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Published on: June 23, 2013
CTX-M-33, a CTX-M-15 derivative conferring reduced susceptibility to carbapenems
Laurent Poirel1,2,3, José-Manuel Ortiz de la Rosa4, Anaïs Richard4
1Emerging Antibiotic Resistance Unit, Medical and Molecular Microbiology, Department of Medicine, University of Fribourg laurent.poirel@unifr.ch.
Abstract:
CTX-M-type extended-spectrum ß-lactamases (ESBL) are widespread among Enterobacterales worldwide. The most common variant is CTX-M-15 hydrolyzing ceftazidime at high rate, but sparing carbapenems. We identified here CTX-M-33, a point mutant derivative of CTX-M-15 (Asp to Ser substitution at Ambler position 109), exhibiting a low carbapenemase activity. ß-Lactamase CTX-M-33 was identified in a Klebsiella pneumoniae isolate belonging to ST405, lacking the outer membrane protein OmpK36, that was resistant to broad-spectrum cephalosporins and ß-lactam/ß-lactamase inhibitor combinations, and displayed a decreased susceptibility to carbapenems. Comparative hydrolytic activity assays showed that CTX-M-33 hydrolyzed ceftazidime at a lower level than CTX-M-15, but significantly hydrolyzed meropenem. In addition, CTX-M-33 showed higher Mutant Prevention Concentration values and wider mutant selection window in presence of meropenem, in accordance with its observed hydrolytic properties. We identified here the very first CTX-M enzyme possessing a weak carbapenemase activity, that may correspond to an emerging phenomenon when considering its possibility to evolve from the widespread ESBL CTX-M-15.
Insights
A novel enzyme, CTX-M-33, derived from CTX-M-15, shows weak carbapenemase activity. This finding in Klebsiella pneumoniae suggests a potential emerging threat of carbapenem resistance among Enterobacterales.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- CTX-M-type extended-spectrum beta-lactamases (ESBL) are prevalent globally in Enterobacterales.
- CTX-M-15 is a common variant, effective against cephalosporins but not carbapenems.
Purpose of the Study:
- To identify and characterize a novel CTX-M enzyme with potential carbapenemase activity.
- To investigate the hydrolytic properties and clinical implications of CTX-M-33.
Main Methods:
- Enzyme characterization through comparative hydrolytic activity assays.
- Analysis of Mutant Prevention Concentration (MPC) and mutant selection window (MSW) with meropenem.
- Identification of the enzyme in a Klebsiella pneumoniae isolate with specific genetic traits.
Main Results:
- CTX-M-33, a point mutant of CTX-M-15, exhibits reduced hydrolysis of ceftazidime but significant hydrolysis of meropenem.
- The enzyme was found in a Klebsiella pneumoniae strain (ST405) lacking OmpK36, showing resistance to cephalosporins and decreased susceptibility to carbapenems.
- CTX-M-33 demonstrated higher MPC values and a wider MSW for meropenem, correlating with its hydrolytic activity.
Conclusions:
- CTX-M-33 represents the first identified CTX-M enzyme with weak carbapenemase activity.
- This discovery highlights a potential emerging mechanism for carbapenem resistance evolving from widespread ESBLs like CTX-M-15.
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