Effects of different resistance mechanisms on susceptibility to different classes of antibiotics in Klebsiella pneumoniae strains: a strategic system for the screening and activity testing of new antibiotics
| Autor: | Feng-Yee Chang, L. Kristopher Siu, Jung-Chung Lin, Ci-Hong Liou, Chang-Phone Fung, Yu-Kuo Tsai |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Male Cefotaxime Klebsiella pneumoniae medicine.drug_class 030106 microbiology Antibiotics Drug Evaluation Preclinical Mutagenesis (molecular biology technique) Ceftazidime Drug resistance Microbial Sensitivity Tests Biology Microbiology 03 medical and health sciences In vivo Drug Resistance Bacterial medicine Animals Pharmacology (medical) Pharmacology Mice Inbred BALB C biology.organism_classification Survival Analysis Anti-Bacterial Agents Klebsiella Infections Disease Models Animal Infectious Diseases Bacteria medicine.drug |
| Zdroj: | The Journal of antimicrobial chemotherapy. 72(12) |
| ISSN: | 1460-2091 |
| Popis: | Objectives A strategic system for the screening and testing of new antibiotics was created to facilitate the development of antibiotics that are robustly effective against MDR bacteria. Methods In-frame deletion, site-directed mutagenesis and plasmid transformation were used to generate genetically engineered strains with various resistance mechanisms from a fully susceptible clinical isolate of Klebsiella pneumoniae. Antimicrobial susceptibility testing and a mouse infection model were used to test antibiotics against these strains in vitro and in vivo, respectively. Results A total of 193 strains, including 29 strains with chromosome-mediated resistance, 33 strains with plasmid-mediated resistance and 131 strains with a combination of both resistance mechanisms were constructed; these strains covered resistance to β-lactams, quinolones, aminoglycosides, tetracyclines, folate pathway inhibitors and other antibiotics. MICs for all strains were tested, and the effects of genetic modifications on increasing the MICs were assessed. Ceftazidime and cefotaxime were used to assess the correlation between antibacterial activities in vitro and in vivo. Against a K. pneumoniae strain with blaOXA-48, ceftazidime had a lower MIC (0.5 mg/L) than cefotaxime (2 mg/L). Ceftazidime had an ED50 of 30 mg/kg, and no mice survived treatment with the same dose of cefotaxime. A positive correlation was observed between these in vitro and in vivo results. Conclusions The system developed here could reduce the considerable time required to evaluate the effectiveness of new antibiotics against MDR bacteria, particularly in the early stages of drug development. This system could also be expanded as new resistance mechanisms emerge. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|