Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones

Malik, Muhammad Abdul; Mustaev, Arkady; Schwanz, Heidi A.; Luan, Gan; Shah, Nirali N.; Oppegard, Lisa M.; Souza, Ernane; Hiasa, Hiroshi; Zhao, Xilin; Kerns, Robert J.; Drlica, Karl

doi:10.1093/nar/gkw161

Cited by 24 publications

(16 citation statements)

References 59 publications

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“…In support of this idea, we recently found that an aryl group appended to the C7 piperazinyl ring of ciprofloxacin, which according to X-ray structures should extend into GyrB, suppresses the protective effect of GyrA resistance substitutions. 65 The most active example found to date is a C7 dinitrophenyl derivative of ciprofloxacin (compound 7 ), a compound that selectively enriches cells carrying an uncommon gyrA resistance mutation. To our knowledge, C7-aryl derivatives of ciprofloxacin have not been examined as potential imaging agents.…”

Section: Fluoroquinolone Actionmentioning

confidence: 99%

Fluoroquinolones as imaging agents for bacterial infection

Naqvi

Drlica

2017

Dalton Trans.

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Diagnosis of deep-seated bacterial infection is difficult, as neither standard anatomical imaging nor radiolabeled, autologous leukocytes distinguish sterile inflammation from infection. Two recent imaging efforts are receiving attention: 1) radioactive derivatives of sorbitol show good specificity with Gram-negative infections, and 2) success from combining anatomical and functional imaging for cancer diagnosis has rekindled interest in 99mTc-fluoroquinolone-based imaging. With the latter, computed tomography (CT) would be combined with single-photon-emission-computed tomography (SPECT) to detect a 99mTc-fluoroquinolone-bacterial interaction. The present minireview provides a framework for advancing with fluoroquinolone-based imaging by identifying gaps in our understanding of the process. One issue is the reliance of 99mTc labeling on reduction of sodium pertechnetate, which can lead to colloid formation and loss of specificity. Specificity problems may be reduced by altering quinolone structure (an example is switching from ciprofloxacin to sitafloxacin). Another issue is the uncharacterized nature of 99mTc-ciprofloxacin binding to, or sequestration in, bacteria -- specific interactions with DNA gyrase, an intracellular fluoroquinolone target, are unlikely. Replacing the C6-F of the fluoroquinolone with 18F provides an alternative to pertechnetate that may lead to imaging based on drug interactions with gyrase. Gyrase-based imaging requires knowledge of fluoroquinolone action, which we update. We conclude that quinolone-based probes show promise for diagnosis of bacterial infection, but improvements in specificity and sensitivity are needed. Those improvements require optimization of quinolone structure and reduction of pertechnetate, chemistry efforts that can be accelerated by refining microbiological assays.

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Section: Fluoroquinolone Actionmentioning

confidence: 99%

Fluoroquinolones as imaging agents for bacterial infection

Naqvi

Drlica

2017

Dalton Trans.

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“…The most common, quinolone and its derivatives like ciprofloxacin (CIP), is targeting the DNA gyrase A (GyrA) which is essential for DNA replication [8,9]. Quinolone interaction with GyrA has been well studied thanks to the 3D structure of the E.coli protein [10]. The mutation of critical sites lead to resistance; these sites are located in the so-called Quinolone Resistant-Determining Region (QRDR) [11].…”

Section: Introductionmentioning

confidence: 99%

“…A map of E.coli GyrA protein featuring structural and functional domains is shown at the bottom for comparison. The map was generated based on the following references[10,12,13]. The GyrA protein sequence of E.coli and N.meningitidis reference strain 053442 (GB-ID CP000381) were compared (AdditionalTable 4).…”

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confidence: 99%

Evolutionary analysis of gyrA gene from Neisseria meningitidis bacterial strains of clonal complex 4821 collected in China between 1978 and 2016

Zhao

Zhang

et al. 2020

BMC Microbiol

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Background: Neisseria meningitidis (N.meningitidis) bacteria belonging to clonal complex 4821 (CC4821) have been mainly reported in China and have been characterized by a high resistance rate to ciprofloxacin (CIP). The aim of this study was to assess the evolution of the DNA gyrase A (gyrA) gene from N.meningitidis CC4821 strains collected in China between 1978 and 2016. The complete sequence of gyrA gene from 77 strains are reported in this study and analyzed in the context of publicly available sequences from N. meningitidis of other CCs as well as other Neisseria species. Results: The phylogenetic analysis of CC4821 gyrA gene reveals at least 5 distinct genetic clusters. These clusters are not CC4821-specific showing that gyrA evolution is independent of CC4821 evolution. Some clusters contain sequences from other Neisseria species. Recombination within N.meningitidis strains and between Neisseria species was identified in SimPlot analysis. Finally, amino acid substitutions within GyrA protein were analyzed. Only one position, 91 (83 in E.coli gyrA gene), was linked to CIP resistance. Thirty-one additional putative resistance markers were identified, as amino acid substitutions were only found in resistant strains. Conclusions: The evolution of gyrA gene of CC4821 N.meningitidis strains is not dependent on CC4821 evolution or on CIP resistance phenotype. Only amino acid 91 is linked to CIP resistance phenotype. Finally, recombination interand intra-species is likely to result in the acquisition of various resistance markers, 31 of them being putatively mapped in the present study. Analyzing the evolution of gyrA gene within CC4821 strains is critical to monitor the CIP resistance phenotype and the acquisition of new resistance markers. Such studies are necessary for the control of the meningococcal disease and the development of new drugs targeting DNA gyrase.

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“…The most common, quinolone and its 4 derivatives, is targeting the DNA gyrase A which is essential for DNA replication (11,12). Quinolone interaction with DNA gyrase has been well studied thanks to the 3D structure of the E.coli protein (13). The mutation of critical sites lead to resistance and they are located in the so called Quinolone Resistant-Determining Region (QRDR) (14).…”

Section: Introductionmentioning

confidence: 99%

Genetic diversity and characteristics of gyrA gene in Neisseria spp

Zhao

Zhang

Zhu

et al. 2019

Preprint

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Background Neisseria meningitidis bacteria characterized by clonal complex (CC4821) showed a high resistance rate to quinolones. The aim of this study was to assess whether the DNA gyrase A gene from N.meningitidis CC4821 strains collected in China featured any specific characteristics compared to other Neisseria species. Two hundred fifty two gyrase gene sequences were analyzed, among them 77 generated in this study from N.meningitidis CC4821 strains collected in China between 1978 and 2016. Results The quinolone resistance-related gene, coding for the DNA gyrase subunit A (GyrA) protein, was highly divergent within the N.meningitidis strains whereas N. gonorrhoeae and N.lactamica counterparts appeared well conserved. Only one position, 91 (83 in E.coli gyrA gene), was linked to quinolone resistance, all resistant strains featuring the substitution T91I. The E.coli position 87, which was mutated in quinolone-resistant strains, was also divergent (position 95) in some Neisseria resistant strains. Moreover, twenty eight additional putative resistance markers were identified. Finally, putative recombination events between N.meningitidis and either N.subflava, or N.lactamica or N.cinerea as well as between N.meningitidis strains were reported. Conclusions Analyzing the evolution of gyrA gene within Neisseria spp. is critical to monitor the quinolone resistance phenotype and the acquisition of new resistance markers. Such studies are necessary for the control of the meningococcal disease and the development of new drugs targeting DNA gyrase.

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Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones

Cited by 24 publications

References 59 publications

Fluoroquinolones as imaging agents for bacterial infection

Fluoroquinolones as imaging agents for bacterial infection

Evolutionary analysis of gyrA gene from Neisseria meningitidis bacterial strains of clonal complex 4821 collected in China between 1978 and 2016

Genetic diversity and characteristics of gyrA gene in Neisseria spp

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