<i>In Vitro</i>
            Antibacterial Activity of AZD0914, a New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-Positive, Fastidious Gram-Negative, and Atypical Bacteria

Self Cite

125

cThe unmet medical need for novel intervention strategies to treat Neisseria gonorrhoeae infections is significant and increasing, as rapidly emerging resistance in this pathogen is threatening to eliminate the currently available treatment options. AZD0914 is a novel bacterial gyrase inhibitor that possesses potent in vitro activities against isolates with high-level resistance to ciprofloxacin and extended-spectrum cephalosporins, and it is currently in clinical development for the treatment of N. gonorrhoeae infections. The propensity to develop resistance against AZD0914 was examined in N. gonorrhoeae and found to be extremely low, a finding supported by similar studies with Staphylococcus aureus. The genetic characterization of both first-step and second-step mutants that exhibited decreased susceptibilities to AZD0914 identified substitutions in the conserved GyrB TOPRIM domain, confirming DNA gyrase as the primary target of AZD0914 and providing differentiation from fluoroquinolones. The analysis of available bacterial gyrase and topoisomerase IV structures, including those bound to fluoroquinolone and nonfluoroquinolone inhibitors, has allowed the rationalization of the lack of cross-resistance that AZD0914 shares with fluoroquinolones. Microbiological susceptibility data also indicate that the topoisomerase inhibition mechanisms are subtly different between N. gonorrhoeae and other bacterial species. Taken together, these data support the progression of AZD0914 as a novel treatment option for the oral treatment of N. gonorrhoeae infections.

Section: Resultsmentioning

confidence: 99%

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

Alm

Lahiri

Kutschke

et al. 2015

Self Cite

125

“…Cross-resistance between AZD0914 and other important Gram-positive class agents, including fluoroquinolones, ␤-lactams, macrolides, and glycopeptides, was not observed. The current indication being pursued for AZD0914 is uncomplicated gonococcal infections with additional in vitro activity demonstrated against other organisms responsible for sexually transmitted infections (STI), including C. trachomatis (13)(14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

“…AZD0914 has a primary spectrum of activity that includes clinically relevant Gram-positive and fastidious Gram-negative bacterial species, including N. gonorrhoeae (12)(13)(14)(15). Published in vitro data on Chlamydia trachomatis and Chlamydia pneumoniae have shown that AZD0914 also has activity against these species (16).…”

mentioning

confidence: 99%

In Vitro Activity of AZD0914, a Novel Bacterial DNA Gyrase/Topoisomerase IV Inhibitor, against Clinically Relevant Gram-Positive and Fastidious Gram-Negative Pathogens

Biedenbach¹,

Huband

Hackel³

et al. 2015

Self Cite

Following the introduction of nalidixic acid into clinical practice in the 1960s, fluoroquinolones have undergone profound structural modifications, leading to the development of numerous molecules in this class (1-3). Modifications to the quinolone structure, particularly the addition of fluorine(s) at key positions, have provided compounds with increased potency, broader spectrum of activity, and acceptable safety profiles. However, safety has been problematic in fluoroquinolone development (4-6). Several potent compounds have either been determined to be unsuitable for human use due to unacceptable toxicities, have required black box warnings on their labels, have been restricted to topical applications, or have resulted in removal from the market (7-9). Resistance development to fluoroquinolones is also becoming a significant concern among several Gram-positive and Gramnegative pathogens, including Staphylococcus aureus, Escherichia coli, and Neisseria gonorrhoeae.AZD0914 is a new orally administered spiropyrimidinetrione bacterial DNA gyrase inhibitor that demonstrates a novel mode of inhibition distinct from that of fluoroquinolones (10, 11). AZD0914 is a selective and potent inhibitor of the supercoiling and decatenation activity of DNA gyrase and topoisomerase IV, with the ability to overcome fluoroquinolone resistance by the inhibition of DNA biosynthesis through the accumulation of double-stranded cleaved DNA bound to the tetramer topoisomerase II.AZD0914 has a primary spectrum of activity that includes clinically relevant Gram-positive and fastidious Gram-negative bacterial species, including N. gonorrhoeae (12)(13)(14)(15). Published in vitro data on Chlamydia trachomatis and Chlamydia pneumoniae have shown that AZD0914 also has activity against these species (16). Its activity is maintained against strains with common fluoroquinolone resistance mutations in gyrase and topoisomerase IV within the quinolone resistance-determining region (QRDR) (12). Resistance to other key antimicrobial classes, such as ␤-lactams, macrolides, and glycopeptides, also do not diminish the activity of AZD0914. Currently, AZD0914 is being investigated in phase 2 trials for the treatment of uncomplicated N. gonorrhoeae infections (14,15).In this study, the in vitro activity of AZD0914 against key bacterial groups isolated from intra-abdominal, urinary tract, skin and soft tissue, and respiratory tract infections collected in a 2013 global surveillance survey was analyzed and compared to that of levofloxacin, moxifloxacin, and other nonfluoroquinolone compounds.(This study was presented, in part, at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy in 2014 [12].) MATERIALS AND METHODSClinical isolates (n ϭ 21,152) from hospitalized patients were collected at 169 medical centers in 39 countries distributed across North America, Latin America, Europe, Asia-Pacific, and Middle East/Africa during 2013. Isolates were obtained from specimens collected from patients with documented intra-abdominal infections...

“…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)(13)(14)(15). Cross-resistance between ETX0914 and fluoroquinolones has not been observed (16).…”

mentioning

confidence: 99%

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

Wang

et al. 2016

Self Cite

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...