Pharmacodynamic evaluation of zoliflodacin treatment of Neisseria gonorrhoeae strains with amino acid substitutions in the zoliflodacin target GyrB using a dynamic Hollow Fiber Infection Model
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ABSTRACT:
PROVIDER: PRJEB50904 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR8961040_1.fastq.gz | Fastqsanger.gz | |||
| ERR8961040_2.fastq.gz | Fastqsanger.gz | |||
| ERR8961042_1.fastq.gz | Fastqsanger.gz | |||
| ERR8961042_2.fastq.gz | Fastqsanger.gz |
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Project description:Pharmacodynamic evaluation of dosing, bacterial kill and resistance suppression for zoliflodacin against Neisseria gonorrhoeae in a dynamic Hollow Fibre Infection Model (HFIM)
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Project description:Novel antimicrobials for effective treatment of uncomplicated gonorrhea are essential, and the first-in-class, oral spiropyrimidinetrione DNA gyrase B inhibitor zoliflodacin appears promising. Using our newly developed Hollow Fiber Infection Model (HFIM), the pharmacodynamics of zoliflodacin was examined. A clinical zoliflodacin-susceptible N. gonorrhoeae strain, SE600/18 (harbouring a GyrB S467N amino acid substitution; MIC = 0.25 mg/L), and SE600/18-D429N (zoliflodacin-resistant mutant with a second GyrB substitution, D429N, selected in the HFIM experiments; zoliflodacin MIC = 2 mg/L), were examined. Dose-range experiments, simulating zoliflodacin single oral dose regimens of 0.5, 1, 2, 3, and 4 g, were performed for SE600/18. For SE600/18-D429N, dose-range experiments, simulating zoliflodacin single oral 2, 3, 4, and 6 g doses, and zoliflodacin oral dose-fractionation experiments with 4, 6, and 8 g administered as q12 h were performed. Both strains grew well in the untreated HFIM growth control arms and mostly maintained growth at 1010-1011 CFU/ml for 7 days. Zoliflodacin 3 and 4 g single dose oral regimens successfully eradicated SE600/18 and no growth was recovered during the 7-days experiments. However, the single oral 0.5, 1, and 2 g doses failed to eradicate SE600/18, and zoliflodacin-resistant populations with a GyrB D429N substitution were selected with all these doses. The zoliflodacin-resistant SE600/18-D429N mutant was not eradicated with any examined treatment regimen. However, this in vitro-selected zoliflodacin-resistant mutant was substantially less fit compared to the zoliflodacin-susceptible SE600/18 parent strain. In conclusion, the rare clinical gonococcal strains with GyrB S467N substitution are predisposed to develop zoliflodacin resistance and may require treatment with zoliflodacin ≥3 g. Future development may need to consider the inclusion of diagnostics directed at identifying strains resistant or predisposed to resistance development at a population level and to strengthen surveillance (phenotypically and genetically), and possibly also at the patient level to guide treatment.
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Project description:Pharmacodynamics of zoliflodacin and doxycycline in gonorrhea treatment
| PRJEB64051 | ENA
Project description:Antimicrobial resistance in Neisseria gonorrhoeae is threatening the treatment and control of gonorrhea globally, and new treatment options are imperative. Utilizing our dynamic in vitro hollow fiber infection model (HFIM), we examined the pharmacodynamics of the first-in-class spiropyrimidinetrione (DNA gyrase B inhibitors), zoliflodacin, against the N. gonorrhoeae reference strains World Health Organization F (susceptible to all relevant antimicrobials) and WHO X (extensively drug resistant, including resistance to ceftriaxone) over 7 days. Dose-range experiments with both strains, simulating zoliflodacin single oral dose regimens of 0.5-8 g, and dose-fractionation experiments with WHO X, simulating zoliflodacin oral dose therapy with 1-4 g administered as q12 h and q8 h for 24 h, were performed. A kill-rate constant that reflected a rapid bacterial kill during the first 6.5 h for both strains and all zoliflodacin doses was identified. In the dose-range experiments, the zoliflodacin 2-8 g single-dose treatments successfully eradicated both WHO strains, and resistance to zoliflodacin was not observed. However, zoliflodacin as a single 0.5 g dose failed to eradicate both WHO strains, and a 1 g single dose failed to eradicate WHO X in one of two experiments. The zoliflodacin 1 g/day regimen also failed to eradicate WHO X when administered as two and three divided doses given at q12 h and q8 h in the dose-fractionation studies, respectively. All failed regimens selected for zoliflodacin-resistant mutants. In conclusion, these data demonstrate that zoliflodacin should be administered at >2 g as a single oral dose to provide effective killing and resistance suppression of N. gonorrhoeae. Future studies providing pharmacokinetic data for zoliflodacin (and other gonorrhea therapeutic antimicrobials) in urogenital and extragenital infection sites, particularly in the pharynx, and evaluation of gonococcal strains with different gyrB mutations would be important.
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Project description:Pharmacodynamic evaluation of lefamulin in the treatment of gonorrhea
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Project description:Knowledge of pharmacokinetic/pharmacodynamic (PK/PD) relationships can enhance the speed and economy of drug development by enabling informed and rational decisions at every step, from lead selection to clinical dosing. For anti-infective agents in particular, dynamic in vitro hollow-fiber cartridge experiments permit exquisite control of kinetic parameters and the study of their consequent impact on pharmacodynamic efficacy. Such information is of great interest for the cost-restricted but much-needed development of new antimalarial drugs, especially since the major human pathogen Plasmodium falciparum can be cultivated in vitro but is not readily available in animal models. This protocol describes the materials and procedures for determining the PK/PD relationships of antimalarial compounds.
| S-EPMC4811375 | biostudies-literature
Project description:Purpose: In this study, we aimed to elucidate the specific molecular mechanisms that are activated when hepatic cells are cultured in the 3D environment of an interwoven hollow fiber bioreactor device. Methods: HepG2 human hepatocellular carcinoma cells were either cultured in an interwoven hollow fiber bioreactor or on a conventional two-dimensional (2D) surface. The cells were harvested and RNA sequencing was performed to identify the differentially expressed genes between the two culture conditions. Ingenuity Pathway Analysis (IPA) software was utilized to algorithmically generate gene networks and canonical pathways that were either activated or repressed as a result of the experimental conditions. Results: RNA sequencing analysis identified 5,711 genes that were differentially expressed (FDR < 0.05). Of these, 1,248 genes were biologically upregulated (FC > 2) and 629 genes were biologically downregulated (FC < -2). Several of these upregulated genes have known associations with metabolic activity, cellular proliferation, and apico-basal cell organization. IPA analysis confirmed the likely activation of metabolic pathways in 3D culture and suggest a strong relationship between hepatic metabolism, cell-cell interactions, and polarity markers Conclusions: Our results demonstrate the likely activation of metabolic pathways in 3D culture and suggest a strong relationship between hepatic metabolism, cell-cell interactions, and polarity markers. Further experimentation must be performed to further elucidate the connections between these pathways.
2025-05-27 | GSE132043 | GEO
Project description:Antimicrobial resistance in the sexually transmitted bacterium Neisseria gonorrhoeae is compromising the management and control of gonorrhea globally. Optimized use and enhanced stewardship of current antimicrobials and development of novel antimicrobials are imperative. 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. Doxycycline, the first-line treatment for chlamydia and empiric treatment for non-gonococcal urethritis, will be frequently given together with zoliflodacin because gonorrhea and chlamydia coinfections are common. 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. In this study, our dynamic in vitro hollow-fiber infection model (HFIM) was used to investigate combination therapies with zoliflodacin and doxycycline. Dose-range experiments using the three gonococcal strains WHO F (susceptible to relevant therapeutic antimicrobials), WHO X (extensively drug-resistant, including ceftriaxone-resistant; zoliflodacin-susceptible), and SE600/18 (zoliflodacin-susceptible strain with GyrB S467N substitution) were conducted simulating combination therapy with a single oral dose of zoliflodacin 0.5-4 g combined with a doxycycline daily oral dose of 200 mg administered as 100 mg twice a day, for 7 days (standard dose for chlamydia treatment). Comparing combination therapy of zoliflodacin (0.5-4 g single dose) plus doxycycline (200 mg divided into 100 mg twice a day orally, for 7 days) to zoliflodacin monotherapy (0.5-4 g single dose) showed that combination therapy was slightly more effective than monotherapy in the killing of N. gonorrhoeae and suppressing emergence of zoliflodacin resistance. Accordingly, WHO F was eradicated by only 0.5 g single dose of zoliflodacin in combination with doxycycline, and WHO X and SE600/18 were both eradicated by a 2 g single dose of zoliflodacin in combination with doxycycline; no zoliflodacin-resistant populations occurred during the 7-day experiment when using this zoliflodacin dose. When using suboptimal (0.5-1 g) zoliflodacin doses together with doxycycline, gonococcal mutants with increased zoliflodacin MICs, due to GyrB D429N and the novel GyrB T472P, emerged, but both the mutants had an impaired biofitness. 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.
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Project description:Liver-on-a-chip models predictive for both metabolism and transport of drug candidates in humans are lacking. Here, we have established an advanced, bioengineered and animal-free hepatocyte-like millifluidic system based on 3D hollow fiber membranes (HFMs), recombinant human laminin 332 and adult human stem cell-derived organoids. Organoid cells formed polarized and tight monolayers on HFMs, which displayed improved hepatocyte-like maturation over standard organoid cultures in Matrigel from matched donors. mRNA sequencing and immunofluorescence revealed that HFM cultures exhibited the expression of broad panel of phase I and II drug metabolizing enzymes, and of drug transporters. Functionally, in both static conditions and under flow circulation, HFM monolayers metabolized a cocktail of drugs that are targets for most important phase I and II enzymes. In addition, we were able to study disposition of those parental compounds and their metabolites in the basal circulation and apical compartment of the chip. Moreover, we demonstrated that our system can be used to study drug disposition in a modular setting with other PK/ADME-relevant organ systems. In conclusion, we have generated a proof-of-concept liver organoid-on-a-chip model for examining both metabolism and transport of drugs, which can be further developed towards prediction of PK/ADME profiles in humans.
2025-03-05 | GSE269150 | GEO