Lecture 21: Antimicrobial agents and antimicrobial resistance Flashcards
1
Q
- What are the characteristics of Acinetobacter baumannii?
- Where are most infections acquired?
- What do Acinetobacter baumannii infections cause?
A
- Gram-negative, aerobic, non-motile, cocco-bacillus
- Highly dessication resistant
- Survives very well in the environment.
- Tendency to develop antibiotic resistance.
- An emerging opportunistic pathogen
- Most infections are acquired in hospital settings- patients are more vulnerable and susceptible to infections.
- Infections cause pneumonia (ventilator-associated), septicaemia (blood infection), wound, burns and UTIs
2
Q
What are the resistance mechanisms of Acinetobacter baumannii?
A
- All four classes of β-lactamases intrinsically present:
Metallo- β-lactamases, AmpC Cephalosporinases, Oxa Oxacillinases and cabapenemasess.
- Multiple efflux systems
E.g. tetracycline efflux
- Reduced expression/inactivaion of porins
E.g. CarO- important for carbapenem uptake
- Aminoglycoside modifying enzymes
Acetyltransferases, adenyltransferases and phosphotransferases.
Mostly acquired via horizontal transfer
- Mutations altering targets
Gyrase (gyrA and parC), penicillin binding proteins
3
Q
- What is colistin?
- What are th chemical and structural properties of colistin?
- Why is colisin only used as a last-resort option?
A
- Colistin or Polymyxin is an antibiotic medication used as a last-resort treatment for MDR gram-negative bacteria.
- Colisitn is a short, cyclic antimicrobial peptide,
- It has a positively charged section
- It has a hydrophilic and hydrophobic section
- Colistin is used as a last-resort treatment as it is reasonably nephrotoxic
4
Q
What is the mechanism of action of colistin?
A
- Interact with the negatively charged lipopolysaccharide of grame -ve bacteria.
- Insert themselves in the outer and inner membranes, causing cell leakage and eventually cell death.
5
Q
What are the mechanisms by which bacteria become resistant to colistin?
A
- Complete loss of LPS
- Phosphoethanolamine (PEtn) addition to LPS
6
Q
- How does complete loss of LPS act as a resistance mechansim against colistin?
- How does the loss of LPS lead to colistin resistance?
A
Spontaneous mutations in lipid A biosynthesis genes
- lpxA, lpxC, lpxD*
- -* LpxA gene encodes for the lpxA enzyme- which catalyses the first step in Lipid A synthesis.
- Lipid A is the membrane anchor for LPS
- Therefore mutations in lpxA lead to decreased/no production of lipid A and therefore decreased/no production of LPS.
Loss of LPS alters membrane charge
- Reduced/inefficent interaction with positively charged colistin and therefore high level of resistance.
7
Q
How does addition of phosphoethanolamine (PEtn) to the LPS act as a mechanism for resistance against colistin?
A
- Mutations in two-component regulatory system genes, pmrA or pmrB leads to increased expression of PEtn transferase PmrC which is the enzyme that catalyses the additon of PEtn to LPS.
- PEtn is added to phosphate groups of LPS, and causes a reduction of charge on LPS (becomes more positive).
- Therefore colisitin cannot efficiently interact with positively charged LPS- colistin and LPS repel each other.
8
Q
Can pan-drug resistant Acinetobacter baumannii be treated?
A
- Very difficult
- Possible treatment could be combined antibtiotic treatment:
- E.g. colistin + rifampycin
- However, most combinations are not rationally designed or appropriately tested.
- Novel treatments such as phage therpay plus antibiotics may be a better option.
9
Q
- Describe the features of Staphylococcus aureus?
- What are the main outcomes of infections by Staphylococcus aureus ?
A
- Gram-positive bacteria
- Member of the usual microbiota of the body.
- Skin commensals- reside on our skin, deriving benefir from us, but we do not benefit from them.
- >10% of infections are hospital acquired
- Staphylococcus aureus infections can can cause bloood stream infections, sepsis, osteomyletis (bone infections) and endocarditis (heart infections)
10
Q
What are the major resistant strains of S. aureus?
A
- Methicillin resistnant S. aureus
- Vancomycin resistant S. aureus
11
Q
How is resistance to methicillin established?
How is methicillin resistant Staphylococcus aureus (MRSA) treated?
A
- Via mecA gene which encodes a modified penicillin binding site with very low affinity to the β-lactams.
- mecA genes are horizontally spread.
- Vancomycin is a crtical treatment option for MRSA
- binds to peptidoglycan not the penicillin binding protein (PBP).
- Combination treatments
- Two different targets are targeted
- Linezolid - protein synthesis inhibition.
12
Q
- What are the multiple levels of vancomycin resistance?
A
- Vancomycin intermediate Staphylococcus aureus = VISA
- Vancomycin resistant Staphylococcus aureus = VRSA
13
Q
What factors/mechanisms lead to the formation of VISA and VRSA?
A
VISA develops from pre-existing strains of methicillin-resistant S.aureus
- Acquired by mutation
- Associated with a thickened cell wall due to accumulation of excess amounts of peptodoglycan.
- Thick cell wall reduces vancomycin penetration.
- Poorly cross-linked cell wall
VRSA
- Relatively uncommon
- Can be plasmid-mediated
14
Q
How are new linezolid antibiotics being designed?
A
- Cryogenic electron microscopy
- Observe and study rRNA interaction with linezolid.
- Understand the difference between sensitive and resistant 3D structures and how this structure influences interaction with linezolid.
- Use this knowledge to design new and modified versions of the drug, e.g. linezolid to target resistant strains.
15
Q
- What is Mycobacterium tuberculosis?
- How is M. tuberculosis spread?
- What are the structural features of M. tuberculosis ?
A
- Pathogenic bacteria
- Causative agent of tuberculosis
- Spread via air droplets/ aerosol
- Unusual cell wall
- Peptidoglycan, arabinogalactan and thick layer of mycolic acids.
- Hydrophopic and hydrophilic compunds cannot enter easily.
