Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea

Taylor, Stephanie N.; Marrazzo, Jeanne; Batteiger, Byron E.; Hook, Edward W.; Seña, Arlene C.; Long, Jill; Wierzbicki, Michael R.; Kwak, Hannah; Johnson, Shacondra M.; Lawrence, Kenneth; Mueller, John P.

doi:10.1056/nejmoa1706988

Cited by 158 publications

(125 citation statements)

References 27 publications

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“…The stepping-stone hypothesis may have general implications. For example, zoliflodacin (ETX0914), a novel bacterial topoisomerase inhibitor, has just completed a human phase 2 clinical trial (47). It shows promising activity against multidrug-resistant infections, including those caused by N. gonorrhoeae (48).…”

Section: Discussionmentioning

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.

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…To investigate the feasibility of the "stepping-stone" hypothesis, here we have focused on ciprofloxacin, a widely employed and well-characterized fluoroquinolone antibiotic 64 The "stepping-stone" hypothesis may have general implications. For example, zoliflodacin (ETX0914), a novel bacterial topoisomerase inhibitor has just completed a human phase 2 clinical trial 65 . It shows promising activity against multidrug-resistant infections, including N. gonorrhoeae 66 .…”

Section: Discussionmentioning

confidence: 99%

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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“…Thus, gonorrhoea may soon become untreatable. There are some promising antibiotics in the pipeline, such as zoliflodacin and gemifloxacin, which have not reached market yet .…”

Section: Antimicrobial‐resistant Gonorrhoeamentioning

confidence: 99%

Current challenges in the clinical management of sexually transmitted infections

Vries

2019

J Intern AIDS Soc

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Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea

Cited by 158 publications

References 27 publications

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

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

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

Current challenges in the clinical management of sexually transmitted infections

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