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Interactions of meropenem, with beta-lactamases, including enzymes with extended-spectrum activity against
Abstract:
The interactions of a meropenem were studied with a set of beta-lactamases including the new TEM- and SHV-related plasmid-mediated enzymes that have extended-spectrum activity against third-generation cephalosporins ('cefotaximases' and 'ceftazidimases'). Meropenem and imipenem were highly resistant to the hydrolytic activity of all the TEM and SHV related beta-lactamases, and to the OXA enzymes, as were the cephamycins: cefoxitin and cefotetan. The two carbapenems were also highly stable to Class C beta-lactamases (chromosomal cephalosporinases) whereas third-generation cephalosporins and cephamycins were slowly hydrolyzed. Both carbapenems demonstrated quite similar affinities for all the enzymes studied. In some instances, and particularly with Class A (TEM- and SHV-derived) enzymes, meropenem inactivated the beta-lactamase activity. Imipenem appeared less reactive in this respect.
Insights
Meropenem and imipenem carbapenems show high resistance to common beta-lactamases. Meropenem also inactivates some enzymes, offering potential advantages against resistant bacteria.
Area of Science:
- Microbiology
- Pharmacology
- Biochemistry
Background:
- Beta-lactamases are enzymes that confer bacterial resistance to beta-lactam antibiotics.
- Emergence of extended-spectrum beta-lactamases (ESBLs) and other resistant enzymes poses a significant therapeutic challenge.
- Carbapenems like meropenem are crucial for treating infections caused by multidrug-resistant bacteria.
Purpose of the Study:
- To investigate the interaction of meropenem with a panel of beta-lactamases, including novel TEM- and SHV-related enzymes.
- To compare the stability and activity of meropenem and imipenem against various classes of beta-lactamases.
- To assess the potential of meropenem to inactivate beta-lactamase enzymes.
Main Methods:
- Enzyme kinetics studies were performed using purified beta-lactamase enzymes.
- Hydrolysis assays were conducted to measure the degradation of meropenem, imipenem, third-generation cephalosporins, and cephamycins.
- Enzyme inactivation experiments were carried out to assess the effect of carbapenems on beta-lactamase activity.
Main Results:
- Meropenem and imipenem exhibited high stability against TEM, SHV, and OXA beta-lactamases.
- Both carbapenems were stable against Class C chromosomal cephalosporinases, unlike third-generation cephalosporins and cephamycins.
- Meropenem demonstrated enzyme inactivation for some Class A beta-lactamases, a property less pronounced with imipenem.
Conclusions:
- Meropenem and imipenem are highly effective against a broad range of clinically relevant beta-lactamases.
- Meropenem's ability to inactivate certain beta-lactamases suggests a potential mechanism for overcoming resistance.
- These findings support the continued use of carbapenems in treating infections caused by bacteria producing diverse beta-lactamases.