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Penem derivatives: beta-lactamase stability and affinity for penicillin-binding proteins in Escherichia coli
Abstract:
Penem derivatives, a new group of beta-lactam antibiotics with potent activities against a wide range of bacteria, including Pseudomonas aeruginosa, were tested for their stability against hydrolysis by beta-lactamases purified from clinical isolates of Morganella morganii. Proteus vulgaris, and Escherichia coli and by a penicillinase from Bacillus cereus. Penems having 6 alpha substituents, such as hydroxyethyl, hydroxymethyl, and ethyl groups, were very stable against hydrolysis by each of the enzymes. Penems having no 6 alpha substituents were easily hydrolyzed by P. vulgaris and E. coli enzymes, whereas they were rather stable against hydrolysis by M. morganii and B. cereus enzymes, a typical cephalosporinase and penicillinase, respectively. Affinity of the penems for E. coli penicillin-binding proteins (PBPs) was also tested. beta-Lactamase-stable penems having a 6 alpha-hydroxyethyl group showed high affinity for PBP-4, -5, and -6 as well as for PBP-1A, -1Bs, and -2. However, the penems having no 6 alpha substituents showed a far lower affinity for PBP-4, -5, and -6 than that shown by the corresponding 6 alpha-hydroxyethyl penems. Among the penems tested, affinity for PBP-4, -5, and -6 was closely related to their beta-lactamase stability, as was the case among cephamycins and cephalosporins. Effects of the penems on the morphology of a strain of E. coli are also described.
Insights
New penem antibiotics with 6 alpha substituents show enhanced stability against bacterial beta-lactamases. This stability correlates with high affinity for penicillin-binding proteins (PBPs), suggesting improved efficacy against resistant bacteria.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Biochemistry
Background:
- Beta-lactam antibiotics are crucial for treating bacterial infections.
- Beta-lactamase enzymes confer resistance by hydrolyzing beta-lactam rings.
- Penem derivatives represent a novel class of beta-lactam antibiotics with broad-spectrum activity.
Purpose of the Study:
- To evaluate the stability of novel penem derivatives against various beta-lactamases.
- To investigate the relationship between penem structure, beta-lactamase stability, and penicillin-binding protein (PBP) affinity.
- To assess the impact of penems on bacterial cell morphology.
Main Methods:
- Purification of beta-lactamases from clinical isolates (Morganella morganii, Proteus vulgaris, Escherichia coli) and Bacillus cereus.
- Hydrolysis assays to determine penem stability against purified enzymes.
- Affinity studies of penems for E. coli penicillin-binding proteins (PBPs).
- Microscopic examination of E. coli morphology following penem treatment.
Main Results:
- Penems with 6 alpha substituents (e.g., hydroxyethyl) exhibited high stability against M. morganii, P. vulgaris, E. coli, and B. cereus enzymes.
- Unsubstituted penems were readily hydrolyzed by P. vulgaris and E. coli enzymes but showed stability against M. morganii and B. cereus enzymes.
- Beta-lactamase-stable penems with a 6 alpha-hydroxyethyl group demonstrated high affinity for multiple PBPs (PBP-4, -5, -6, PBP-1A, -1Bs, -2).
- Penems lacking 6 alpha substituents showed significantly lower affinity for PBP-4, -5, and -6 compared to their substituted counterparts.
- Penem affinity for PBP-4, -5, and -6 correlated strongly with their beta-lactamase stability.
Conclusions:
- The 6 alpha substituent is critical for enhancing penem stability against diverse beta-lactamases.
- High affinity for specific PBPs, particularly PBP-4, -5, and -6, is linked to beta-lactamase stability in penems.
- These findings suggest that specific penem derivatives hold promise as effective antibiotics against beta-lactamase-producing bacteria.