Neisseria gonorrhoeae is a major public health problem globally, especially because the bacterium has developed resistance to most antimicrobials introduced for first-line treatment of gonorrhea. In the present study, 96 N. gonorrhoeae isolates with highlevel resistance to penicillin from 121 clinical isolates in Thailand were examined to investigate changes related to their plasmidmediated penicillin resistance and their molecular epidemiological relationships. A -lactamase (TEM) gene variant, bla , that may be a precursor in the transitional stage of a traditional bla TEM-1 gene into an extended-spectrum -lactamase (ESBL), possibly causing high resistance to all extended-spectrum cephalosporins in N. gonorrhoeae, was identified. Clonal analysis using multilocus sequence typing (MLST) and N. gonorrhoeae multiantigen sequence typing (NG-MAST) revealed the existence of a sexual network among patients from Japan and Thailand. Molecular analysis of the bla TEM-135 gene showed that the emergence of this allele might not be a rare genetic event and that the allele has evolved in different plasmid backgrounds, which results possibly indicate that it is selected due to antimicrobial pressure. The presence of the bla TEM-135 allele in the penicillinaseproducing N. gonorrhoeae population may call for monitoring for the possible emergence of ESBL-producing N. gonorrhoeae in the future. This study identified a bla TEM variant (bla TEM-135 ) that is a possible intermediate precursor for an ESBL, which warrants international awareness. N eisseria gonorrhoeae is the causative agent of gonorrhea, which is the second most prevalent bacterial sexually transmitted infection globally. During recent decades, N. gonorrhoeae has rapidly developed resistance to most classes of antimicrobials used for treatment of gonorrhea (4,6,17,18,20). Penicillinase-producing N. gonorrhoeae (PPNG), with plasmid-mediated high-level resistance to penicillin, was first reported in 1976 (1, 14) and has since been disseminated worldwide (2). The first gonococcal strain with high-level clinical resistance to ceftriaxone, which is the last remaining option for first-line gonorrhea treatment, was recently found in Japan and completely characterized (9, 11). However, the resistance to ceftriaxone was chromosomally mediated, and no extended-spectrum -lactamase (ESBL) has yet been identified in N. gonorrhoeae. If an ESBL did emerge in N. gonorrhoeae and spread internationally, gonorrhea would become an extremely serious public health problem. PPNG strains are rare in Japan, but these strains have remained highly prevalent in several other countries in Asia (19) and worldwide (20). Penicillin is still also used as the first-line drug in, e.g., some Pacific island countries and the northern part of Australia, because of maintained efficacy in the settings and its low cost.Although the -lactamase (TEM) gene of authentic PPNG is the bla TEM-1 allele, a recently isolated PPNG in Thailand possessed the bla TEM-135 allele, which differs from the bla TEM-1 allel...
Carbapenem-resistant are urgent threats to global human health. These organisms produce β-lactamases with carbapenemase activity, such as the metallo-β-lactamase NDM-1, which is notable due to its association with mobile genetic elements and the lack of a clinically useful inhibitor. Here we examined the ability of copper to inhibit the activity of NDM-1 and explored the potential of a copper coordination complex as a mechanism to efficiently deliver copper as an adjuvant in clinical therapeutics. An NDM-positive isolate, MS6192, was cultured from the urine of a patient with a urinary tract infection. MS6192 was resistant to antibiotics from multiple classes, including diverse β-lactams (penicillins, cephalosporins, and carbapenems), aminoglycosides, and fluoroquinolones. In the presence of copper (range, 0 to 2 mM), however, the susceptibility of MS6192 to the carbapenems ertapenem and meropenem increased markedly. In standard checkerboard assays, copper decreased the MICs of ertapenem and meropenem against MS6192 in a dose-dependent manner, suggesting a synergistic mode of action. To examine the inhibitory effect of copper in the absence of other β-lactamases, the gene from MS6192 was cloned and expressed in a recombinant K-12 strain. Analysis of cell extracts prepared from this strain revealed that copper directly inhibited NDM-1 activity, which was confirmed using purified recombinant NDM-1. Finally, delivery of copper at a low concentration of 10 μM by using the FDA-approved coordination complex copper-pyrithione sensitized MS6192 to ertapenem and meropenem in a synergistic manner. Overall, this work demonstrates the potential use of copper coordination complexes as novel carbapenemase adjuvants.
Behcet's Disease (BD) is a multisystem chronic inflammatory disease. The pathology is believed to involve both genetic susceptibility and environmental factors. Hypomethylation leading to activation of interspersed repetitive sequences (IRSs) such as LINE-1 and Alu contributes to the pathologies of autoimmune diseases and cancer. Herein, the epigenetic changes of IRSs in BD were evaluated using combined bisulfite restriction analysis-interspersed repetitive sequences (COBRA-IRS). DNA from neutrophils and peripheral blood mononuclear cells (PBMCs) of BD patients with ocular involvement that were in active or inactive states and healthy controls were used to analyze LINE-1 and Alu methylation levels. For Alu sequences, significant differences were observed in the frequency of uCuC alleles between PBMCs of patients and controls (p = 0.03), and between inactive patients and controls (p = 0.03). For neutrophils, the frequency of uCuC was significantly higher between patients and controls (p = 0.006) and between inactive patients and controls (p = 0.002). The partial methylation (uCmC + mCuC) frequencies of Alu between inactive patients and control samples also differed (p = 0.02). No statistically significant differences for LINE-1 were detected. Thus, changes in the methylation level of IRS elements might contribute to the pathogenesis of BD. The role of Alu transcripts in BD should be investigated further.
Background/Aims Epigenetic mechanisms via DNA methylation may be related to glaucoma pathogenesis. This study aimed to determine the global DNA methylation level of the trabeculectomy specimens among patients with different types of glaucoma and normal subjects. Methods Trabeculectomy sections from 16 primary open-angle glaucoma (POAG), 12 primary angle-closure glaucoma (PACG), 16 secondary glaucoma patients, and 10 normal controls were assessed for DNA methylation using combined-bisulfite restriction analysis. The percentage of global methylation level of the interspersed repetitive sequences for LINE-1, Alu, HERV-E, and HERV-K were compared between the 4 groups. Results There were no significant differences in the methylation for LINE-1 and HERV-E between patients and normal controls. For the Alu marker, the methylation was significantly lower in all types of glaucoma patients compared to controls (POAG 52.19% versus control 52.83%, p = 0.021; PACG 51.50% versus control, p = 0.005; secondary glaucoma 51.95% versus control, p = 0.014), whereas the methylation level of HERV-K was statistically higher in POAG patients compared to controls (POAG 49.22% versus control 48.09%, p = 0.017). Conclusions The trabeculectomy sections had relative DNA hypomethylation of Alu in all glaucoma subtypes and relative DNA hypermethylation of HERV-K in POAG patients. These methylation changes may lead to the fibrotic phenotype in the trabecular meshwork.
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