In Vitro Synergy Testing of Gentamicin, an Old Drug Suggested as Future Treatment Option for Gonorrhoea, in Combination With Six Other Antimicrobials Against Multidrug-Resistant Neisseria gonorrhoeae Strains

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.

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Targeting self-renewal of cancer stem cells in colorectal cancer—a future treatment option?

Nature Reviews Gastroenterology & Hepatology ◽

10.1038/nrgastro.2013.252 ◽

2013 ◽

Vol 11 (2) ◽

pp. 75-75 ◽

Cited By ~ 2

Author(s):

Isobel Leake

Keyword(s):

Colorectal Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Treatment Option ◽

Self Renewal ◽

Future Treatment ◽

Future Treatment Option

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Comparative in Vitro Activity of Zabofloxacin (DW-224a) Tested Against Multidrug-Resistant Neisseria gonorrhoeae

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2008.05.450 ◽

2008 ◽

Vol 12 ◽

pp. e181 ◽

Cited By ~ 1

Author(s):

R. Jones ◽

D. Biedenbach ◽

H. Sader ◽

T. Fritsche ◽

P. Ambrose ◽

...

Keyword(s):

Neisseria Gonorrhoeae ◽

Multidrug Resistant ◽

Vitro Activity ◽

In Vitro Activity

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New β-Lactam–β-Lactamase Inhibitor Combinations

Clinical Microbiology Reviews ◽

10.1128/cmr.00115-20 ◽

2020 ◽

Vol 34 (1) ◽

Cited By ~ 2

Author(s):

Dafna Yahav ◽

Christian G. Giske ◽

Alise Grāmatniece ◽

Henrietta Abodakpi ◽

Vincent H. Tam ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Treatment Option ◽

Clinical Data ◽

Multidrug Resistant ◽

Drug Resistant ◽

Content Type ◽

Carbapenem Resistant ◽

Class D ◽

Lactamase Inhibitor

SUMMARY The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel β-lactam–β-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa. Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D β-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa. Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales. Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa. Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-β-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii. Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales, with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).

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Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914

Journal of Biological Chemistry ◽

10.1074/jbc.m115.663534 ◽

2015 ◽

Vol 290 (34) ◽

pp. 20984-20994 ◽

Cited By ~ 21

Author(s):

Gunther Kern ◽

Tiffany Palmer ◽

David E. Ehmann ◽

Adam B. Shapiro ◽

Beth Andrews ◽

...

Keyword(s):

Neisseria Gonorrhoeae ◽

Bacterial Species ◽

Dna Gyrase ◽

Resistant Mutant ◽

Multidrug Resistant ◽

Type Ii ◽

Topoisomerase Iv ◽

Gram Positive ◽

Gram Negative

We characterized the inhibition of Neisseria gonorrhoeae type II topoisomerases gyrase and topoisomerase IV by AZD0914 (AZD0914 will be henceforth known as ETX0914 (Entasis Therapeutics)), a novel spiropyrimidinetrione antibacterial compound that is currently in clinical trials for treatment of drug-resistant gonorrhea. AZD0914 has potent bactericidal activity against N. gonorrhoeae, including multidrug-resistant strains and key Gram-positive, fastidious Gram-negative, atypical, and anaerobic bacterial species (Huband, M. D., Bradford, P. A., Otterson, L. G., Basrab, G. S., Giacobe, R. A., Patey, S. A., Kutschke, A. C., Johnstone, M. R., Potter, M. E., Miller, P. F., and Mueller, J. P. (2014) In Vitro Antibacterial Activity of AZD0914: A New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-positive, Fastidious Gram-negative, and Atypical Bacteria. Antimicrob. Agents Chemother. 59, 467–474). AZD0914 inhibited DNA biosynthesis preferentially to other macromolecules in Escherichia coli and induced the SOS response to DNA damage in E. coli. AZD0914 stabilized the enzyme-DNA cleaved complex for N. gonorrhoeae gyrase and topoisomerase IV. The potency of AZD0914 for inhibition of supercoiling and the stabilization of cleaved complex by N. gonorrhoeae gyrase increased in a fluoroquinolone-resistant mutant enzyme. When a mutation, conferring mild resistance to AZD0914, was present in the fluoroquinolone-resistant mutant, the potency of ciprofloxacin for inhibition of supercoiling and stabilization of cleaved complex was increased greater than 20-fold. In contrast to ciprofloxacin, religation of the cleaved DNA did not occur in the presence of AZD0914 upon removal of magnesium from the DNA-gyrase-inhibitor complex. AZD0914 had relatively low potency for inhibition of human type II topoisomerases α and β.

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