scholarly journals JMM Profile: Carbapenems: a broad-spectrum antibiotic

2021 ◽  
Vol 70 (12) ◽  
Author(s):  
Tom Armstrong ◽  
Samuel Jacob Fenn ◽  
Kim R. Hardie
Keyword(s):  
Essential Medicine ◽  
Cell Wall Biosynthesis ◽  
Drug Resistant ◽  
Broad Spectrum Antibiotic ◽  
Class A ◽  
Clinical Resistance ◽  
Class B ◽  
Main Driver ◽  
Lactam Ring ◽  
Hydrolysis Of

Carbapenems are potent members of the β-lactam family that inhibit bacterial cell-wall biosynthesis inhibitors . They are highly effective against Gram-negative and Gram-positive drug-resistant infections . As such, carbapenems are typically reserved as an antibiotic of last resort. The WHO lists meropenem as an essential medicine. Nausea and vomiting are reported in ≤20% of carbapenem recipients, with 1.5% suffering seizures. Enzymatic hydrolysis of the β-lactam ring is the main driver of clinical resistance. These enzymes can be classified as Class A, B and D. Classes A and D are serine β-lactamases, whereas Class B rely on metal-mediated hydrolysis, typically through zinc.

scholarly journals In Vitro Activity of Cefiderocol against Multi-Drug Resistant Carbapenemase-Producing Gram-Negative Pathogens

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S376-S376 ◽  
Author(s):  
Sandra Boyd ◽  
Karen Anderson ◽  
Valerie Albrecht ◽  
Davina Campbell ◽  
Maria S Karlsson ◽  
...  
Keyword(s):  
Vitro Activity ◽  
Burkholderia Cepacia Complex ◽  
Uptake System ◽  
Drug Resistant ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Class A ◽  
Class D ◽  
Class B

Abstract Background Few options remain for treatment of infections caused by multi-drug resistant (MDR), carbapenemase-producing gram-negative pathogens. Cefiderocol (CFDC; Shionogi & Co. Ltd), is a novel parenteral siderophore cephalosporin that enters the bacterial cell through the iron–siderophore uptake system. Here we report on the in vitro activity of CFDC against a set of well-characterized MDR gram-negative isolates collected by the Centers for Disease Control and Prevention. Methods Minimum inhibitory concentrations (MIC) values for CFDC in iron-depleted cation-adjusted Mueller Hinton broth were determined using reference broth microdilution. Study isolates (n = 315) included Enterobacteriaceae (59%), Pseudomonas aeruginosa (19%), Acinetobacter baumannii (17%), Stenotrophomonas maltophilia (4%), and Burkholderia cepacia complex (1%). Of these, 229 (73%) were carbapenemase-producers including Ambler Class A- (37%), Class B- (29%) and Class D- type (29%) enzymes. The remaining isolates included 51 β-lactam-resistant isolates that were non-carbapenemase-producers, and 35 β-lactam-susceptible isolates. Results were interpreted using suggested CFDC breakpoints of Sensitive ≤4 μg/mL and Resistant ≥16 μg/mL. Results The majority of the isolates (90.8%) were categorized as CFDC susceptible; the percentage of isolates with a CFDC MIC ≤4 μg/mL among Enterobacteriaceae, P. aeruginosa, and A. baumannii was 87.5%, 100%, and 89%, respectively. Percentage of isolates with a CFDC MIC ≤4 μg/mL that harbored a carbapenemase of the Class A-, Class B-, and Class D-type was 91.8%, 74.8%, 98.0%, respectively. By applying suggested breakpoints, 12 isolates were categorized as intermediate and 17 as resistant. The resistant isolates included 11 NDM-, 2 OXA-23- and 4 KPC-positive organisms. Conclusion Cefiderocol showed potent activity against MDR gram-negative pathogens including Class A, B, and D carbapenemase-producing isolates. Of note, all P. aeruginosa, including Class B metallo-β-lactamase producers, were susceptible to CFDC. Disclosures All authors: No reported disclosures.

scholarly journals Mechanism of Action of NB2001 and NB2030, Novel Antibacterial Agents Activated by β-Lactamases

2004 ◽  
Vol 48 (2) ◽  
pp. 477-483 ◽  
Author(s):  
Geoffrey W. Stone ◽  
Qin Zhang ◽  
Rosario Castillo ◽  
V. Ramana Doppalapudi ◽  
Analia R. Bueno ◽  
...  
Keyword(s):  
Antibacterial Agents ◽  
Mechanisms Of Action ◽  
Enoyl Reductase ◽  
Penicillin Binding Proteins ◽  
E Coli ◽  
Class A ◽  
Biochemical Assays ◽  
Lactam Ring ◽  
A Cell ◽  
Hydrolysis Of

ABSTRACT Two potent antibacterial agents designed to undergo enzyme-catalyzed therapeutic activation were evaluated for their mechanisms of action. The compounds, NB2001 and NB2030, contain a cephalosporin with a thienyl (NB2001) or a tetrazole (NB2030) ring at the C-7 position and are linked to the antibacterial triclosan at the C-3 position. The compounds exploit β-lactamases to release triclosan through hydrolysis of the β-lactam ring. Like cephalothin, NB2001 and NB2030 were hydrolyzed by class A β-lactamases (Escherichia coli TEM-1 and, to a lesser degree, Staphylococcus aureus PC1) and class C β-lactamases (Enterobacter cloacae P99 and E. coli AmpC) with comparable catalytic efficiencies (k cat/Km ). They also bound to the penicillin-binding proteins of S. aureus and E. coli, but with reduced affinities relative to that of cephalothin. Accordingly, they produced a cell morphology in E. coli consistent with the toxophore rather than the β-lactam being responsible for antibacterial activity. In biochemical assays, they inhibited the triclosan target enoyl reductase (FabI), with 50% inhibitory concentrations being markedly reduced relative to that of free triclosan. The transport of NB2001, NB2030, and triclosan was rapid, with significant accumulation of triclosan in both S. aureus and E. coli. Taken together, the results suggest that NB2001 and NB2030 act primarily as triclosan prodrugs in S. aureus and E. coli.

Interaction of β-lactamases I and II from Bacillus cereus with semisynthetic cephamycins. Kinetic studies

1991 ◽  
Vol 279 (1) ◽  
pp. 111-114 ◽  
Author(s):  
J Martin Villacorta ◽  
P Arriaga ◽  
J Laynez ◽  
M Menendez
Keyword(s):  
Bacillus Cereus ◽  
Kinetic Studies ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Class A ◽  
Rate Determining Step ◽  
Class B ◽  
Lactam Ring ◽  
Beta Lactamase Ii

The influence of C-6 alpha- or C-7 alpha-methoxylation of the beta-lactam ring in the catalytic action of class A and B beta-lactamases has been investigated. For this purpose the kinetic behaviour of beta-lactamases I (class A) and II (class B) from Bacillus cereus was analysed by using several cephamycins, moxalactam, temocillin and related antibiotics. These compounds behaved as poor substrates for beta-lactamase II, with high Km values and very low catalytic efficiencies. In the case of beta-lactamase I, the substitution of a methoxy group for a H atom at C-7 alpha or C-6 alpha decreased the affinity of the substrates for the enzyme. Furthermore, the acylation of cephamycins was completely blocked, whereas that of penicillins was slowed down by a factor of 10(4)-10(5), acylation being the rate-determining step of the process.

scholarly journals The pH-dependence of class B and class C β-lactamases

1983 ◽  
Vol 213 (1) ◽  
pp. 61-66 ◽  
Author(s):  
R Bicknell ◽  
V Knott-Hunziker ◽  
S G Waley
Keyword(s):  
Ph Dependence ◽  
Beta Lactamase ◽  
Beta Lactamases ◽  
Class A ◽  
Class B ◽  
Class C ◽  
Beta Lactamase Ii ◽  
Hydrolysis Of ◽  
Ionic Forms ◽  
Do So

The classification by structure allots beta-lactamases to (at present) three classes, A, B and C. The pH-dependence of the kinetic parameters for class B and class C have been determined. They differ from each other and from class A beta-lactamases. The class B enzyme was beta-lactamase II from Bacillus cereus 569/H/9. The plots of kcat against pH for the hydrolysis of benzylpenicillin by Zn(II)-requiring beta-lactamase II and Co(II)-requiring beta-lactamase II were not symmetrical, but those of kcat/Km were. A similar feature was observed for the hydrolysis of both benzylpenicillin and cephalosporin C by a class C beta-lactamase from Pseudomonas aeruginosa. The results have been interpreted by a scheme in which two ionic forms of an intermediate can give product, but do so at differing rates.

scholarly journals The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 854 ◽  
Author(s):  
Alexey Egorov ◽  
Maya Rubtsova ◽  
Vitaly Grigorenko ◽  
Igor Uporov ◽  
Alexander Veselovsky
Keyword(s):  
Active Site ◽  
Bacterial Resistance ◽  
Structural Flexibility ◽  
Allosteric Inhibitors ◽  
Penicillin Binding Proteins ◽  
Global Challenge ◽  
Class A ◽  
Lactam Ring ◽  
Hydrolysis Of

Bacterial resistance to β-lactams, the most commonly used class of antibiotics, poses a global challenge. This resistance is caused by the production of bacterial enzymes that are termed β-lactamases (βLs). The evolution of serine-class A β-lactamases from penicillin-binding proteins (PBPs) is related to the formation of the Ω-loop at the entrance to the enzyme’s active site. In this loop, the Glu166 residue plays a key role in the two-step catalytic cycle of hydrolysis. This residue in TEM–type β-lactamases, together with Asn170, is involved in the formation of a hydrogen bonding network with a water molecule, leading to the deacylation of the acyl–enzyme complex and the hydrolysis of the β-lactam ring of the antibiotic. The activity exhibited by the Ω-loop is attributed to the positioning of its N-terminal residues near the catalytically important residues of the active site. The structure of the Ω-loop of TEM-type β-lactamases is characterized by low mutability, a stable topology, and structural flexibility. All of the revealed features of the Ω-loop, as well as the mechanisms related to its involvement in catalysis, make it a potential target for novel allosteric inhibitors of β-lactamases.

The structure of β-lactamases

1980 ◽  
Vol 289 (1036) ◽  
pp. 321-331 ◽  
Keyword(s):  
Amino Acid ◽  
Sequence Analysis ◽  
Amino Acid Sequence ◽  
Homology Group ◽  
Gram Negative Bacteria ◽  
Sequence Determination ◽  
Present Evidence ◽  
Class A ◽  
Class B ◽  
Lactam Ring

The β-lactamases are widely distributed in both Gram-positive and Gram-negative bacteria. They all inactivate penicillins and cephalosporins by opening the β-lactam ring. Many varieties of the enzyme can be distinguished on the basis of their catalytic and molecular properties, but only amino acid sequence determination gives information upon which a molecular phylogeny can be based. The present evidence suggests that the β-lactamases have a polyphyletic origin. All the β-lactamases of currently known amino acid sequence belong to one homology group, here called class A enzymes. Class B consists of the mechanistically distinct Bacillus cereus β-lactamase II, which preliminary partial sequence analysis suggests to be structurally unrelated to the class A enzymes. It is predicted that sequence analysis will show that further classes will need to be created to account for particular β-lactamases of distinctive molecular and mechanistic properties.

scholarly journals Biochemical Activity of Vaborbactam

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Ruslan Tsivkovski ◽  
Olga Lomovskaya
Keyword(s):  
The United States ◽  
Common Mechanism ◽  
Class A ◽  
Small Molecule Drugs ◽  
Class D ◽  
Potent Inhibition ◽  
Class B ◽  
Lactam Ring ◽  
Insight Into

ABSTRACT The most common mechanism of resistance to β-lactams antibiotics in Gram-negative bacteria is production of β-lactamase enzymes capable of cleaving the β-lactam ring. Inhibition of β-lactamase activity with small-molecule drugs is a proven strategy to restore the potency of many β-lactam antibiotics. Vaborbactam (formerly RPX7009) is a cyclic boronic acid β-lactamase inhibitor (BLI) with a broad spectrum of activity against various serine β-lactamases, including KPC carbapenemases. The combination of vaborbactam and meropenem is approved in the United States and Europe for the treatment of various nosocomial infections. We attempted to gain more insight into the mechanism of action of vaborbactam by conducting detailed kinetic characterization of its interaction with various recombinant His-tagged β-lactamases. Vaborbactam demonstrated potent inhibition of class A and class C enzymes with Ki values ranging from 0.022 to 0.18 μM, while inhibition of class D enzymes was rather poor, and no activity against class B β-lactamases was detected. Importantly, vaborbactam inhibited KPC-2, KPC-3, BKC-1, and SME-2 carbapenemases at 1:1 stoichiometry, while these numbers were higher for other class A and C enzymes. Vaborbactam was also shown to be a potent progressive inactivator of several enzymes, including KPCs with inactivation constants k2/K in the range of 3.4 × 103 to 2.4 × 104 M−1 s−1. Finally, experiments on the recovery of enzyme activity demonstrated the high stability of the vaborbactam-KPC complex, with 0.000040 s−1 koff values and a corresponding residence time of 7 h, whereas the release of vaborbactam bound to other serine β-lactamases was substantially faster. The biochemical characteristics of vaborbactam described in this study may facilitate further chemical optimization efforts to develop boronic BLIs with improved affinity and broader spectrum of inhibition.

scholarly journals Crystal Structure of Phosphoserine BlaC from Mycobacterium tuberculosis Inactivated by Bis(Benzoyl) Phosphate

2019 ◽  
Vol 20 (13) ◽  
pp. 3247
Author(s):  
Timothy W. Moural ◽  
Dawanna Shar-Day White ◽  
Cindy J. Choy ◽  
Chulhee Kang ◽  
Clifford E. Berkman
Keyword(s):  
Crystal Structure ◽  
Mycobacterium Tuberculosis ◽  
Bacterial Resistance ◽  
Crystallographic Analysis ◽  
Dependent Manner ◽  
Serine Residue ◽  
Class A ◽  
Protein X ◽  
Lactam Ring ◽  
Hydrolysis Of

Mycobacterium tuberculosis, the pathogen responsible for tuberculosis (TB), is the leading cause of death from infectious disease worldwide. The class A serine β-lactamase BlaC confers Mycobacterium tuberculosis resistance to conventional β-lactam antibiotics. As the primary mechanism of bacterial resistance to β-lactam antibiotics, the expression of a β-lactamase by Mycobacterium tuberculosis results in hydrolysis of the β-lactam ring and deactivation of these antibiotics. In this study, we conducted protein X-ray crystallographic analysis of the inactivation of BlaC, upon exposure to the inhibitor bis(benzoyl) phosphate. Crystal structure data confirms that serine β-lactamase is phosphorylated at the catalytic serine residue (Ser-70) by this phosphate-based inactivator. This new crystallographic evidence suggests a mechanism for phosphorylation of BlaC inhibition by bis(benzoyl) phosphate over acylation. Additionally, we confirmed that bis(benzoyl) phosphate inactivated BlaC in a time-dependent manner.

scholarly journals Interactions of β-Lactamases with Sanfetrinem (GV 104326) Compared to Those with Imipenem and with Oral β-Lactams

1998 ◽  
Vol 42 (5) ◽  
pp. 1168-1175 ◽  
Author(s):  
Gioia S. Babini ◽  
Meifang Yuan ◽  
David M. Livermore
Keyword(s):  
Functional Group ◽  
Klebsiella Oxytoca ◽  
Enterobacter Cloacae ◽  
Proteus Vulgaris ◽  
Morganella Morganii ◽  
Full Activity ◽  
Class A ◽  
Extended Spectrum ◽  
Class B ◽  
Hydrolysis Of

ABSTRACT Sanfetrinem is a trinem β-lactam which can be administered orally as a hexatil ester. We examined whether its β-lactamase interactions resembled those of the available carbapenems, i.e., stable to AmpC and extended-spectrum β-lactamases but labile to class B and functional group 2f enzymes. The comparator drugs were imipenem, oral cephalosporins, and amoxicillin. MICs were determined for β-lactamase expression variants, and hydrolysis was examined directly with representative enzymes. Sanfetrinem was a weak inducer of AmpC β-lactamases below the MIC and had slight lability, with ak cat of 0.00033 s−1 for theEnterobacter cloacae enzyme. Its MICs for AmpC-derepressedE. cloacae and Citrobacter freundii were 4 to 8 μg/ml, compared with MICs of 0.12 to 2 μg/ml for AmpC-inducible and -basal strains; MICs for AmpC-derepressed Serratia marcescens and Morganella morganii were not raised. Cefixime and cefpodoxime were more labile than sanfetrinem to theE. cloacae AmpC enzyme, and AmpC-derepressed mutants showed much greater resistance; imipenem was more stable and retained full activity against derepressed mutants. Like imipenem, sanfetrinem was stable to TEM-1 and TEM-10 enzymes and retained full activity against isolates and transconjugants with various extended-spectrum TEM and SHV enzymes, whereas these organisms were resistant to cefixime and cefpodoxime. Sanfetrinem, like imipenem and cefixime but unlike cefpodoxime, also retained activity against Proteus vulgaris and Klebsiella oxytoca strains that hyperproduced potent chromosomal class A β-lactamases. Functional group 2f enzymes, including Sme-1, NMC-A, and an unnamed enzyme fromAcinetobacter spp., increased the sanfetrinem MICs by up to 64-fold. These enzymes also compromised the activities of imipenem and amoxicillin but not those of the cephalosporins. The hydrolysis of sanfetrinem was examined with a purified Sme-1 enzyme, and biphasic kinetics were found. Finally, zinc β-lactamases, including IMP-1 and the L1 enzyme of Stenotrophomonas maltophilia, conferred resistance to sanfetrinem and all other β-lactams tested, and hydrolysis was confirmed with the IMP-1 enzyme. We conclude that sanfetrinem has β-lactamase interactions similar to those of the available carbapenems except that it is a weaker inducer of AmpC types, with some tendency to select derepressed mutants, unlike imipenem and meropenem.

مهارة الكلام منظور من عملية التعلم والتعليم في جامعة باتوسنجكر الاسلامية الحكومية سومطرى الغربية

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Suharmon Suharmon
Keyword(s):  
Teaching Strategies ◽  
Language Education ◽  
Arabic Language ◽  
Descriptive Statistics ◽  
Quantitative Approach ◽  
Motivation To Learn ◽  
Education Department ◽  
Class A ◽  
Class B ◽  
Speaking Skill

This research aims to obtain infomation about Arabic learning especially speaking skill in Arabic Language Education Department at IAIN Batusangkar. The research uses a quantitative approach. The instruments to collect the data are test and questionnaire. The data were analyzed using descriptive statistics. The results of the research state that the students’ speaking ability at class “ A “ are 28% low, 36% moderate, and 36% high. While, at class “B”, students’ speaking abilities are 36.4% low, 40,9% moderate, and 22.7% high. The cause of students’ low ability is the unappropriateness of teachers’ strategy in teaching speaking. There are about 96% students at class “A” agreed and 86.4% students at class “B” had similar answer. Another cause is students’ low motivation in learning. Class “A” students agreed for about 76% of them and 77% of class “B” students answered the same. From the finding, it can be concluded that the inability of students to speak Arabic can be overcomed by improving teaching strategies and encouraging maximum motivation  to learn Arabic.

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