scholarly journals Beta-lactamase inhibitors from laboratory to clinic.

1988 ◽  
Vol 1 (1) ◽  
pp. 109-123 ◽  
Author(s):  
K Bush
Keyword(s):  
Side Effects ◽  
Clavulanic Acid ◽  
Broad Spectrum ◽  
Pathogenic Bacteria ◽  
Defense Mechanism ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
Tract Infections

beta-Lactamases constitute the major defense mechanism of pathogenic bacteria against beta-lactam antibiotics. When the beta-lactam ring of this antibiotic class is hydrolyzed, antimicrobial activity is destroyed. Although beta-lactamases have been identified with clinical failures for over 40 years, enzymes with various abilities to hydrolyze specific penicillins or cephalosporins are appearing more frequently in clinical isolates. One approach to counteracting this resistance mechanism has been through the development of beta-lactamase inactivators. beta-Lactamase inhibitors include clavulanic acid and sulbactam, molecules with minimal antibiotic activity. However, when combined with safe and efficacious penicillins or cephalosporins, these inhibitors can serve to protect the familiar beta-lactam antibiotics from hydrolysis by penicillinases or broad-spectrum beta-lactamases. Both of these molecules eventually inactivate the target enzymes permanently. Although clavulanic acid exhibits more potent inhibitory activity than sulbactam, especially against the TEM-type broad-spectrum beta-lactamases, the spectrum of inhibitory activities are very similar. Neither of these inhibitors acts as a good inhibitor of the cephalosporinases. Clavulanic acid has been most frequently combined with amoxicillin in the orally active Augmentin and with ticarcillin in the parenteral beta-lactam combination Timentin. Sulbactam has been used primarily to protect ampicillin from enzymatic hydrolysis. Sulbactam has been used either in the orally absorbed prodrug form as sultamicillin or as the injectable combination ampicillin-sulbactam. Synergy has been demonstrated for these combinations for most members of the Enterobacteriaceae, although those organisms that produce cephalosporinases are not well inhibited. Synergy has also been observed for Neisseria gonorrhoeae, Haemophilus influenzae, penicillinase-producing Staphylococcus aureus, and anaerobic organisms. These antibiotic combinations have been used clinically to treat urinary tract infections, bone and soft-tissue infections, gonorrhea, respiratory infections, and otitis media. Gastrointestinal side effects have been reported for Augmentin and sultamicillin; most side effects with these agents have been mild. Although combination therapy with beta-lactamase inactivators has been used successfully, the problem of resistance development to two agents must be considered. Induction of cephalosporinases can occur with clavulanic acid. Permeability mutants could arise, especially with added pressure from a second beta-lactam.(ABSTRACT TRUNCATED AT 250 WORDS)

The Ultra-Broad-Spectrum Beta-lactamase Inhibitor QPX7728 Restores the Potency of Multiple Oral Beta-lactam Antibiotics against Beta-lactamase Producing Strains of Resistant Enterobacterales

2021 ◽  
Author(s):  
Olga Lomovskaya ◽  
Debora Rubio-Aparicio ◽  
Ruslan Tsivkovski ◽  
Jeff Loutit ◽  
Michael Dudley
Keyword(s):  
Broad Spectrum ◽  
Resistance Mechanisms ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Intrinsic Resistance ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
The Impact ◽  
Lactamase Inhibitor

QPX7728 is a cyclic boronate ultra-broad-spectrum beta-lactamase inhibitor, with potent activity against both serine and metallo beta-lactamases. QPX7728 can be delivered systemically by the IV or oral route of administration. Oral β-lactam antibiotics alone or in combination with QPX7728 were evaluated for 1) sensitivity to hydrolysis by various common beta-lactamases and inhibition of hydrolysis by QPX7728; 2) the impact of non-beta-lactamase-mediated resistance mechanisms on potency of beta-lactams; and 3) in vitro activity against a panel of clinical strains producing diverse beta-lactamases. The carbapenem tebipenem had stability for many serine beta-lactamases from all molecular classes followed by cephalosporin ceftibuten. Addition of QPX7728 to tebipenem, ceftibuten and mecillinam completely reversed beta-lactamase-mediated resistance in cloned beta-lactamases from serine and metallo enzyme classes; the degree of potentiation of other beta-lactams varied according to the beta-lactamase produced. Tebipenem, ceftibuten and cefixime had the lowest MICs against laboratory strains with various combinations of beta-lactamases and the intrinsic drug-resistance mechanisms of porin and efflux mutations. There was a high degree of correlation between potency of various combinations against cloned beta-lactamases and efflux/porin mutants and the activity against clinical isolates, showing the importance of both inhibition of beta-lactamase along with minimal impact of general intrinsic resistance mechanisms affecting the beta-lactam. Tebipenem and ceftibuten appeared to be the best beta-lactam antibiotics when combined with QPX7728 for activity against Enterobacterales that produce serine or metallo beta-lactamases.

scholarly journals Phenotypic detection of Carbapenamase among Klebsiella pneumoniae isolated from clinical samples using modified Hodged test

2020 ◽  
Vol 13 (3) ◽  
pp. 135-140
Author(s):  
HauwaYakubu ◽  
Mahmud Yerima Iliyasu ◽  
Asma’u Salisu ◽  
Abdulmumin Ibrahim Sulaiman ◽  
Fatima Tahir ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Susceptibility Testing ◽  
University Teaching ◽  
Diffusion Method ◽  
Clinical Samples ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
Microbiological Techniques ◽  
Tract Infections

Carbapenemases are microbial enzymes that confer resistance to virtually all available beta-lactam antibiotics and the most frequent carbapenemases are the Klebsiella pneumoniae Carbapenamase (KPC). Detection of carbapenemases is a significant infection control strategy as the enzymes are often associated with extensive antimicrobial resistance, therapeutic failures and mortality associated with infectious diseases. A total of 400 clinical samples were collected from different groups of patients in Abubakar Tafawa Balewa University Teaching Hospital, Bauchi, Nigeria and 118 K. pneumoniae were isolated using standard microbiological techniques. The isolates were subjected to antibiotic susceptibility testing by Kirby-Bauer disc diffusion method, then screened for Carbapenamase production using modified Hodge test. The results indicated that the isolates were resistant to Ampicillin (61.9%), Ceftriaxone (50.8%) and Ceftazidime (50.8%), then Ciprofloxacin (54.2%), but predominantly sensitive to Imipenem (66.9%), Eterpenem (60.2%) and Meropenem (65.3%). It was found that 38 (32.2%) of the isolates phenotypically shows the presence of Carbapenamase, with highest frequency of (40.7%) among patients, mainly adult females with cases of Urinary Tract Infections (UTIs) and the least from wound (11.8%).This study revealed that the isolates produced other beta-lactamases than KPC or variants of Carbapenamase that cannot be detected by modified Hodge test, thus shows low resistance to carbapenems. Therefore further studies is needed to genotypically confirm the presence of KPC in these isolates.

scholarly journals Properties of IRT-14 (TEM-45), a newly characterized mutant of TEM-type beta-lactamases.

1997 ◽  
Vol 41 (2) ◽  
pp. 374-378 ◽  
Author(s):  
M M Caniça ◽  
M Barthélémy ◽  
L Gilly ◽  
R Labia ◽  
R Krishnamoorthy ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Kinetic Parameters ◽  
Clavulanic Acid ◽  
Broad Spectrum ◽  
Promoter Region ◽  
Beta Lactamase ◽  
Beta Lactamases ◽  
Structural Modifications ◽  
E Coli

IRT-14 (TEM-45) is a new mutant TEM-type beta-lactamase that was isolated from clinical Escherichia coli P37 and that confers resistance to broad-spectrum penicillins with reduced sensitivity to beta-lactamase inhibitors. The MICs of amoxicillin alone and of amoxicillin combined with 2 micrograms of clavulanic acid or 2 micrograms of tazobactam per ml were 4,096, 2,048, and 1,024 micrograms/ml, respectively. The strain was susceptible to cephalosporins, aztreonam, moxalactam, and imipenem. The enzyme was purified to homogeneity, and values of the kinetic parameters Kcat, Km, and Kcat/Km were determined for different substrates. This enzyme, with a pI of 5.2, was found to have reduced affinity for broad-spectrum penicillins and cephalosporins. The values of 50% inhibitory concentrations of clavulanic acid, sulbactam, tazobactam, and brobactam are correlated with the higher KmS for substrates. The resistance of E. coli P37 to mechanism-based inactivators results from a higher level of production of the TEM-derived enzyme due to the G-to-T substitution at position 162 (G-162-->T) in the promoter region of blaTEM and from the structural modifications resulting from the Met-69-->Leu and Arg-275-->Gln substitutions that characterize IRT-14 beta-lactamase.

scholarly journals Evaluation of the presence of AmpC (FOX) beta-lactamase gene in clinical strains of Escherichia coli isolated from hospitalized patients in Tabriz, Iran

2021 ◽  
Vol 38 (3) ◽  
pp. 301-304
Author(s):  
Zahra SADEGHI DEYLAMDEH ◽  
Abolfazl JAFARI SALES
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Hospitalized Patients ◽  
Disk Diffusion ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Clinical Strains ◽  
Beta Lactam Antibiotics ◽  
Lactamase Gene

Beta-lactamases are the most common cause of bacterial resistance to beta-lactam antibiotics. AmpC-type beta-lactamases hydrolyze cephalosporins, penicillins, and cephamycins. Therefore, the study aims was to determine antibiotic resistance and to investigate the presence of AmpC beta-lactamase gene in clinical strains of Escherichia coli isolated from hospitalized patients in Tabriz. In this cross-sectional descriptive study, 289 E. coli specimens were collected from clinical specimens. Disk diffusion method and combined disk method were used to determine the phenotype of extended spectrum β-Lactamase producing (ESBLs) strains. Then PCR was used to evaluate the presence of AmpC (FOX) beta-lactamase gene in the strains confirmed in phenotypic tests. Antibiotic resistance was also determined using disk diffusion by the Kibry-Bauer method. A total of 121 isolates were identified as generators of beta-lactamase genes. 72 (59.5 %) isolates producing ESBL and 49 (40.5 %) isolates were identified as AmpC generators. In the PCR test, 31 isolates contained the FOX gene. The highest resistance was related to the antibiotics amoxicillin (76.12%), ceftazidime (70.24%) and nalidixic acid (65.05%). The results indicate an increase in the prevalence of beta-lactamase genes and increased resistance to beta-lactam antibiotics, which can be the result of improper use of antibiotics and not using antibiotic susceptibility tests before starting treatment. Also, using phenotypic and molecular diagnostic methods such as PCR together can be very useful.

scholarly journals Biochemical Characterization of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Ruslan Tsivkovski ◽  
Maxim Totrov ◽  
Olga Lomovskaya
Keyword(s):  
High Efficiency ◽  
Biochemical Characterization ◽  
Molar Ratio ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Content Type ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
Class D ◽  
Extended Spectrum Beta Lactamases

ABSTRACT QPX7728 is a new ultrabroad-spectrum inhibitor of serine and metallo-beta-lactamases (MBLs) from a class of cyclic boronates that gave rise to vaborbactam. The spectrum and mechanism of beta-lactamase inhibition by QPX7728 were assessed using purified enzymes from all molecular classes. QPX7728 inhibits class A extended-spectrum beta-lactamases (ESBLs) (50% inhibitory concentration [IC50] range, 1 to 3 nM) and carbapenemases such as KPC (IC50, 2.9 ± 0.4 nM) as well as class C P99 (IC50 of 22 ± 8 nM) with a potency that is comparable to or higher than recently FDA-approved beta-lactamase inhibitors (BLIs) avibactam, relebactam, and vaborbactam. Unlike those other BLIs, QPX7728 is also a potent inhibitor of class D carbapenemases such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/58, IC50 range, 1 to 2 nM) as well as MBLs such as NDM-1 (IC50, 55 ± 25 nM), VIM-1 (IC50, 14 ± 4 nM), and IMP-1 (IC50, 610 ± 70 nM). Inhibition of serine enzymes by QPX7728 is associated with progressive inactivation with a high-efficiency k2/K ranging from 6.3 × 104 (for P99) to 9.9 × 105 M−1 s−1 (for OXA-23). This inhibition is reversible with variable stability of the QPX7728-beta-lactamase complexes with target residence time ranging from minutes to several hours: 5 to 20 min for OXA carbapenemases from A. baumannii, ∼50 min for OXA-48, and 2 to 3 h for KPC and CTX-M-15. QPX7728 inhibited all tested serine enzymes at a 1:1 molar ratio. Metallo-beta-lactamases NDM, VIM, and IMP were inhibited by a competitive mechanism with fast-on–fast-off kinetics, with Kis of 7.5 ± 2.1 nM, 32 ± 14 nM, and 240 ± 30 nM for VIM-1, NDM-1, and IMP-1, respectively. QPX7728’s ultrabroad spectrum of BLI inhibition combined with its high potency enables combinations with multiple different beta-lactam antibiotics.

scholarly journals Protein extracts from streptomyces sps. inhibits beta-lactamases secreted by pathogenic bacteria

2018 ◽  
Vol 9 (3) ◽  
Author(s):  
Rohit Mani Yadava ◽  
Manjula Ishwara Kalyani
Keyword(s):  
Enzyme Activity ◽  
Pathogenic Bacteria ◽  
Clinical Importance ◽  
Beta Lactamase ◽  
Bacterial Isolates ◽  
Beta Lactam ◽  
Biochemical Tests ◽  
Beta Lactamases ◽  
Culture Extract ◽  
Dialysis Technique

<p>Beta-lactamases are enzymes produced by pathogenic microorganisms which exhibit resistance to beta-lactam group of antibiotics and are of considerable clinical importance. In our study, we examined the pathogenic organisms for the secretion of beta-lactamase using the antibiotic ampicillin. The extracted beta-lactamase from the isolates was characterized biochemically for enzyme activity and to initiate their inhibition activities.  The protein extracts separated from the potential actinomycetes species were analyzed by targeting against the beta lactamase enzyme activity. The beta-lactamase enzymes from bacterial isolates were purified from the cell free culture extract and activity was estimated spectrophotometrically.<em>  </em>The actinomycetes isolated from the soil source were tested for their efficiency to inhibit the beta-lactamase enzyme activity. The protein fractions were extracted by salt precipitation using ammonium sulfate and further salt removal by dialysis technique. The assays for enzyme inhibition were performed by plate well diffusion along with absorbance readings of the enzyme and substrate using spectrophotometer. The beta-lactamase enzyme activity of <em>Proteus</em> sp. had shown highest enzymatic activity followed by <em>Staphylococcus aureus </em>and <em>Pseudomonas </em>sp<em>. </em>The protein extracts of four actinomycetes isolates that showed beta-lactamase inhibition were identified belonging to the genus <em>Streptomyces </em>based on their colony morphology, microscopic observation, and biochemical tests. The beta-lactamase inhibition activities were analyzed to combat antibiotitc resistances exerted by the pathogenic bacteria in infections.</p><p> </p>

scholarly journals beta-Lactamases in laboratory and clinical resistance.

1995 ◽  
Vol 8 (4) ◽  
pp. 557-584 ◽  
Author(s):  
D M Livermore
Keyword(s):  
Bacterial Resistance ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Producer Strain ◽  
Phenotypic Properties ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
Clinical Resistance ◽  
Gram Negative Organisms

beta-Lactamases are the commonest single cause of bacterial resistance to beta-lactam antibiotics. Numerous chromosomal and plasmid-mediated types are known and may be classified by their sequences or phenotypic properties. The ability of a beta-lactamase to cause resistance varies with its activity, quantity, and cellular location and, for gram-negative organisms, the permeability of the producer strain. beta-Lactamases sometimes cause obvious resistance to substrate drugs in routine tests; often, however, these enzymes reduce susceptibility without causing resistance at current, pharmacologically chosen breakpoints. This review considers the ability of the prevalent beta-lactamases to cause resistance to widely used beta-lactams, whether resistance is accurately reflected in routine tests, and the extent to which the antibiogram for an organism can be used to predict the type of beta-lactamase that it produces.

scholarly journals ESBL and AmpC beta-lactamase-producing Enterobacteriaceae in poultry in the Czech Republic

2010 ◽  
Vol 55 (No. 3) ◽  
pp. 119-124 ◽  
Author(s):  
M. Kolar ◽  
J. Bardon ◽  
M. Chroma ◽  
K. Hricova ◽  
T. Stosova ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Czech Republic ◽  
Molecular Characteristics ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
The Czech Republic ◽  
Beta Lactamases ◽  
E Coli ◽  
Beta Lactam Antibiotics ◽  
Composite Samples

A major reason for resistance of <I>Enterobacteriaceae</I> to beta-lactam antibiotics is production of ESBLs and AmpC beta-lactamases. As their more detailed description in poultry is unavailable in the Czech Republic, the presented study aimed at assessing their occurrence and molecular characteristics. A total of 154 composite samples from broilers and 150 cloacal swabs from turkeys were examined. Production of ESBLs was detected in seven <I>Escherichia coli</I> isolates and AmpC enzymes in two <I>E. coli</I> isolates. The most frequent ESBL types were CTX-M-1 and SHV-12 and the most common AmpC enzymes were the CMY-2 types.

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