topoisomerase ParC resistance determining regions: QRDR GyrA ParC ciprofloxacin CPFX levofloxacin LVFX gatifloxacin GFLX

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1 prulifloxacin NM 39 type topoisomerase gyra parc quinolone resistance determining regions: QRDR GyrA ParC prulifloxacin NM 39 gyra parc 77 3 GyrA ParC ParC NM 39 ciprofloxacincpfxlevofloxacinlvfx gatifloxacingflx GyrA ParC NM 39CPFX LVFX NM 39 MIC CPFX LVFX typetopoisomerase NM 39 CPFX LVFX Key words: NM39gyrasetopoisomerase type topoisomerasedna gyrasetopoisomerase 69 DNA gyrase DNA DNA A GyrA B GyrB gyra gyrb topoisomerase DNA DNA parc pare ParC ParE 3 gyra parc quinolone resistance determining regions: QRDR PrulifloxacinPUFX PUFX NM gyra parc NM 39 3 I PUFX NM 39 CiprofloxacinCPFX levofloxacinlvfx gatifloxacin 76

2 NM 39 QRDR GFLX 3 Mueller Hinton agardifco MIC Mueller Hinton brothmhbdifco MHB 6 CFUmL CFU ml. PCR DNA DNA Mouneimne 9 DNA gyra PSE GAC GGC CTG AAG CCG GTG CAC 3 nt 3 PAGA ACG CTC GAC CAT CGC TTC CA 3nt 6parC PAPC ATG AGC GAA TCC CTC GAT CTG 3nt 6 PAPC TGG CCC AGT TCG CTG AGC AGC A 3nt 3 3 QRDR PCR.M TaKaRa Ex Taq TM. U PCR ; 9 ; 6 ; 7 ; ABI drhodamine Terminator Cycle Sequencing Ready Reaction kit gyra PSE PYO GCC CAC GGC GAT ACC GCT GGA 3nt 3 parc PAPC PAPC ABI 37 P. aeruginosa PAO II. QRDR 77 GyrA GyrA ParC GyrA ParC Table gyra QRDR 3. 3 Thr Table Amino acid changes encoded by mutations in gyra and parc Replacement in QRDR Number Group of strains GyrA ParC tested 3 Thy 7 Asp 7 Ser 9 Glu 3 3 no mutation Asn Tyr Asn Gly Leu Trp Leu Leu Lys GyrA 7 Asp Asn Gly parc QRDR 7 Ser Leu Trp 7 9 Glu Lys ParC GyrA GyrA 3 Thr ParC 7 Ser Leu 7 9 Glu Lys GyrA 3. QRDR MIC 77 NM 39CPFXLVFX GFLX MIC Fig GyrA ParC NM 39 CPFX MIC.3 ml LVFX.3 ml GFLX.6 ml GyrA NM 39 CPFX MIC ml LVFX GFLX MIC 6 ml NM 39CPFXLVFX GFLX MIC ml GyrA ParC NM 39 CPFX MIC 6 mllvfx GFLX MIC 6 ml ParC 9 Glu Lys 7 Ser Trp

3 7 Ser Leu GyrA Number of strains Number of strains Number of strains Number of strains 3 NM ciprofloxacin 3 levofloxacin 3 gatifloxacin QRDR NM 39CPFX LVFX MIC MIC 3 6 CFUmL Fig NM 39 MIC log NM 39 FigACPFX MIC NM 39 Agroup 3 h 6 h log CFU/mL B group 3 h 6 h log CFU/mL MICg/mL control NM39 ciprofloxacin levofloxacin Fig Susceptibility distribution of 77 isolates of Pseudomonas aeruginosa to four quinolones. The isolates were classified into four groups according to the presence of QRDR mutations in the gyra andor parc genes. See Table for the definitions of groups Fig Bactericidal activities of NM 39ciplofloxacin and levofloxacin against Pseudomonas aeruginosa with or without mutations in the gyra andor parc genes of the QRDR. The means of five or two strains are shown. AAntibiotic concentration of MIC; BAntibiotic concentration of MIC. See Table for the definitionsofgroups

4 NM 39 QRDR NM 39 LVFX MIC CPFX NM 39 NM 39 MICFigB MIC CPFX MIC LVFX NM 39 III 77 typetopoisomerase QRDR 77 QRDR 3. gyra parc Akasaka DNA gyrase topoisomerase DNA gyrase NM 39 DNA gyrase topoisomerase DNA gyrase gyra gyra parc DNA gyrase gyra parc parc gyra 3 Thr Ilu 3 Ser Leu gyra 7 Asp Asn Gly gyra parc 7 Ser Leu 7 Ser Trp 9 Glu Lys gyra parc parc NM 39 MIC CPFX LVFX MIC NM 39 NM 39 CPFX LVFX MIC NM 39 CPFX LVFX 6 DNA gyrase topopisomerase QRDR QRDR NM 39 MIC NM 39 QRDR : : : 3: : 993 Jpn. J. Antibiot. : : 9 7: 999 : No.3 : : : Piddock L JHall M CBellido Fet al.: A pleiotropic posttherapy enoxacin resistant mutant of Pseudomonas aeruginosa.antimicrob. Agents Chemother. 36: 7699 Masuda NGotoh NOhya Set al.: Quantitative correlation between susceptibility and OprJ

5 production in NfxB mutants of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. : Drlica KZhao X: DNA gyrasetopoisoimerase and quinolones. Microbiol. Mol. Biol. Rev. 6: Gellert MMizuguchi KO Dea M Het al.: DNA gyrase: an enzyme that introduces super helical turns into DNA. Proc. Natl. Acad. Sci. USA. 73: Reece R JMaxwell A: DNA gyrase: structure and function. Crit. Rev. Biochem. Mol. Biol. 6: Wang J C: DNA topoisomerases. Ann. Rev. Biochem. 6: Ferrero LCameron BManse Bet al.: Cloning and primary structure of Staphylococcus aureus DNA topoisomerase: Aprimarytargetoffluoroquinolones. Mol. Microbiol. 3: Yoshida HBogaki MNakamura Met al.: Quinolone resistance determining region in DNA gyrase gyra gene of Escherichia coli. Antimicrob. Agents Chemother. 3: 7799 Jahal SWrethlind B: Mechanisms of quinolone resistance in clinical strains of Pseudomonas aeruginosa. Microb. Drug Resist. : Yoshida TMitsuhashi S: Antibacterial activity of NM 39the active form of prodrug NM new quinolone. Antimicrob. Agents Chemother. 37: : in vitro Jpn. J. Antibiot. 3: 936 : MIC Chemotherapy 9: Mouneimne HRobert JJarlier Vet al.: Type topoisomerase mutations in ciprofloxacin resistant strains of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 3: Takenouchi TSakagawa ESugawara M: Detection of gyra mutation among 33 Pseudomonas aeruginosa strains isolated in Japan and their susceptibilities to fluoroquinolones. Antimicrob. Agents Chemother. 3: Akasaka TTanaka MYamaguchi Aet al.: Type topoisomerase mutation in fluoroquinolone resistant clinical strains of Pseudomonas aeruginosa isolated in 99 and 999: role of target enzyme in mechanism of fluoroquinolone resistance. Antimicrob. Agents Chemother. : 636 : Prulifloxacin NM 39 Topoisomerase Jpn. J. Antibiot. : 3 Nakano MDeguchi TKawamura Met al.: Mutation in the gyra and parc genes in fluoroquinolone resistant clinical strains of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. : Jalal SWrethlind B: Mechanisms of quinolone resistance in clinical strains of Pseudomonas aeruginosa. Microb. Drug Resist. : 7699 Heisig PSchedletzky HFalkenstein Paul H: Mutation in the gyra gene of a high fluoroquinolone resistant clinical isolate of Escherichia coli. Antimicrob. Agents Chemother. 37: Fukuda HHosaka MIyobe Set al.: nfxc type quinolone resistance in a clinical isolate of Pseudomonas aeruginosa.antimicrob. Agents Chemother. 39: Jahal SCiofu OHoiby Net al.: Molecular mechanism of fluoroquinolone resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob. Agents Chemother. : 7 7 Kohler TMichea Hamzehpour MPlesiat Pet al.: Differential selection of multidrug efflux systems by quinolones in Pseudomonas aeruginosa.antimicrob. Agents Chemother. : 3997

6 NM 39 QRDR Antimicrobial activity of NM 39an active form of prulifloxacinagainst clinical isolates of Pseudomonas aeruginosa with a type II topoisomerase mutation Minako Araake Mariko Tani Kazunori Maebashi Tetsuro Hara Hiroomi Watabe Hiroshi Takahashi Yutaka Tokue Shigeru Fujimura Kazunori Gomi and Akira Watanabe Pharmaceutical Research CenterMeiji Seika KaishaLtd., 76 Morooka cho Kouhoku kuyokohamakanagawajapan Department of Respiratory Oncology and Molecular MedicineInstitute of Development Aging and CancerTohoku University We examined mutations in the quinolone resistance determining regionsqrdrof gyra and parc genes in 77 clinical isolates of Pseudomonas aeruginosa and compared the susceptibility of these isolates to NM 39an active form of the prodrug prulifloxacinwith those to ciprofloxacincpfxlevofloxacin LVFXand gatifloxacingflxof the 77 strains isolates exhibited an amino acid replacement in the GyrA or both the GyrA and ParC regions as a result of mutations in gyra or both gyra and parc respectively. All of the isolates had amino acid replacements in GyrA; none of the strains had amino acid replacements restricted to ParC. Amino acid replacement in GyrA but not in ParC was found in 6 isolates whose susceptibility to NM 39 was decreased; the susceptibilities of these 6 isolates to CPFX LVFX and GFLX were also decreased. Amino acid replacement in GyrA and ParC was found in isolates that were highly resistant to NM 39LVFXCPFX and GFLX. The short term bactericidal activity of NM 39 at the MIC concentration against strains with or without amino acid replacement in GyrA or both GyrA and ParC was similar. The short term bactericidal activities of CPFX and LVFX against strains with amino acid replacements in GyrA or both GyrA and ParC were lower than those against the strains with no amino acid replacements. These results demonstrate that the bactericidal activity of NM 39 against strains with a mutation in their type II topoisomerase genes was higher than those of CPFX and LVFX.

gyra Mutations in Ciprofloxacin-resistant Clinical Isolates of Pseudomonas aeruginosa in a Silesian Hospital in Poland

Polish Journal of Microbiology 2005, Vol. 54, No 3, 201 206 gyra Mutations in Ciprofloxacin-resistant Clinical Isolates of Pseudomonas aeruginosa in a Silesian Hospital in Poland ZENOBIA WYDMUCH 1, OLGA