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PB > Lecture 5: Antibiotic Resitance > Flashcards

Lecture 5: Antibiotic Resitance Flashcards

1
Q

What are antibiotics

A

Compounds produced by bacteria, plants, chemist that kill or inhibit bacteria growth

They originiated as anitmicrobial agents in the environment

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2
Q

antibiotics dervied from bacteria

A

bacterias create sometimes own antibiotics (to extablish a niche) and have resistance mechanisms to protect themselves

other bacteria will respond to these compounds (move away, expresss resistance mechanisms, get eliminated from the environment)

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3
Q

What are antibiotic targets and what is resistance

A

Target: specific to a bacterial cell (cell wall, bacterial ribosome)

Resistance: occurs when interaction no longer occurs

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4
Q

What does that antibiotic binding do

A

Prevents proper function causing either:
- the death
- growth inhibition

of the bacteria

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5
Q

Bacterial strcutures/processes targeted by antibiotics

A

Cell wall integrity

Cell wall synthesis

Protein synthesis

DNA synthesis

DNA Gyrase

RNA poymerase

phospholipid membranes

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6
Q

General antibiotic resistance mechanisms

A

1) Alteration of outer membrane (prevent antibiotic from getting INTO cell)
2) Up-regulation of drug efflux pumps
3) Alteration of the target
4) Inactivation of the antibiotic (cleavage on outside of the cell or Acyl group added once inside the cell)

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7
Q

How does antibiotic resistance arise (2 general ways) and 2 other ways

A

1) Mutation and selection
- Random mutations naturally occur at low frequency (DNA polymerase make mistaje ever 10-8)
- Antibiotic resistant mutants can be SELECTED for by the ENVIRONMENT

2) Bacterial cells producing antibiotics have intrinsic resistance mechanisms
3) Horizontal transfer of genes that have resistance
- Transformation (DNA from environment)
- Transduction (Bacteriophage)
- Conjugaison (pilus)
4) the more ofter bacteria is exposed to antibiotic the more likely they will develop resistance (not always the case, some have intrinsic like soil dwelling to protect against their own antibiotics)

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8
Q

Soil bacteria resistance antibiotics

A

Expermiment showed that soil dwelling bacteria were resistant to many antibioics

Potential that these mechanisms could be transfered to pathogenic bacteria (and has happened in the past)

Need to study the soil resistome and understand the resistance mechanisms

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9
Q

What is the antibiotic resistome

A

Group of all existing antibiotic resistance genes (known or unknown) in the world

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10
Q

Factors that cause the development of resistance related to exposure to antibiotics

A

Overuse of antibiotics (in humans + in agriculture)

Non-compliance: Patients dont finish antibiotic presciption

Natural exposure to antimicrobial agents

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11
Q

What are reasons of overuse of antibiotics in humans

A

used to treat viruses

Long term antibiotics of patient has acne, UTI, recurrent ear infections

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12
Q

Resistance spread going up rapidly for what antibiotic and by what %

A

Went up 60% since discovered MRSA

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13
Q

Antibiotics in the environment where do they come from

A

Soil organisms produce antimicrobiol agents naturally

Humans and animals excrete antibiotics

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14
Q

Acquired vs intrinsic resistance

A

A: Resistance gene not present in genome. Acquired either through:
- Mutation and selection
OR
- Transfered from other bacteria

I: Opposit for I

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15
Q

4 classes of antibiotics and what they target

A

Cell wall: B-lactams

Macrolides and Aminoglycosides: Ribosomes

Quinolones: DNA replication

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16
Q

B-lactam
- Target and desiption of structure
- What it does
- Types of B-lactams

A

Gram + cell wall (giant peptidoglycan layer) is the type of bacteria it acts on

Peptidoglycan is made of:
- NAG
- NAM
- Tetrapide chains are fixed to NAM
- Transpeptidation are cross linking between tetrapeptides

Bactericidal (kills bacteria)

Penicillin. Cephalosporins and carbapenems are all B-lactams

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17
Q

Mechanism of action of B-lactams

A

Inhibitis peptidoglycan synthesis by binding penicillin-binding proteins (transpeptidases)

18
Q

B-lactam resistance

A

Loss or diminished expression of outer membrane proteins

Alteration in penicllin binding proteins so that they have reduced affinity for B-lactams

Production of B-lactamases (hydrolyze the B-lactam rings)

19
Q

Antibiotics that inhibite protein synthesis

A

Macrolides and aminoglycosides

20
Q

Macrolides

A

Binds to large ribosomeal sununit

Mostly bacteriostatic (inhibit bacterial growth) but can be bacteriacidal in HIGH concentrations

21
Q

Resistance to Macrolides

A

Active efflux pumps

Alteration of antibiotic binding site by methylation (doesnnt change the ribosomal function)

22
Q

Aminoglycosides

A

Bactericidal

binds to Small subunit
Includes ribosomal dissociation

23
Q

Resistance to aminoglycosides

A

Dcreased permeability of outer membrane

Active efflux

Inactivation of aminoglycosides by the addition of acyl or phosphate group

24
Q

Inhibitor of nucleic acid synthesis

A

Quinolones

25
Q

Revise before exam

Quinolones function
Revise before exam

A

Targer DNA gyrase or topoisomerase IV or both and tertiary negative supercoiling (those 2 enxymes restore proper conformation of DNA after replication fork)

Bactericidal

3 generations of quinolones (1st generation is Nalidoxic acid)

26
Q

Resistance to the quinolones
Revise before exam

A

Alteration of targets (topo IV and DNA gyrase) - doesnt change their function

Efflux/perneability changes of the outer membrane

Plasmid based qnr genes: encodes protein that probably binds DNA gyrase and topoisomerase to protect them from quinolones

27
Q

Some antibiotic resistant pathogens of concern

A

MRSA (Methicillin resistant) and P.aeruginosa (multidruf resistant)

28
Q

MRSA
Revise before exam

A

Methicillin is a B-lactam

MRSA is a major hospital aqured infection

Its resistance is due to the presence of mecA gene that encodes a variant of penicillin binding protein that does not bind to B-lactams so the transpeptidation step can occur

29
Q

Where is mecA located
Revise before exam

A

on the SCCmec and there are 11 major tupes of these that all have that gene but differe in additional drug resistance genes

30
Q

p.aeruginosa resistance
Revise before exam

A

Can be resistant to many drugs because of aquired and intrinsic resistance

Has limited outer membrane permeability (intrinsic)

Efflx pumps (intinsic and aquired)

  • 4 maj RND efflux pumps: MexAB, MexXY, MexCDm, NexEF
  • Intrisic: MexAB, MexXY
  • Aquired: OVEREXPRESSION of MexAB (because mecR gene is mutated so no repression of MexAB) , MexXY (in CF patients, MexZ is a negative regulator and is mutated) and MexCD
31
Q

RND efflux pumps
Revise before exam

A

Made of 3 different compounants:

OMP is no OM

MPF: intermembrane

Transporter in IN

32
Q

Major p.aeruginosa efflux pumps and their substrate (what they pump out)

A

MexAB: fluoroquinolones, aminoglycosides, B-lactames

MexCD: Fluoroquinolones, macrolides

MexEF: fluoroquinolones

MexXY: fluoroquinolones, aminoglycosides

33
Q

eDNA (found in biofilm matrix) and antibiotic resistance

A

Found in biofilm matrix due to active release od DNA from cell and cell death

it has an anionic nature which results in low Mg 2+ in matrix which causes alteration of LPS which resukts in make outer membrane more impermeable to certain antimicrobial agents

34
Q

There are genes that are expressed only in biofilms whose gene products protect biofilm cells from antibiotics

A

Hypothesis

35
Q

How to identify genes taht are important for biofilm-specific antibiotic resistance

A
  • screen 10 000 random transposon-insertion mutants
  • Let biofilm grow and add antibiotics
  • Identify the ones that survived
  • Use that cadidates in several other secondary screens (growth, biofilm formation, plaktonic antibodic resistance)
36
Q

After screening what is found

A

isolated 6 mutants

Properties are:
- Grow as well as the WT
- Have same planktonic resistance level as the WT
- Make a biofilm
- More susceptible to Tb (antibiotic) compared to WT in biofilm

THis is an example if intrinsic antibiotic resistance in biofilms

37
Q

How to confirm biofilm specific antibiotic phenotypes
Revise before exam

A

Delete gene that is thought to be important, biofilm will be smaller in mutant 1

mutant 1 has a Tn5 insertion in a predicted glucosyltransferase (similar to the ndvB gene that synthesises a cyclic sugar molecule called cyclodextrin)

ndvB gene is expressed in WT biofilm but not in WT planktonic

*never dive below

38
Q

Possible roles of ndvB-derived glucans
Revise before exam

A

Biofilm achritecture (when doing a 3D reconstruction there is no change between WT and ndvB absent mutant)
Sequestration (the cyclodextrin molecule has a barrel like structure where hydrophobic molecules can hide from water so that might be where antibiotic is attaching. tests indicated that ndvB mutant is defective of glucacan synthesis. a in virto interaction assay is done to see if p.aeruginosa glucans and Tb interact. Tb flows through tube when glucagon is not present. Glucacans interact with Tb and prevent Tb from reaching target in cytoplasm)
Signaling: glucagon can affect the expression of genes important for protecting cells agains the cytotoxic effects of ROS

39
Q

What are biofilm sepcific antibiotic resistance due to

A

MUltiple intrinsic resistance and not due to mutattion

40
Q

Targeting virulence factors

A

preventing virulence:
- Inhibition of toxin functions
- Inhibition of secretion (ex: toxin)
- Controlling regulation of virulence gene expression)
- Inhibition of adhesion

41
Q

Bacteriophages

A

promising therapy

42
Q

Bacteria attacking gram - bacteira

A

B.bacteriovorus

PB (9 decks)

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