the resistance problems can be undertaken more rationally. This review focuses on the history and evolution of gonorrhea treatment regimens and emerging resistance to them, on genetic and phenotypic determinants of gonococcal resistance to previously and currently recommended antimicrobials, including biological costs or benefits; and on crucial actions and future advances necessary to detect and treat resistant gonococcal strains and, ultimately, retain gonorrhea as a treatable infection.

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Section: Future Perspectives For Treatmentmentioning

confidence: 99%

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

2014

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“…The quinolone resistance-determining region (QRDR) of the gyrA gene and an AZD0914 resistance-determining region of gyrB (28) were sequenced to verify the lack of cross-resistance to fluoroquinolones and AZD0914 resistance mutations, respectively.…”

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confidence: 99%

High In Vitro Activity of the Novel Spiropyrimidinetrione AZD0914, a DNA Gyrase Inhibitor, against Multidrug-Resistant Neisseria gonorrhoeae Isolates Suggests a New Effective Option for Oral Treatment of Gonorrhea

Jacobsson

Golparian

Alm

et al. 2014

Antimicrob Agents Chemother

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We evaluated the activity of the novel spiropyrimidinetrione AZD0914 (DNA gyrase inhibitor) against clinical gonococcal isolates and international reference strains (n ‫؍‬ 250), including strains with diverse multidrug resistance and extensive drug resistance. The AZD0914 MICs were substantially lower than those of most other currently or previously recommended antimicrobials. AZD0914 should be further evaluated, including in vitro selection, in vivo emergence and mechanisms of resistance, pharmacokinetics/pharmacodynamics in humans, optimal dosing, and performance, in appropriate randomized and controlled clinical trials. Gonorrhea is a significant public health problem globally (1). Neisseria gonorrhoeae has developed antimicrobial resistance (AMR) to all drugs previously used as first-line treatments. In the past decade, resistance to the last options for empirical first-line antimicrobial monotherapy, i.e., the extended-spectrum cephalosporins (ESCs) cefixime and ceftriaxone, has emerged (2-18). Alarmingly, extensively drug-resistant (XDR) (3) gonococcal isolates with high-level ESC resistance were recently described (9,13,19).The World Health Organization (WHO) (20), Centers for Disease Control and Prevention (CDC) (21), and European Centre for Disease Prevention and Control (ECDC) (22) have published action plans aiming to control the spread of AMR gonorrhea. One of the few new antimicrobial classes incorporates a novel spiropyrimidinetrione that operates via a novel DNA gyrase/topoisomerase IV mode-of-inhibition (23). DNA gyrase (GyrA 2 and GyrB 2 ) and topoisomerase IV (ParC 2 and ParE 2 ) are type II DNA topoisomerases, which catalyze changes in the topology of DNA and their function is vital for DNA replication, repair, and decatenation (24-27). AZD0914 (Fig. 1) is a novel spiropyrimidinetrione that inhibits DNA biosynthesis, causing accumulations of doublestrand cleavages, that was recently shown to have potent in vitro activity against many different bacterial species (23).We detailed the in vitro activity of the novel spiropyrimidinetrione AZD0914 against a large geographically (global representativeness), temporally (obtained from 1991 to 2013), and genetically diverse collection of clinical gonococcal isolates and international reference strains (n ϭ 250). The quinolone resistance-determining region (QRDR) of the gyrA gene and an AZD0914 resistance-determining region of gyrB (28) were sequenced to verify the lack of cross-resistance to fluoroquinolones and AZD0914 resistance mutations, respectively.The strains comprised 29 international gonococcal reference strains, including the 2008 WHO reference strains (29), 100 consecutive clinical Swedish gonococcal isolates obtained in 2013, and 121 isolates selected for their resistance phenotype. The collection included all of the currently described XDR gonococcal strains (9, 13, 19), additional isolates with in vitro and clinical ESC resistance (8-11, 13, 15, 16), different types of ciprofloxacin resistance, and other high-level clinical resistance and ...

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“…and Moraxella catarrhalis, and also atypical and anaerobic organisms (12)(13)(14)(15). Cross-resistance between ETX0914 and fluoroquinolones has not been observed (16). The rates of resistance in N. gonorrhoeae to ciprofloxacin and other antimicrobials have been high in China (17)(18)(19)(20)(21).…”

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confidence: 93%

Multidrug-Resistant Neisseria gonorrhoeae Isolates from Nanjing, China, Are Sensitive to Killing by a Novel DNA Gyrase Inhibitor, ETX0914 (AZD0914)

Wang

et al. 2016

Antimicrob Agents Chemother

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We tested the activity of ETX0914 against 187 Neisseria gonorrhoeae isolates from men with urethritis in Nanjing, China, in 2013. The MIC 50 , MIC 90 , and MIC range for ETX0914 were 0.03 g/ml, 0.06 g/ml, and <0.002 to 0.125 g/ml, respectively. All isolates were resistant to ciprofloxacin, and 36.9% (69/187) were resistant to azithromycin. Of the isolates, 46.5% were penicillinase-producing N. gonorrhoeae (PPNG), 36% were tetracycline-resistant N. gonorrhoeae (TRNG), and 13% (24 isolates) had an MIC of 0.125 g/ml for ceftriaxone. ETX0914 may be an effective treatment option for gonorrhea. In the absence of an effective gonococcal vaccine, the prevention and control of gonorrhea depend on early diagnosis and effective antimicrobial therapy for patients at risk for acquiring infection and their sex partners. Currently, the first-line agents for the treatment of gonorrhea in most countries are extended-spectrum cephalosporins (ESCs), such as cefixime and ceftriaxone. However, gonococcal strains with reduced susceptibility or frank resistance to ESCs have emerged, and treatment failures with the oral agent cefixime (1-5) and injectable ceftriaxone have been documented in several countries (6-10).ETX0914 (also known as AZD0914) is a novel spiropyrimidinetrione bacterial DNA gyrase/topoisomerase inhibitor, which functions by inhibiting DNA biosynthesis and stabilizing cleaved covalent complexes of gyrase and double-stranded broken DNA. This results in the blockage of religation of the double-strand cleaved DNA to form fused circular DNA (11). ETX0914 has displayed potent in vitro antibacterial activity against N. gonorrhoeae, including multidrugresistant strains, certain Gram-positive organisms, such as Staphylococcus aureus and Streptococcus pneumoniae, and fastidious Gramnegative organisms, such as Haemophilus spp. and Moraxella catarrhalis, and also atypical and anaerobic organisms (12-15). Cross-resistance between ETX0914 and fluoroquinolones has not been observed (16). The rates of resistance in N. gonorrhoeae to ciprofloxacin and other antimicrobials have been high in China (17-21). Our previous study showed that 99.8% of the N. gonorrhoeae strains isolated from symptomatic men attending a sexually transmitted diseases (STD) clinic in Nanjing, China, between April 2011 and December 2012 were resistant to ciprofloxacin (22). Here, we investigated the in vitro activity of ETX0914 against 187 clinical gonococcal strains isolated from men with gonococcal urethritis attending this clinic a year later in 2013, and we compared the activity of ETX0914 to that of other currently or previously used antimicrobials administered for the treatment of gonorrhea.The Gram stains of 177/187 urethral exudates showed polymorphonuclear leukocytes (PMNs) and Gram-negative intracellular diplococci, criteria that are highly specific (Ͼ99%) for gonococcal infection (23-24). Urethral swab specimens from men with urethritis were also inoculated onto Thayer-Martin medium (DL Biotech, China) and cultured in candle jars at 36°C. Gonococcal i...

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Characterization of the Novel DNA Gyrase Inhibitor AZD0914: Low Resistance Potential and Lack of Cross-Resistance in Neisseria gonorrhoeae

Cited by 80 publications

References 30 publications

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

High In Vitro Activity of the Novel Spiropyrimidinetrione AZD0914, a DNA Gyrase Inhibitor, against Multidrug-Resistant Neisseria gonorrhoeae Isolates Suggests a New Effective Option for Oral Treatment of Gonorrhea

Multidrug-Resistant Neisseria gonorrhoeae Isolates from Nanjing, China, Are Sensitive to Killing by a Novel DNA Gyrase Inhibitor, ETX0914 (AZD0914)

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