scholarly journals Stemming the tide of drug-resistant Neisseria gonorrhoeae: the need for an individualized approach to treatment

2014 ◽  
Vol 70 (2) ◽  
pp. 374-381 ◽  
Author(s):  
S. A. Buono ◽  
T. D. Watson ◽  
L. A. Borenstein ◽  
J. D. Klausner ◽  
M. W. Pandori ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Drug Resistant ◽  
Individualized Approach

scholarly journals trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zachary D. Aron ◽  
Atousa Mehrani ◽  
Eric D. Hoffer ◽  
Kristie L. Connolly ◽  
Pooja Srinivas ◽  
...  
Keyword(s):  
Oral Dose ◽  
Neisseria Gonorrhoeae ◽  
Multiple Drug ◽  
Specific Inhibition ◽  
Drug Resistant ◽  
Peptidyl Transfer ◽  
Bacterial Ribosome ◽  
Multiple Drug Resistant ◽  
Unique Site

AbstractBacterial ribosome rescue pathways that remove ribosomes stalled on mRNAs during translation have been proposed as novel antibiotic targets because they are essential in bacteria and are not conserved in humans. We previously reported the discovery of a family of acylaminooxadiazoles that selectively inhibit trans-translation, the main ribosome rescue pathway in bacteria. Here, we report optimization of the pharmacokinetic and antibiotic properties of the acylaminooxadiazoles, producing MBX-4132, which clears multiple-drug resistant Neisseria gonorrhoeae infection in mice after a single oral dose. Single particle cryogenic-EM studies of non-stop ribosomes show that acylaminooxadiazoles bind to a unique site near the peptidyl-transfer center and significantly alter the conformation of ribosomal protein bL27, suggesting a novel mechanism for specific inhibition of trans-translation by these molecules. These results show that trans-translation is a viable therapeutic target and reveal a new conformation within the bacterial ribosome that may be critical for ribosome rescue pathways.

scholarly journals Susceptibility trends of zoliflodacin against multidrug-resistant Neisseria gonorrhoeae clinical isolates in Nanjing, China (2014-2018)

2020 ◽  
Author(s):  
Wenjing Le ◽  
Xiaohong Su ◽  
Xiangdi Lou ◽  
Xuechun Li ◽  
Xiangdong Gong ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Dna Sequencing ◽  
Multidrug Resistant ◽  
Quinolone Resistance ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Extended Spectrum ◽  
High Level ◽  
Level Resistance

ABSTRACTPreviously, we reported potent activity of a novel spiropyrimidinetrione, zoliflodacin, against N. gonorrhoeae isolates from symptomatic men in Nanjing, China, collected in 2013. Here, we investigated trends of susceptibilities of zoliflodacin in 986 gonococcal isolates collected from men between 2014 and 2018. N. gonorrhoeae isolates were tested for susceptibility to zoliflodacin and seven other antibiotics. Mutations in gyrA, gyrB, parC and parE genes were determined by PCR and DNA sequencing. The MIC of zoliflodacin for N. gonorrhoeae ranged from ≤0.002 to 0.25 mg/L; the overall MIC50s and MIC90s were 0.06 mg/L and 0.125mg/L in 2018, increasing two-fold from 2014. However, the percent of isolates with lower zoliflodacin MICs declined in each year sequentially while the percent with higher MICs increased yearly (P≤0.00001). All isolates were susceptible to spectinomycin but resistant to ciprofloxacin (MIC ≥1 μg/ml); 21.2% (209/986) were resistant to azithromycin (≥1 μg/ml), 43.4% (428/986) were penicillinase-producing (PPNG), 26.9% (265/986) tetracycline-resistant (TRNG) and 19.4% (191/986) were multi-drug resistant (MDR) isolates. Among 143 isolates with higher zoliflodacin MICs (0.125-0.25 mg/L), all had quinolone resistance associated double or triple mutations in gyrA; 139/143 (97.2%) also had mutations in parC. There were no D429N/A and/or K450T mutations in GyrB identified in the 143 isolates with higher zoliflodacin MICs; a S467N mutation in GyrB was identified in one isolate. We report that zoliflodacin has excellent in vitro activity against clinical gonococcal isolates, including those with high-level resistance to ciprofloxacin, azithromycin and extended spectrum cephalosporins.

scholarly journals Detection in the United Kingdom of the Neisseria gonorrhoeae FC428 clone, with ceftriaxone resistance and intermediate resistance to azithromycin, October to December 2018

2019 ◽  
Vol 24 (10) ◽  
Author(s):  
David W Eyre ◽  
Katy Town ◽  
Teresa Street ◽  
Leanne Barker ◽  
Nicholas Sanderson ◽  
...  
Keyword(s):  
United Kingdom ◽  
Neisseria Gonorrhoeae ◽  
Whole Genome ◽  
Drug Resistant ◽  
Genome Sequences ◽  
Sexual Network ◽  
The United Kingdom ◽  
Intermediate Resistance ◽  
Azithromycin Resistance ◽  
Urgent Action

We describe detection in the United Kingdom (UK) of the drug-resistant Neisseria gonorrhoeae FC428 clone, with ceftriaxone resistance and intermediate azithromycin resistance. Two female patients developed infection following contact with UK-resident men from the same sexual network linked to travel to Ibiza, Spain. One case failed treatment with ceftriaxone, and azithromycin and gentamicin, before successful treatment with ertapenem. Both isolates had indistinguishable whole-genome sequences. Urgent action is essential to contain this drug-resistant strain.

scholarly journals New treatment options for Neisseria gonorrhoeae in the era of emerging antimicrobial resistance

Sexual Health ◽  
2019 ◽  
Vol 16 (5) ◽  
pp. 449 ◽  
Author(s):  
David A. Lewis
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Sex Workers ◽  
Antimicrobial Agents ◽  
Treatment Options ◽  
Single Agent ◽  
Dual Therapy ◽  
Clinical Development ◽  
Drug Resistant ◽  
Therapy Regimen ◽  
First Line Therapy

Neisseria gonorrhoeae, the causative agent of gonorrhoea, has rapidly evolved from an exquisitely susceptible pathogen into a ‘superbug’ with the capacity to exhibit an extensively drug resistant (XDR) phenotype. The threat of untreatable gonorrhoea now looms on the horizon while the arsenal of effective antimicrobial agents diminishes with time. Ceftriaxone remains the mainstay of first-line therapy as a single agent or as the backbone of a dual therapy regimen. The implementation of new assays to facilitate ‘precision’ treatment, based on the prediction of N. gonorrhoeae susceptibility to old anti-gonococcal drugs, may enable sparing use of ceftriaxone in those countries that can afford this technology. A few existing drugs, such as ertapenem, can be repositioned to help manage multi-drug resistant and XDR gonorrhoea. Recent clinical trials involving solithromycin and delafloxacin have generated disappointing results in that both agents failed to show non-inferiority to conventional ceftriaxone-based regimens. At present, zoliflodacin and gepotidacin appear to be the most promising antimicrobial agents in clinical development. Both drugs performed well in eradicating urogenital gonorrhoea in recent Phase 2 trials; however, treatment failures were reported at the oropharyngeal site, which is an important site of infection in men who have sex with men and sex workers. Given this observation, it is unlikely that either of these new agents could be promoted for monotherapy of gonorrhoea. The pre-clinical pipeline remains relatively empty of agents likely to progress to clinical development for gonorrhoea treatment and increased investment into gonorrhoea-specific drug discovery is recommended.

scholarly journals Molecular epidemiology of drug-resistant Neisseria gonorrhoeae in Russia (Current Status, 2015)

2016 ◽  
Vol 16 (1) ◽  
Author(s):  
Alexey Kubanov ◽  
Denis Vorobyev ◽  
Aleksandr Chestkov ◽  
Arvo Leinsoo ◽  
Boris Shaskolskiy ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Molecular Epidemiology ◽  
Current Status ◽  
Drug Resistant

scholarly journals Accuracy and reproducibility of the Etest to detect drug-resistant Neisseria gonorrhoeae to contemporary treatment

2018 ◽  
Vol 67 (1) ◽  
pp. 68-73 ◽  
Author(s):  
John R. Papp ◽  
Marie-Claire Rowlinson ◽  
Norman P. O’Connor ◽  
Jason Wholehan ◽  
Jafar H. Razeq ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Drug Resistant

scholarly journals Antimicrobial Susceptibility of Neisseria gonorrhoeae Isolates in Baltimore, Maryland, 2016: The Importance of Sentinel Surveillance in the Era of Multi-Drug-Resistant Gonorrhea

Antibiotics ◽  
2018 ◽  
Vol 7 (3) ◽  
pp. 77 ◽  
Author(s):  
Johan Melendez ◽  
Justin Hardick ◽  
Mathilda Barnes ◽  
Kathleen Page ◽  
Charlotte Gaydos
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Antimicrobial Susceptibility ◽  
Tetracycline Resistance ◽  
Sentinel Surveillance ◽  
Test Method ◽  
Nucleic Acid Amplification ◽  
Drug Resistant ◽  
Surveillance Programs ◽  
Resistance To Penicillin ◽  
High Level

The increasing rates of gonorrhea infections and the global emergence and spread of multi-drug-resistant Neisseria gonorrhoeae (NG) threaten the successful management of gonorrhea. In the era of nucleic acid amplification tests (NAATs), surveillance projects are urgently needed to monitor prevalence and trends in the antimicrobial susceptibility of NG. In this study, we retrospectively determined the susceptibility profile of NG isolates to previously and currently prescribed antimicrobials. NG isolates collected in Baltimore, Maryland between January and October 2016 were evaluated by the E-test method and/or molecular methods for susceptibility to ceftriaxone, azithromycin, ciprofloxacin, tetracycline, gentamicin, and penicillin. One-hundred and forty-three NG isolates from African-American males (98.6%), primarily heterosexual (88.8%), ranging in age from 15 to 69 years of age were included in the study. Ciprofloxacin resistance was observed in 44.1% of isolates. Plasmid-mediated resistance to penicillin and tetracycline resistance was detected in 22.4% and 10.1% of isolates, respectively. Three isolates (2.1%) displayed high-level resistance to azithromycin (minimum inhibitory concentration (MIC) > 256 μg/mL). Forty-three percent of isolates were resistant or had decreased susceptibility to three antimicrobials (ciprofloxacin, tetracycline, and penicillin). All isolates were susceptible to ceftriaxone and gentamicin. Overall, the epidemiology of antimicrobial resistant NG in Baltimore continues to evolve, and the emergence of azithromycin resistance in this population emphasizes the need for continued sentinel surveillance programs to monitor susceptibility trends and aid in treatment recommendations.

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