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Results for “beta-Lactamase Inhibitors”

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At least 19 recordsLinked to original sources
PubMed1979

In vitro synthesis of peptidoglycan by beta-lactam-sensitive and -resistant strains of Neisseria gonorrhoeae: effects of beta-lactam and other antibiotics.

The synthesis in vitro of peptidoglycan by Neisseria gonorrhoeae was studied in organisms made permeable to nucleotide precursors by treatment with ether. Optimum synthesis occurred at 30 degrees C in tris(hydroxymethyl)aminomethane-maleate buffer (0.05 M; pH 6) in the presence of 20 mM Mg(2+). The incorporation from uridine 5'-diphosphate-N-acetyl-[(14)C]glucosamine into peptidoglycan, measured after precipitation of the cells with trichloroacetic acid, was sensitive to the beta-lactam antibiotics, bacitracin, diumycin, and tunicamycin and relatively resistant to spectinomycin and tetracycline. Differences in sensitivity between preparations from a beta-lactamase producer and a laboratory segregant derived from it were not great. Synthesized peptidoglycan was also fractionated into sodium dodecyl sulfate-soluble and -insoluble portions. beta-Lactam antibiotics at concentrations equivalent to the minimal inhibitory concentrations for growth of the organisms did not inhibit peptidoglycan synthesis, but rather caused a small enhancement. At higher concentrations, above about 0.5 mug/ml, incorporation into sodium dodecyl sulfate-insoluble material was progressively inhibited, whereas the amount of sodium dodecyl sulfate-soluble product increased greatly, more than compensating for the loss of the precipitable fraction. Similar observations were made with three strains, and also with the beta-lactam clavulanic acid, normally considered as a beta-lactamase inhibitor rather than as itself an effective antibiotic.

Anti-Bacterial Agents↗
PubMed2026

Molecular determinants associated with resistance to imipenem and imipenem-relebactam in clinical Pseudomonas aeruginosa isolates.

BACKGROUND: Pseudomonas aeruginosa accounts for 10-20% of hospital-acquired infections and is a major pathogen in immunocompromised patients. Combination therapies with beta-lactam antibiotics and beta-lactamase inhibitors, such as imipenem-relebactam have improved treatment options, yet resistant strains have already emerged, with mechanisms still not fully elucidated. RESULTS: We sequenced and analyzed 10 clinical P. aeruginosa isolates resistant to imipenem-relebactam (IMI/REL) and compared them with publicly available genomes of imipenem-resistant (IMI-R) and imipenem-susceptible (IMI-S) strains. Resistance genes were identified using the RGI CARD database, while amino acid variations in core-genome proteins were evaluated through Gene Ontology overrepresentation analysis (GO), followed by GWAS. In total, 15,758 ARGs were detected, 25.85% associated with carbapenem resistance, but only 568 classified as beta-lactamases. Among IMI/REL isolates, 36.36% carried Ambler class A and 54.54% class B beta-lactamases, contrasting with much lower frequencies in IMI-R (5.4% and 3.6%) and IMI-S (0% and 0.73%). Core-genome analysis revealed 1,106 proteins with resistance-associated variations. Comparative analyzes identified 1,618 proteins differing between IMI/REL and IMI-R genomes, and 1,015 differing between IMI/REL and all other strains. GWAS highlighted candidate genes with strong statistical associations, including those involved in metal ion transport (e.g., tonB, foxA, phuR, pfeA) and efflux pumps (e.g., czcB), as well as regulators such as mexT and biofilm-related proteins. CONCLUSIONS: These findings suggest that, beyond classical beta-lactamases, resistance may be associated with multifactorial contributions from periplasmic and outer membrane proteins, metal ion homeostasis, efflux regulation, and biofilm-associated pathways. Our results expand current knowledge of P. aeruginosa resistome and highlight novel genomic signatures potentially driving resistance to imipenem-relebactam.

Imipenem↗
PubMed2025

Comparative in vitro activity of ceftazidime-avibactam plus aztreonam and the fixed combination aztreonam/avibactam against multidrug-resistant Pseudomonas aeruginosa.

BACKGROUND AND OBJECTIVES: MDR Pseudomonas aeruginosa is difficult to treat, despite some new beta-lactam/beta-lactamase inhibitors. A combination of ceftazidime-avibactam and aztreonam (CAZ/AVI + AZT) is frequently used to treat Gram-negative bacteria expressing metallo-beta-lactamases. A fixed combination of aztreonam/avibactam was recently licenced for use in Europe, but it remains unknown whether there are differences between both options for use against P. aeruginosa. This study evaluates the comparative in vitro efficacy of the fixed combination aztreonam/avibactam compared to the three antibiotics CAZ/AVI + AZT against clinical MDR P. aeruginosa isolates. METHODS: MICs for aztreonam/avibactam and CAZ/AVI + AZT were determined in 38 MDR P. aeruginosa isolates recovered from routine diagnostics using broth microdilution with checkerboard assays in triplicates as the reference method. Fractional inhibitory concentration (FIC) indices were calculated. Whole-genome sequencing was performed on all isolates. RESULTS: At a fixed ceftazidime concentration of 8 mg/L (EUCAST breakpoint), 25 isolates exhibited lower MICs for CAZ/AVI + AZT compared to aztreonam/avibactam alone in microdilution assays. On FIC analysis, additive and synergistic effects were seen in 28 and 2 cases, respectively. Verona integron-encoded metallo-beta-lactamase (VIM) was the most prevalent carbapenemase (21/38 isolates), followed by Imipenemase (IMP, 4/38) and New Delhi metallo-beta-lactamase (NDM, 2/38). Lower MICs were observed for the combination CAZ/AVI + AZT in isolates carrying VIM-2 as compared to VIM-1. CONCLUSIONS: In vitro testing of CAZ/AVI + AZT revealed increased in vitro susceptibility among MDR P. aeruginosa isolates in comparison to the fixed combination of aztreonam/avibactam.

Pseudomonas aeruginosa↗
PubMed2026

Treatment strategies for imipenemase-producing Gram-negative infections: lessons from Japan.

Carbapenems remain essential for treating serious infections caused by drug-resistant Gram-negative bacteria because of their broad-spectrum activities and favourable safety profiles. However, the emergence of carbapenemase-producing Enterobacterales, which produce enzymes that efficiently hydrolyse β-lactams including carbapenems, continues to undermine their clinical utility. Although new antibiotics such as ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, aztreonam-avibactam, and cefiderocol have expanded therapeutic options, their effectiveness varies substantially across different carbapenemase families. Carbapenemases produced by Enterobacterales include serine β-lactamases (Ambler classes A and D) and metallo-β-lactamases (MBLs; Ambler class B), each with distinct substrate and inhibitor profiles. Clinically relevant MBLs-including imipenemase (IMP), New Delhi MBL (NDM), and Verona integron-encoded MBL (VIM) variants-show markedly different biochemical properties and inhibitor susceptibilities. Despite their clinical relevance, optimal treatment strategies for infections caused by IMP-producing Enterobacterales remain poorly defined. The unique reactivity of IMP-type MBLs to inhibitors differs from that of other MBLs such as NDMs or VIMs, underscoring the need for tailored therapeutic approaches. In this Personal View, we summarise current evidence and, drawing on Japan's experience as an endemic setting for IMP producers, outline key scientific, clinical, and public health challenges that should be addressed globally to develop effective, evidence-based treatment strategies for IMP-producing Enterobacterales infections.

Humans↗
PubMed1979

The inhibition of staphylococcal beta-lactamase by clavulanic acid.

Clavulanic acid inhibited both the extracellular and cell-extract beta-lactamases of the four Staphylococcus aureus strains tested. The inhibition of S. aureus Russell cell-extract enzyme appeared to be active-site-directed and proceeded in a first-order fashion consistent with the formation of a covalent intermediate. Inhibited enzyme free of excess clavulanic acid was shown to regenerate enzyme activity slowly at pH 7.0, but the rate of reactivation increased at acid pH. When the enzyme was incubated with excess clavulanic acid complete inhibition was rapidly obtained, during further incubation clavulanic acid was shown to disappear slowly and complete loss of clavulanic acid from the reaction mixture coincided with the onset of the return of enzyme activity. A reactive enamine resulting from enzymic hydrolysis of the beta-lactam ring of clavulanic acid has been proposed as a possible intermediate in the inhibitory mechanism.

Anti-Bacterial Agents↗
PubMed1978

Inhibition of beta-lactamase in Neisseria gonorrhoeae by sodium clavulanate.

Sodium clavulanate at subinhibitory concentrations affected the activity of penicillin G, ampicillin, or amoxicillin on beta-lactamase-positive strains of Neisseria gonorrhoeae as demonstrated by marked reduction in the minimal inhibitory concentrations of the drugs for the organisms. The compound did not affect the activity of these penicillins on beta-lactamase-negative strains of N. gonorrhoeae. It also had no effect on the activity of cefoxitin against either beta-lactamase-negative or -positive strains. The reduction in minimal inhibitory concentrations of the penicillins for the beta-lactamase-positive organisms brought about by sodium clavulanate is probably due to inhibition of the beta-lactamase by the compound.

Anti-Bacterial Agents↗
PubMed1976

Formation of beta-lactamase in Bacteroides fragilis: cell-bound and extracellular activity.

Nine strains of Bacteroides fragilis were cultivated in stirred fermentors and tested for their ability to produce beta-lactamase. There was a correlation between formation of beta-lactamase and high values of the minimal inhibitory concentration against beta-lactam antibiotics. B. fragilis strain B70 was used for optimizing the production of beta-lactamase. The highest bacterial yield was obtained in a proteose peptone-yeast extract medium. Optimal conditions for growth and beta-lactamase production were obtained at 37 C and pH 7.0. The beta-lactamase was released into the surrounding medium during the growth period to about 50%. Osmotic shock released about 20% of the total activity, and remaining activity was found in the cytoplasmic fraction. Substrate profile studies on four beta-lactamase-producing strains showed that the enzymes were mainly cephalosporinases. They are inhibited by cloxacillin, p-chloromercuribenzoate, and iodine. Analytical isoelectric focusing in polyacrylamide gel gave an isoelectric point of 4.9 +/- 0.2 for three of the strains and 5.6 +/- 0.2 for one. Comparison with beta-lactamases from aerobic gram-negative species with regard to isoelectric points showed no similarities. Also the molecular weight of the beta-lactamase from strain B70 of 43,000 indicates that this is a new class of beta-lactamase.

Bacteroides fragilis↗
PubMed1979

In vitro microbiological evaluation of TEI-1194 and TEI-2012, novel antipseudomonal semisynthetic penicillins.

TEI-1194, sodium 6-[D-(-)-alpha-(coumarin-3-carboxamide)-phenylacetamide] penicillanate and TEI-2012, sodium 6[D-(-)alpha-(8-hydroxy-coumarin-3-carboxamide)-phenylacetamide] penicillanate are new semisynthetic penicillin derivatives both possessing a broad spectrum of in vitro antibacterial activities. Minimal inhibitory concentrations of both agents were compared with carbenicillin. TEI-1194 and TEI-2012 were clearly found to have more potent activities especially against Pseudomonas aeruginosa than carbenicillin. At a concentration at 6.25 micrograms/ml, 85 approximately 90% of a total of 50 strains of clinically isolated P. aeruginosa were inhibited by TEI-1194 and TEI-2012, whereas carbenicillin had no effect. Evaluation of the antibacterial activity against a series of mutants producing different levels of beta-lactamases and test of the susceptibilities to some beta-lactamases demonstrated that TEI-1194 and TEI-2012 had low susceptibility to various cephalosporinases. However, both compounds were susceptible to penicillinase from Klebsiella pneumoniae H-2 at a rate of about 15% of penicillin-G taking its absolute rate as 100.

Bacteria↗
PubMed1979

Antibiotic susceptibility of anaerobic bacteria with special reference to Bacteroides fragilis.

It was shown that recent Swedish clinical isolates of anaerobic bacteria are susceptible to many antibiotics by the agar dilution method with the exception of the Bacteroides group versus beta-lactam antibiotics or tetracyclines. Strains of B. fragilis were inhibited by 4--greater than 128 micrograms benzylpenicillin or cephalothin/ml, 1.0--64 micrograms cefoxitin/ml, 0.064--2 micrograms clindamycin or metronidazole/ml, 2--8 micrograms chloramphenicol/ml, 2--16 micrograms fusidic acid/ml and 0.032--32 micrograms doxycycline/ml. Resistance to beta-lactam antibiotics was partly due to the production of beta-lactamase. Growth of beta-lactamase producing strains in the presence of enzyme inhibitors such as clavulanic acid or CP-45899 together with cephaloridine lowered the MIC's manyfold. Cefoxitin with relative resistance to beta-lactamases inhibited the majority of the strains at 8 micrograms/ml. Cefoxitin-resistant strains (MIC greater than or equal to 16 micrograms/ml) were also resistant to the new cephalosporins BL-S786 and HR-756 as well as to the new cefamycins A, B, CL619-183, CS-1170 and Sq-14359 and to thienamycin. Cefamycin CL619-183, only showed a slightly higher in vitro activity than cefoxitin. Resistance to the cefamycins could not be correlated to the production of beta-lactamases.

Anti-Bacterial Agents↗
PubMed1978

Purification and properties of beta-lactamase from Bacteroides fragilis.

Beta-Lactamase activity was detected either biologically or using the chromogenic cephalosporin 87/312 in 20 clinical isolates of Bacteroides fragilis with penicillin G minimal inhibitory concentrations of 10 to 100 micrograms/ml. Strain AM78 (minimal inhibitory concentration, greater than 1,000 micrograms/ml) was used to optimize the conditions for production, assay, and storage of the enzyme. The enzymes are cell associated, with less than 1% of activity being found in culture fluids during growth, and can be released from the cell surface by modified osmotic shock procedure. This procedure causes concomitant release of cyclic phosphodiesterase activity. Substrate profiles and the effects of inhibitors were determined for enzymes partially purified by osmotic shock release and gel filtration. The enzymes are cephalosporinases with some penicillinase activity and are inhibited by p-chloromercuribenzoate, cloxacillin, and carbenicillin. The molecular weight, as determined by gel filtration, is 29,000 to 31,000. A method for the purification of the beta-lactamase from strain AM78 is described: the specific activity of the purified enzyme was 3,424 U/mg, about 3,000-fold that of the crude, cell-associated enzyme.

Bacteroides fragilis↗
PubMed1978

beta-lactamase stability of HR 756, a novel cephalosporin, compared to that of cefuroxime and cefoxitin.

The stability to beta-lactamase hydrolysis of HR 756, a new cephalosporin antibiotic, was compared to the beta-lactamase stability of cefoxitin and cefuroxime. HR 756, cefoxitin, and cefuroxime were not hydrolyzed by Richmond type I, III, IV, and V beta-lactamases. Antibacterial activity of HR 756 correlated well with resistance to beta-lactamase hydrolysis except against Pseudomonas aeruginosa. HR 756, cefoxitin, and cefuroxime inhibited type I beta-lactamases, but not type III, IV, or V enzymes. HR 756 was the most active inhibitor.

Cephalosporins↗
PubMed1978

Clavulanic acid inhibition of beta-lactamase I from Bacillus cereus 569/H.

Inactivation of beta-lactamase I by clavulanic acid was investigated. Clavulanic acid induced inhibition of the enzyme was found to be progressive with time. Benzylpenicillin provided protection against the adverse effects of the inhibitor initially, however, the enzyme was irreversibly inhibited in a progressive manner even in the presence of substrate. Reaction of beta-lactamase I with clavulanic acid, in the presence of ampicillin, led to a very rapid inactivation of the enzyme.

Ampicillin↗
PubMed1979

Purification by affinity chromatography and properties of a beta-lactamase isolated from Neisseria gonorrhoeae.

beta-Lactamase activity was detected in cell-free preparations obtained from ultrasonic treatment of Neisseria gonorrhoeae after growth in liquid medium. Crude preparations of beta-lactamase were subjected to affinity chromatography, using several beta-lactam antibiotics as ligands bound to agarose supports. Affinity gels produced by coupling 7-aminocephalosporanic acid or 6-aminopenicillanic acid by their amino groups to carboxyl-terminal agarose via a five- to eight-carbon spacer arm proved to be effective chromatography media. beta-Lactamase preparations subjected to chromatography using these gels were purified 200-fold, with approximately 80% recovery of active material. Purified preparations were judged homogeneous by their behavior during electrophoresis on polyacrylamide in both the presence and absence of sodium dodecyl sulfate. Characterization of the purified enzyme established a molecular weight of approximately 25,000 and an isoelectric point of 5.4. Analyses of substrate specificity, effect of inhibitors, pH, and kinetic parameters were performed. The evidence suggests that the beta-lactamase produced in N. gonorrhoeae closely resembles the character of class IIIa (TEM-type) beta-lactamases.

Chromatography, Affinity↗