<i>In Vitro</i>
            Activity of Gepotidacin (GSK2140944) against Neisseria gonorrhoeae

Farrell, Dj; Sader, Hélio S.; Rhomberg, Paul R.; Scangarella-Oman, Nicole; Flamm, Robert K.

doi:10.1128/aac.02047-16

Cited by 55 publications

(59 citation statements)

References 20 publications

(16 reference statements)

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“…Similar results were seen for K. pneumoniae. These findings are consistent with prior single-step resistance selection studies that failed to recover mutants with significant resistance 9,19 . replicates; curve shows the average OD600 values at the corresponding drug concentration.…”

Section: Exceptionally Strong Synergism Between Resistance-associatedsupporting

confidence: 90%

“…Prior studies have demonstrated that gepotidacin selectively inhibits both bacterial DNA gyrase and topoisomerase IV by a unique mechanism 9,17 , but the exact molecular mechanisms of inhibition have not been thoroughly characterized. Therefore, we first sought to study the exact molecular interactions between gepotidacin and Escherichia coli's DNA gyrase and topoisomerase IV protein complexes, using molecular modelling (see Methods).…”

Section: Molecular Modelling With Directed Evolution Accurately Predimentioning

confidence: 99%

“…Currently, designing multi-target antibiotics is a major focus of the pharmaceutical industry, but until now relatively few drugs have been demonstrated to achieve a balanced inhibition of multiple microbial targets. Such exemplary antibiotics include gepotidacin 9 , NBTI 5463 10 , Trius' C3 and C4 11 . However, due to the shortage of indepth resistance studies, our knowledge on the tempo and mode of resistance development against multi-target antibiotics remains limited (but see [12][13][14] ).…”

Section: Introductionmentioning

confidence: 99%

“…The molecule inhibits bacterial DNA gyrase and topoisomerase IV with a novel mode of action. Using a standard frequency-of-resistance test recent studies have failed to identify resistant clones of Neisseria gonorrhoeae and Escherichia coli against this new compound 9,19 , suggesting that individual mutations cannot provide substantial resistance to gepotidacin. It is especially active against Gram-negative pathogens belonging to the Enterobacteriaceae family, such as Klebsiella pneumoniae.…”

Section: Introductionmentioning

confidence: 99%

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Antibiotic usage promotes the evolution of resistance against gepotidacin, a novel multi-targeting drug

Szili

Draskovits

Révész

et al. 2018

Preprint

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Multi-targeting antibiotics, i.e. single compounds capable to inhibit two or more bacterial targets offer a promising therapeutic strategy, but information on resistance evolution against such drugs is scarce.Gepotidacin is an antibiotic candidate that selectively inhibits both bacterial DNA gyrase and topoisomerase IV. In a susceptible organism, Klebsiella pneumoniae, a combination of two specific mutations in these target proteins provide an over 2000-fold increment in resistance, while individually none of these mutations affect resistance significantly. Alarmingly, gepotidacin-resistant strains are found to be as virulent as the wild-type K. pneumoniae strain in a murine model, and extensive crossresistance was demonstrated between gepotidacin and ciprofloxacin, a fluoroquinolone antibiotic widely employed in clinical practice. This suggests that numerous fluoroquinolone-resistant pathogenic isolates carry mutations which would promote the evolution of clinically significant resistance against gepotidacin in the future. We conclude that prolonged antibiotic usage could select for mutations that serve as stepping-stones towards resistance against antimicrobial compounds still under development. More generally, our research indicates that even balanced multi-targeting antibiotics are prone to resistance evolution.

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Section: Exceptionally Strong Synergism Between Resistance-associatedsupporting

confidence: 90%

Section: Molecular Modelling With Directed Evolution Accurately Predimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Antibiotic usage promotes the evolution of resistance against gepotidacin, a novel multi-targeting drug

Szili

Draskovits

Révész

et al. 2018

Preprint

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“…Finally, they may target multiple nonoverlapping regions of a single bacterial protein. Currently, designing multitarget antibiotics is a major focus of the pharmaceutical industry, but until now, relatively few drugs have been demonstrated to achieve a balanced inhibition of multiple microbial targets (8)(9)(10). Due to the shortage of in-depth resistance studies, our knowledge on the tempo and mode of resistance development against multitarget antibiotics remains limited (11)(12)(13).…”

mentioning

confidence: 99%

Rapid Evolution of Reduced Susceptibility against a Balanced Dual-Targeting Antibiotic through Stepping-Stone Mutations

Szili

Draskovits

Révész

et al. 2019

Antimicrob Agents Chemother

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Multitargeting antibiotics, i.e., single compounds capable of inhibiting two or more bacterial targets, are generally considered to be a promising therapeutic strategy against resistance evolution. The rationale for this theory is that multitargeting antibiotics demand the simultaneous acquisition of multiple mutations at their respective target genes to achieve significant resistance. The theory presumes that individual mutations provide little or no benefit to the bacterial host. Here, we propose that such individual stepping-stone mutations can be prevalent in clinical bacterial isolates, as they provide significant resistance to other antimicrobial agents. To test this possibility, we focused on gepotidacin, an antibiotic candidate that selectively inhibits both bacterial DNA gyrase and topoisomerase IV. In a susceptible organism, Klebsiella pneumoniae, a combination of two specific mutations in these target proteins provide an >2,000-fold reduction in susceptibility, while individually, none of these mutations affect resistance significantly. Alarmingly, strains with decreased susceptibility against gepotidacin are found to be as virulent as the wild-type Klebsiella pneumoniae strain in a murine model. Moreover, numerous pathogenic isolates carry mutations which could promote the evolution of clinically significant reduction of susceptibility against gepotidacin in the future. As might be expected, prolonged exposure to ciprofloxacin, a clinically widely employed gyrase inhibitor, coselected for reduced susceptibility against gepotidacin. We conclude that extensive antibiotic usage could select for mutations that serve as stepping-stones toward resistance against antimicrobial compounds still under development. Our research indicates that even balanced multitargeting antibiotics are prone to resistance evolution.

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Pharmacokinetic, Safety, and Tolerability Evaluations of Gepotidacin (GSK2140944) in Healthy Japanese Participants

Barth

Hossain

Perry

et al. 2022

Clinical Pharm in Drug Dev

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Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic in late-phase development for uncomplicated urinary tract infection and uncomplicated urogenital gonorrhea. Two clinical studies were conducted to assess the pharmacokinetics (PK) and interethnic comparisons of oral gepotidacin (free-base and to-be-marketed mesylate formulations) administered as single doses ranging from 1500 to 3000 mg in fed and fasted states, and as 2 × 3000-mg doses given 12 hours apart under fed conditions in healthy participants of Japanese ancestry. Dose proportionality was observed in plasma exposures, and comparable area under the concentration-time curve (AUC) and maximum concentration were observed in fed and fasted states. Interethnic comparisons for Japanese versus non-Japanese participant data showed slightly higher plasma maximum concentration (7%-30%) yet similar plasma AUCs; slightly lower urine AUCs (11%-18%) were observed. The slightly higher plasma exposures in healthy Japanese versus White participants in the same study were attributed to lower mean body weights (64 kg versus ≈80 kg). Adverse events were primarily gastrointestinal, and when administered with food, gastrointestinal tolerability was improved. Overall, the gepotidacin PK and safety-risk profiles in healthy Japanese support potential evaluation of the global clinical doses in future studies.

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In Vitro Activity of Gepotidacin (GSK2140944) against Neisseria gonorrhoeae

Cited by 55 publications

References 20 publications

Antibiotic usage promotes the evolution of resistance against gepotidacin, a novel multi-targeting drug

Antibiotic usage promotes the evolution of resistance against gepotidacin, a novel multi-targeting drug

Rapid Evolution of Reduced Susceptibility against a Balanced Dual-Targeting Antibiotic through Stepping-Stone Mutations

Pharmacokinetic, Safety, and Tolerability Evaluations of Gepotidacin (GSK2140944) in Healthy Japanese Participants

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