Antimicrobial resistance I Flashcards
This deck contains the lectures: Anti-microbial resistance in Gram- and Antimicrobial resistance in returning travellers,
Mode-of-action
- Cell wall synthesis
- DNA, RNA & protein synthesis
- Folic acid metabolism
Classes + representatives + mode-of-action
Why is the cell wall a good target for antibiotics?
Human cells don’t have a cell wall
What do all the B-lactams have in common structure-wise?
Ringstructure B-lactam
What are the members of the beta-lactam family?
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams
What can be said about the structure of the bacterial cell wall of gram-negative bacteria?
Gram-negative bacteria have a very thin layer of peptidoglycan + membrane in- AND out of their cell wall
On what structure do beta-lactams work?
Peptidoglycan
- Sugar layer of NAM and NAG (sugar chains)
- Connected via peptide bridges
The strength of the peptidoglycan network depends on …
It’s compactness, which itself depends on the length of the polysaccharide chains, the number of tetrapeptide bridges and on any hydrogen bonds that may form.
Key enzymes involved in the the peptidoglycan synthesis
Cytoplasm: smaller parts are made –>
Cell surface stage
What are the Penicillin Binding Proteins?
- Transglycosylases
- Transpeptidase
- Carboxypeptidases
Where are the Penicillin Binding Proteins anchored?
In cytoplasmic membrane
Why do beta-lactams kill bacterial cells?
11 min
Explain the fragile dynamic balance between synthesis and hydrolysis of PG
Lytic enzymes or autolysins
- Glycosidases
- N-acetyl-muramyl-L-alanine amidases
- Endopeptidases
On what does the bactericidal effect depend?
lytic enzymes, involved in
breaking down and rearranging PG
Beta-lactams work especially on active bacteria
Differences in activity among the various β-lactams depends on..
Penetration of the Gram-negative cell
Lability to periplasmic β-lactamases
Affinity to the PBPs
Mechanisms of resistance to β-lactam antibiotics (3)
- Impaired permeability of outer membrane
- Mutated PBPs with changed affinity
- Enzymatic hydrolysis of the β-lactam ring
Penetration of β-lactams into Gram-negative bacteria
- Passage via porins
- Physicochemical factors influencing penetration
What is a porin and what is critical for the activity of B-lactams
-A porin is a transmembrane protein
Speed of diffusion of β-lactams through the porins is critical for their activity
Physicochemical factors influencing penetration (3)
-hydrophobicity
-the size of the molecule
-charge
Where can the B-lactamase come from?
- Chromosome
- Plasmid
What can the expression patterns of B-lactamases orginating from the chromosome?
- Inducible
- Constitutive
Example of inducible / phenotype
cephalosporinase
Example of constitutive /phenotype for chromosome and plasmids
penicillinase
What can the expression patterns of B-lactamases orginating from plasmids?
Constitutive
If the enzyme is only effective against penicillin, you can use the other categories
Extended spectrum beta-lactamases?
22min
SHV-1
Why are aminoglycosides suitable for use in humans?
Difference in ribosomal subunits between humans and bacteria
Derivatives of micin and mycin
Mechanism of aminoglycoside Action
Energy-independent phase
Energy-dependent phase
Binding to the 30S ribosomal subunit !! (most important for exam)
Energy-independent phase
electrostatic binding to the outer membrane
Energy-dependent phase
transport into the cytoplasm by PMF (transmembrane electrical potential)
Binding to the 30S ribosomal subunit !! (most important for exam)
inhibition of protein synthesis
misreading of the codons
What does PMF mean?
Mechanisms of resistance to aminoglycosides
Aminoglycoside-modifying enzymes (most important!!)
Alteration in uptake
Change in ribosomal binding sites (methyltransferases)
Name the three categories of aminoglycoside-modifying enzymes
AAC: acetyltransferases
ANT: adenyltransferases
APH: phosphotransferase
AAC: acetyltransferases
acetyl CoA-dependent acetylation of an amino group
ANT: adenyltransferases
ATP-dependent adenylation of an hydroxyl group
APH: phosphotransferase
ATP-dependent phosphorylation of an hydroxyl group
DNA: guinolones, why very powerful and widely used?
Many of these can be taken as tablets and are still sufficiently absorbed and bactericidal –> perfect penetration of tissue
Uptake of quinolones into the bacterium
Mechanism of action of quinolones
Role of topoisomerases
- Regulate the super-coiling of DNA.
- Cuts dsDNA to initiate replication.
Mechanisms of resistance
(chromosomally-encoded) quinolones
- Decreased target-affinity
- Decreased accumulation
Decreased target-affinity
Mutations in DNA-gyrase and topoisomerase IV
- Mutations in ‘quinolone resistance-determinating region (QRDR)’
Decreased accumulation
- Decreased porine-expression (low-level resistance)
- Hyper-expression of natural efflux
Mechanisms of resistance (Plasmid-mediated resistance) quinolones
- qnrA
- Aminoglycoside acetyltransferase
- Quinolone efflux pumps
How does qnrA work?
Binds to DNA gyrase and topoisomerase IV, leading to inability for quinolones to bind
Patient being hospitalized abroad have a higher chance of bringing MDROs
Prevalence of MDROs
Africa
West-Pacific
Southern Asia
Study protocol
Healthytravelers included via travel clinics
2001 travelers
215 household members
Sample kit directly before and after travel
Fecal swabs
Follow up for 12 months
1, 3, 6 and 12 months after return
Risk factors MDRO acquisition
Antibiotic use during travel
Traveller’s diarrhoea
Meal at street food stalls
Protective factors MDRO acquisition
Daily hand washing before meals
Beach holidays
Leading risk factors for acquisition of MDR-E are
Travel to SouthernAsia
Antibiotic use during travel
Traveller’s diarrhoea
Hospitals: unknown carriage could lead to? (3)
- Difficulty treating infections
- Hospitalization without the appropriate infection prevention and control measures
- Spread to other patients, healthcare personnel and the hospital environment
Which division can be made in-hospital (nosocomial) transmission?
- Direct transmission
- Indirect transmission
How is direct transmission established in the hospital?
Patient-to-patient, patient-to-healthcare personnel
How is indirect transmission established in the hospital?
Hospital environment, medical devices
What is the current MDRO screening strategy?
Universal risk assessment with risk-based screening
