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Amino acid substitutions in mosaic penicillin-binding protein 2 associated with reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae.

ABSTRACT: The molecular mechanisms of reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae, particularly amino acid substitutions in mosaic penicillin-binding protein 2 (PBP2), were examined. The complete sequence of ponA, penA, and por genes, encoding, respectively, PBP1, PBP2, and porin, were determined for 58 strains isolated in 2002 from Japan. Replacement of leucine 421 by proline in PBP1 and the mosaic-like structure of PBP2 were detected in 48 strains (82.8%) and 28 strains (48.3%), respectively. The presence of mosaic PBP2 was the main cause of the elevated cefixime MIC (4- to 64-fold). In order to identify the mutations responsible for the reduced susceptibility to cefixime in isolates with mosaic PBP2, penA genes with various mutations were transferred to a susceptible strain by genetic transformation. The susceptibility of partial recombinants and site-directed mutants revealed that the replacement of glycine 545 by serine (G545S) was the primary mutation, which led to a two- to fourfold increase in resistance to cephems. Replacement of isoleucine 312 by methionine (I312M) and valine 316 by threonine (V316T), in the presence of the G545S mutation, reduced susceptibility to cefixime, ceftibuten, and cefpodoxime by an additional fourfold. Therefore, three mutations (G545S, I312M, and V316T) in mosaic PBP2 were identified as the amino acid substitutions responsible for reduced susceptibility to cefixime in N. gonorrhoeae.

SUBMITTER: Takahata S

PROVIDER: S-EPMC1635225 | biostudies-literature | 2006 Nov

REPOSITORIES: biostudies-literature

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Amino acid substitutions in mosaic penicillin-binding protein 2 associated with reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae.

Takahata Sho S Senju Nami N Osaki Yumi Y Yoshida Takuji T Ida Takashi T

Antimicrobial agents and chemotherapy 20060828 11

The molecular mechanisms of reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae, particularly amino acid substitutions in mosaic penicillin-binding protein 2 (PBP2), were examined. The complete sequence of ponA, penA, and por genes, encoding, respectively, PBP1, PBP2, and porin, were determined for 58 strains isolated in 2002 from Japan. Replacement of leucine 421 by proline in PBP1 and the mosaic-like structure of PBP2 were detected in 48 strains (82.8%) and 28 stra ...[more]

PMID: 16940068

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Project description:BackgroundNeisseria gonorrhoeae (NG) infection is a serious public health problem. The third-generation extended-spectrum cephalosporins (ESCs) have been used as the first-line treatment for NG infection for almost three decades. However, in recent years, treatment failures with the oral third-generation ESCs have been reported worldwide. This study aimed to estimate worldwide susceptibility rates of NG to cefixime and cefpodoxime by analyzing data from all relevant published studies.Methodology/principal findingsTwo researchers independently searched five databases to identify studies on susceptibilities of NG to cefixime and cefpodoxime published between January 1, 1984 and October 15, 2012. A fixed-effect model was used to perform group analysis, and a ?2 test was employed to make subgroup comparison. Publication bias was assessed with the Begg rank correlation test. The pooled susceptibility rate of NG isolates to cefixime was 99.8% (95% CI: 99.7%-99.8%). The cefixime susceptibility rate of NG isolates from men was significantly lower than that from patients without information of gender or from men and women; the susceptibility rate of NG isolates from Asia was significantly lower than that from other continents; and the susceptibility rate of NG isolates collected before or during 2003 was significantly higher than that after 2003. The pooled susceptibility rate of NG isolates to cefpodoxime was 92.8% (95% CI: 89.0%-95.3%), which was lower than that to cefixime (92.8% vs. 99.8%, ?2 = 951.809, P<0.01).ConclusionsThe susceptibility rate of NG isolates to cefixime varied with the gender of patients and geographical location from which NG isolates were collected, and declined with time. The reported lower susceptibility rate of NG isolates to cefixime and associated treatment failures, as well as the emergence of NG strains with cephalosporin resistance call for the more effective control of NG infection and the development of new antibiotics.

Dataset Information

Amino acid substitutions in mosaic penicillin-binding protein 2 associated with reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae.

Publications

Amino acid substitutions in mosaic penicillin-binding protein 2 associated with reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae.

Similar Datasets

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