Bacterial Type II Topoisomerases and Target-Mediated Drug Resistance

Gibson, Elizabeth G.; Ashley, Rachel E.; Kerns, Robert J.; Osheroff, Neil

doi:10.1007/978-3-319-78538-7_16

Cited by 19 publications

(182 citation statements)

References 105 publications

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“…Moreover, the putative binding sites of gepotidacin and fluoroquinolones on the GyrA protein are adjacent to each other, separated by a single amino acid only ( Fig. 1B) (31)(32)(33). Despite the functional similarities between these drug classes, a prior paper reported that fluoroquinolone-resistant clinical isolates displayed no cross-resistance to gepotidacin (17).…”

Section: Resultsmentioning

confidence: 93%

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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Section: Resultsmentioning

confidence: 93%

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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“…2 In most cases, this resistance is caused by mutations in gyrase, a type II topoisomerase, which is the cellular target for these drugs. 6–12…”

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confidence: 99%

“…Most bacteria encode two type II topoisomerases, gyrase and topoisomerase IV. 7, 10, 12–16 These enzymes alleviate the torsional stress that accumulates in DNA ahead of replication forks and transcription complexes and remove knots and tangles from the genome, respectively. 12–13, 15, 17–22 They perform these tasks by creating a transient double-stranded DNA break in one DNA segment, passing a second DNA segment through the break, and ligating the broken segment.…”

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confidence: 99%

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Mechanism of Action of Mycobacterium tuberculosis Gyrase Inhibitors: A Novel Class of Gyrase Poisons

et al. 2018

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Tuberculosis is one of the leading causes of morbidity worldwide, and the incidences of drug resistance and intolerance are prevalent. Thus, there is a desperate need for the development of new antitubercular drugs. Mycobacterium tuberculosis gyrase inhibitors (MGIs) are napthyridone/aminopiperidine-based drugs that display activity against M. tuberculosis cells and tuberculosis in mouse models [Blanco, D., et al. (2015) Antimicrob. Agents Chemother. 59, 1868-1875]. Genetic and mutagenesis studies suggest that gyrase, which is the target for fluoroquinolone antibacterials, is also the target for MGIs. However, little is known regarding the interaction of these drugs with the bacterial type II enzyme. Therefore, we examined the effects of two MGIs, GSK000 and GSK325, on M. tuberculosis gyrase. MGIs greatly enhanced DNA cleavage mediated by the bacterial enzyme. In contrast to fluoroquinolones (which induce primarily double-stranded breaks), MGIs induced only single-stranded DNA breaks under a variety of conditions. MGIs work by stabilizing covalent gyrase-cleaved DNA complexes and appear to suppress the ability of the enzyme to induce double-stranded breaks. The drugs displayed little activity against type II topoisomerases from several other bacterial species, suggesting that these drugs display specificity for M. tuberculosis gyrase. Furthermore, MGIs maintained activity against M. tuberuclosis gyrase enzymes that contained the three most common fluoroquinolone resistance mutations seen in the clinic and displayed no activity against human topoisomerase IIα. These findings suggest that MGIs have potential as antitubercular drugs, especially in the case of fluoroquinolone-resistant disease.

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“…The best candidate antibiotic family is fluoroquinolones, as they are widely employed in clinical practice, and similarly to gepotidacin, they target the gyrase/topoisomerase protein complexes, albeit with a notably different molecular mechanism 18,33 . Moreover, the putative binding sites of gepotidacin and fluoroquinolones on the GyrA protein are adjacent to each other, separated by a single amino acid only (see figure 1B, and [34][35][36] ). Despite the functional similarities between these drug classes, a prior paper reported that fluoroquinolone-resistant clinical isolates displayed no crossresistance to gepotidacin 18 .…”

Section: Cross-resistance Between Gepotidacin and Ciprofloxacinmentioning

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.

show abstract

Bacterial Type II Topoisomerases and Target-Mediated Drug Resistance

Cited by 19 publications

References 105 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

Mechanism of Action of Mycobacterium tuberculosis Gyrase Inhibitors: A Novel Class of Gyrase Poisons

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

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