Lecture 15 - Antimicrobial Resistance Mechanisms
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Questions and Answers

Which mechanism describes the enzymatic inactivation of antibiotics through the addition of a carbohydrate?

  • Glycosylation (correct)
  • Nucleotidylation
  • Acylation
  • Phosphorylation

What is the primary function of beta-lactamases in relation to antibiotics?

  • To enhance antibiotic absorption
  • To render beta-lactams ineffective (correct)
  • To transport antibiotics outside the cell
  • To modify antibiotic binding sites

Which type of antibiotic resistance mechanism involves the deletion of a gene, usually a porin?

  • Resistance by absence (correct)
  • Antibiotic efflux
  • Antibiotic target modification
  • Reduced permeability

Which of the following processes involves the modification of an antibiotic's target site to confer resistance?

<p>Antibiotic target replacement (B)</p> Signup and view all the answers

What type of enzymatic action involves the cutting of antibiotic structures leading to inactivation?

<p>Linearization (D)</p> Signup and view all the answers

How many beta-lactamases have currently been identified?

<p>Over 1000 (C)</p> Signup and view all the answers

Which mechanism protects the beta-lactam ring from hydrolysis?

<p>Bulky side groups (D)</p> Signup and view all the answers

Which of the following represents the additional modification of antibiotics by the addition of a phosphate group?

<p>Phosphorylation (D)</p> Signup and view all the answers

What is the primary role of the AmpG transporter in Gram (-) bacteria upon β-lactam antibiotic treatment?

<p>To transport muropeptides into the cytoplasm (C)</p> Signup and view all the answers

Which component interacts with AmpR to induce the expression of the ampC gene?

<p>NAM-oligopeptide (D)</p> Signup and view all the answers

Which mechanism is NOT involved in the induction of β-lactamases in Gram (-) bacteria?

<p>Lipopolysaccharide modification (B)</p> Signup and view all the answers

What is a secondary function of AmpR in Pseudomonas aeruginosa?

<p>Induction of quorum sensing (A)</p> Signup and view all the answers

What type of enzymes do metalloenzymes refer to in the context of β-lactamase classification?

<p>Enzymes that require zinc for activity (B)</p> Signup and view all the answers

What happens to the NAG sugar group during the induction of β-lactamases?

<p>It is removed by the NagZ enzyme (C)</p> Signup and view all the answers

Which of the following best describes the function of the two-component regulatory system (TCRS) in Gram (-) bacteria?

<p>It regulates gene expression in response to environmental stimuli (D)</p> Signup and view all the answers

Which antibiotic class is β-lactamase capable of degrading?

<p>β-lactams (B)</p> Signup and view all the answers

What is the primary role of the two-component regulatory system (TCRS)?

<p>To allow a cell to sense and respond to the outside environment (B)</p> Signup and view all the answers

What effect does overexpression of BlrA have on β-lactamase production?

<p>It increases β-lactamase production (B)</p> Signup and view all the answers

What happens when BlrA is knocked out in genetic studies?

<p>It attenuates β-lactamase expression (C)</p> Signup and view all the answers

The deletion of which element in the promoter region affects the expression of β-lactamase?

<p>BlrB DNA binding site (A)</p> Signup and view all the answers

Which of the following species is mentioned as having similar TCRS as BlrAB?

<p>E.coli (B)</p> Signup and view all the answers

In which genus was the majority of evidence for the TCRS BlrAB gathered?

<p>Aeromonas (D)</p> Signup and view all the answers

What aspect of BlrAB's function is described as not well understood?

<p>Its mechanism of action in signaling (D)</p> Signup and view all the answers

How does the TCRS BlrAB respond to environmental changes?

<p>Through a signaling cascade (C)</p> Signup and view all the answers

What role does BlaR1 play in the mechanism of β-lactamase induction?

<p>It becomes an active protease upon β-lactam exposure. (C)</p> Signup and view all the answers

Which small molecule is mentioned as selectively inhibiting bacterial lytic transglycosylase to enhance β-lactam effectiveness?

<p>Bulgecin A (A)</p> Signup and view all the answers

What is the primary function of β-lactamases in bacterial resistance?

<p>To cleave and inactivate β-lactam antibiotics. (C)</p> Signup and view all the answers

What is the significance of understanding β-lactamase induction mechanisms?

<p>It provides additional targets for antibiotic resistance treatment. (D)</p> Signup and view all the answers

What happens to BlaI in the context of β-lactamase synthesis regulation?

<p>It is inactivated by BlaR2, allowing for blaZ expression. (A)</p> Signup and view all the answers

What is the primary mechanism through which beta-lactamases inactivate antibiotics?

<p>Enzymatic hydrolysis (B)</p> Signup and view all the answers

Which process involves the addition of a carbohydrate to an antibiotic?

<p>Glycosylation (B)</p> Signup and view all the answers

Which of the following is NOT a method of enzymatic modification of antibiotics?

<p>Sequestration (C)</p> Signup and view all the answers

What type of antibiotic is primarily affected by rifamycin monooxygenase?

<p>Rifampicin (D)</p> Signup and view all the answers

How does phosphorylation affect antibiotics?

<p>Increases MIC (D)</p> Signup and view all the answers

Which small molecule inhibitor is a non-β-lactam?

<p>Avibactam (B)</p> Signup and view all the answers

Which modification involves the addition of nucleotides to an antibiotic?

<p>Nucleotidylation (C)</p> Signup and view all the answers

What effect does acylation have on an antibiotic?

<p>Increases steric hinderance (D)</p> Signup and view all the answers

Which enzyme is responsible for the hydrolysis of beta-lactams?

<p>Beta-lactamase (A)</p> Signup and view all the answers

Which small molecule inhibitor is not typically used in conjunction with beta-lactam antibiotics?

<p>Aminoglycoside (C)</p> Signup and view all the answers

Flashcards

Antibiotic Inactivation

Enzymatic inactivation of an antibiotic to make it ineffective against bacteria

β-lactamases

Enzymes that break down beta-lactam antibiotics, rendering them ineffective

Hydrolysis

Breaking a chemical bond by adding water

Antibiotic Efflux

The process of removing antibiotics from a bacterial cell.

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Reduced Permeability

Lower ability of antibiotics to enter bacterial cells.

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Antibiotic Target Modification

Altering the target of an antibiotic, making it less effective

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Enzymatic Modification

Chemically altering an antibiotic using enzymes.

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Antibiotic Resistance Mechanisms

Various ways bacteria develop resistance to antibiotics (inactivation, efflux, permeability change).

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AmpG-AmpR-AmpC Pathway

A mechanism used by Gram-negative bacteria to increase β-lactamase production in response to β-lactam antibiotics.

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AmpG Transporter

A protein responsible for transporting muropeptides (fragments of peptidoglycans) into the bacterial cytoplasm in the AmpG-AmpR-AmpC pathway.

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NagZ Enzyme

An enzyme that removes the NAG sugar group from muropeptides, creating NAM-oligopeptides which can bind to AmpR.

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AmpR Protein

A transcription factor that regulates the expression of β-lactamase genes (ampC) in the AmpG-AmpR-AmpC pathway.

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Muropeptides

Fragments of the bacterial cell wall's peptidoglycan layer.

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β-lactam Antibiotics

A class of antibiotics that target bacterial cell wall synthesis, leading to bacterial death.

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NAM-oligopeptide

A molecule that results from the removal of NAG from a muropeptide by NagZ.

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AmpC β-lactamase

An enzyme that breaks down β-lactam antibiotics, reducing their effectiveness.

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Two-component regulatory system (TCRS)

A signaling pathway in bacteria that allows them to sense and respond to changes in their environment.

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BlrAB

A specific TCRS found in bacteria, particularly in Aeromonas, involved in regulating the production of β-lactamase.

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BlrA

The sensor component of the BlrAB TCRS. It detects environmental changes that might indicate the presence of β-lactam antibiotics.

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BlrB

The response component of the BlrAB TCRS. It activates the production of β-lactamase when triggered by BlrA.

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Overexpression of BlrA

Increasing the amount of BlrA protein in a bacterial cell, leading to an increased production of β-lactamase, conferring resistance to β-lactam antibiotics.

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BlrA knockout

Inactivating the BlrA gene, preventing the detection of β-lactam antibiotics and thus reducing β-lactamase production.

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Deletion of BlrB DNA binding site

Removing the region on DNA where BlrB binds to activate β-lactamase production. This reduces the ability to produce the enzyme.

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Similar TCRS in other species

The BlrAB system is not unique to Aeromonas. Similar TCRS have been found in various other bacterial species, suggesting a widespread mechanism of β-lactamase regulation.

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β-Lactamase Induction

The process where bacteria increase their production of β-lactamases in response to the presence of β-lactam antibiotics.

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BlaR1 and BlaR2

Two key proteins involved in β-lactamase induction in Staphylococcus species. BlaR1 is a sensor that cleaves itself upon β-lactam exposure, activating BlaR2, which inactivates the repressor of β-lactamase gene expression.

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How does Bulgecin A work?

Bulgecin A specifically binds to and inhibits bacterial lytic transglycosylase, a crucial enzyme for bacterial cell wall synthesis. This increases the efficiency of β-lactam antibiotics.

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Beyond β-Lactamase: Other Drug Targets

In addition to targeting β-lactamases, small molecules can also be designed to inhibit other bacterial pathways involved in β-lactam resistance like LT, NagZ, AmpG, and AmpR.

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TCRS and β-Lactamase Synthesis

TCRS are crucial in sensing and inactivating many antibiotics, including β-lactams. They play a role in controlling the synthesis of β-lactamases.

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Clavulanate, Sulbactam, Tazobactam

Small molecule β-lactamase inhibitors that bind to and block the activity of β-lactamases, allowing β-lactam antibiotics to work.

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Avibactam, Vaborbactam

Non-β-lactam β-lactamase inhibitors that work similarly to clavulanate, sulbactam, and tazobactam.

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Linearization

The process of breaking a cyclic antibiotic molecule into a linear form, rendering it inactive.

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Rifamycin monooxygenase (ROX)

An enzyme that linearizes rifampicin, a cyclic antibiotic, making it ineffective.

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Nucleotidylation

A type of enzymatic modification where a nucleotide is added to an antibiotic molecule, often interfering with its function.

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Phosphorylation

A type of enzymatic modification where a phosphate group is added to an antibiotic molecule, frequently reducing its effectiveness.

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Study Notes

Antimicrobial Resistance Modification & Destruction

  • The lecture covers different mechanisms of enzymatic inactivation of antibiotics.

  • Students should be able to describe mechanisms of antibiotic inactivation and different types of antibiotic inactivation after the lecture.

  • Major mechanisms of antibiotic resistance include antibiotic inactivation (enzymatic inactivation of antibiotic to confer drug resistance), antibiotic efflux, reduced permeability to antibiotics, resistance by absence, antibiotic target modification, antibiotic target replacement, and antibiotic target protection.

  • Antibiotic inactivation can occur through enzymatic degradation (hydrolysis by beta-lactamases, linearization by cutting) or enzymatic modification (nucleotidylation, phosphorylation, glycosylation, acylation, hydroxylation).

  • Antibiotic inactivation can also be by sequestration.

  • Early indications of antibiotic resistance were observed where an enzyme from bacteria was able to destroy penicillin.

  • An enzyme called penicillinase destroys penicillin, which is non-dialysable through cellophane membranes and destroyed by heating. The activity of the enzyme is lost during alcohol precipitation. The activity of penicillinase is slight at pH 5 but increases toward alkaline pH ranges.

  • Properties of a penicillin inactivator from penicillin-resistant staphylococci were described.

  • B-lactamases are enzymes that hydrolyze B-lactam antibiotics.

  • Penicillinase (beta-lactamase) is an enzyme that facilitates hydrolysis of beta-lactams, rendering them ineffective at killing bacteria.

  • Over 1000 beta-lactamases have been identified.

  • Bulky side groups in antibiotics protect the B-lactam ring from beta-lactamases.

  • Beta-lactamases are classified into classes A, B, C, and D.

  • Mechanisms for B-lactamase induction include AmpG-AmpR-AmpC and two-component regulatory systems (TCRSs).

  • Similar TCRs have been identified in other species like E. coli, different Aeromonas spp., and P. aeruginosa.

  • TCRSs are involved in sensing and inactivation of many antibiotics including vancomycin, beta-lactams, and bacitracin.

  • TCRSs control B-lactamase synthesis through an activation process leading to the expression of blaZ expression.

  • Understanding mechanisms of β-lactamase induction provides additional therapeutic targets for combating antibiotic resistance.

  • Bulgecin A selectively binds to and inhibits bacterial lytic transglycosylase, improving the efficacy of B-lactam antibiotics.

  • Small molecule inhibitors such as clavulanate, sulbactam, tazobactam, avibactam, and vaborbactam inhibit beta-lactamases.

  • Tetracycline destructases degrade tetracycline antibiotics.

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Lecture 15: Antibiotic Resistance Modification & Destruction PDF

Description

This quiz explores the various mechanisms of enzymatic inactivation of antibiotics. Students will learn to describe different types of antibiotic inactivation and the major mechanisms contributing to antibiotic resistance. Key concepts include enzymatic degradation, modification, and the impact of efflux and permeability on antibiotic effectiveness.

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