Topics

The Crystal Structures of CDD-1, the Intrinsic Class D β-Lactamase from the Pathogenic Gram-Positive Bacterium Clostridioides difficile, and its Complex with Cefotaxime.

08:00 EDT 21st September 2019 | BioPortfolio

Summary of "The Crystal Structures of CDD-1, the Intrinsic Class D β-Lactamase from the Pathogenic Gram-Positive Bacterium Clostridioides difficile, and its Complex with Cefotaxime."

Class D β-lactamases, enzymes that degrade β-lactam antibiotics and are widely spread in Gram-negative bacteria, were for a long time not known in Gram-positive organisms. Recently, these enzymes were identified in various non-pathogenic Bacillus species and subsequently in Clostridioides difficile, a major clinical pathogen associated with high morbidity and mortality rates. Comparison of the BPU-1 enzyme from Bacillus pumilus with the CDD-1 and CDD-2 enzymes from C. difficile demonstrated that the latter enzymes have broadened their substrate profile to efficiently hydrolyze the expanded-spectrum methoxyimino cephalosporins, cefotaxime and ceftriaxone. These two antibiotics are major contributors to the development of C. difficile infection, as they suppress sensitive bacterial microflora in the gut but fail to kill the pathogen which is highly resistant to these drugs. To gain insight into the structural features that contribute to the expansion of the substrate profile of CDD enzymes compared to BPU-1, we solved the crystal structures of CDD-1 and its complex with cefotaxime. Comparison of CDD-1 structures with those of class D enzymes from Gram-negative bacteria showed that in the cefotaxime-CDD-1 complex, the antibiotic is bound in a substantially different mode due to structural differences in the enzyme's active sites. We also found that CDD-1 has a uniquely long Ω-loop when compared to all other class D β-lactamases. This Ω-loop extension allows it to engage in hydrogen bonding with the acylated cefotaxime, thus providing additional stabilizing interactions with the substrate which could be responsible for the high catalytic activity of the enzyme for expanded-spectrum cephalosporins.

Affiliation

Journal Details

This article was published in the following journal.

Name: Journal of structural biology
ISSN: 1095-8657
Pages:

Links

DeepDyve research library

PubMed Articles [12418 Associated PubMed Articles listed on BioPortfolio]

The β-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria β-lactamase enzymes that hydrolyse the amide bond of the four-membered β-lactam ring are the prima...

The role of new β-lactamase inhibitors in gram-negative infections.

In recent years, traditional β-lactams have dramatically reduced their effectiveness against gram-negative bacteria mainly because of their ability to express multiple β-lactamase or carabapenemases...

A DNA aptamer reveals an allosteric site for inhibition in metallo-β-lactamases.

The hydrolysis of β-lactam antibiotics by β-lactamase enzymes is the most prominent antibiotic resistance mechanism for many pathogenic bacteria. Out of this broad class of enzymes, metallo-β-lacta...

Exploration of the antibiotic potentiating activity of indolglyoxylpolyamines.

A series of substituted di-indolglyoxylamido-spermine analogues were prepared and evaluated for intrinsic antimicrobial properties and the ability to enhance antibiotic action. As a compound class, in...

In vivo functional analysis of a class A β-lactamase-related protein essential for clavulanic acid biosynthesis in Streptomyces clavuligerus.

In Streptomyces clavuligerus, the gene cluster involved in the biosynthesis of the clinically used β-lactamase inhibitor clavulanic acid contains a gene (orf12 or cpe) encoding a protein with a C-ter...

Clinical Trials [2307 Associated Clinical Trials listed on BioPortfolio]

Efficacy, Safety, and Tolerability of ATM-AVI in the Treatment of Serious Infection Due to MBL-producing Gram-negative Bacteria

Phase 3 study to determine the efficacy, safety, and tolerability of aztreonam- avibactam (ATM- AVI) versus best available therapy (BAT) in the treatment of hospitalized adults with compli...

Predictors of Rates of Resistant Gram-Negative Bacteria

Antibiotic resistance in gram-negative bacteria continues to increase in US hospitals. This comes at a time when there are few new drugs in development that are active for these resistant ...

TMJ Adaptations by Orthodontic Treatment in Adolescent Males With Angle's Class II Division 2 Malocclusion: MRI Study

the aim of this study is to document the changes brought about in the internal anatomic relationships of the TMJ complex , positional changes of glenoid fossa with respect to adjacent cran...

Co-crystal E-58425 vs Tramadol and Celecoxib for Moderate to Severe Acute Pain After Bunionectomy. Phase III Clinical Trial.

This is a Phase 3, randomized, double-blind, controlled, parallel-group, multicenter clinical trial with co-crystal E-58425 compared to tramadol, to celecoxib, and to placebo. The primary ...

Pharmacokinetic and Safety Study of Ceftolozane/Tazobactam in Pediatric Participants Receiving Antibiotic Therapy for Proven or Suspected Gram-negative Infection or for Peri-operative Prophylaxis (MK-7625A-010)

The purpose of this study is to assess the pharmacokinetics, safety, and tolerability of a single intravenous dose of ceftolozane/tazobactam in pediatric participants. Ceftolozane/tazobac...

Medical and Biotech [MESH] Definitions

Broad-spectrum cephalosporin antibiotic resistant to beta-lactamase. It has been proposed for infections with gram-negative and gram-positive organisms, GONORRHEA, and HAEMOPHILUS.

Coccus-shaped bacteria that retain the crystal violet stain when treated by Gram's method.

A large group of rod-shaped bacteria that retains the crystal violet stain when treated by Gram's method.

Bacteria which retain the crystal violet stain when treated by Gram's method.

Bacteria which lose crystal violet stain but are stained pink when treated by Gram's method.

Quick Search


DeepDyve research library

Relevant Topics

Clostridium difficile (CDI)
A clostridium difficile infection (CDI) is a type of bacterial infection that can affect the digestive system. It most commonly affects people who are staying in hospital.  The symptoms of CDI can range from mild to severe and include: diarrhoe...

Enzymes
Enzymes are proteins that catalyze (i.e., increase the rates of) chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical re...

Infectious-diseases
Antiretroviral Therapy Clostridium Difficile Ebola HIV & AIDS Infectious Diseases Influenza Malaria Measles Sepsis Swine Flu Tropical Medicine Tuberculosis Infectious diseases are caused by pathogenic...


Searches Linking to this Article