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Antibiotic Action amd Resistance > Antibiotic Resistance > Flashcards

Antibiotic Resistance Flashcards

1
Q

Definition of antibiotic resistance?

A

Ability of bacteria to survive and grow in presence of antibiotic concentration safely achievable in patients at site of infection

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2
Q

Two types of antibiotic resistance?

A

Acquired and intrinsic

Acquired when previous susceptible population becomes resistant

Intrinsic from inherent features e.g Mycoplasmae have no peptidoglycan wall so intrinsically resistant to b-lactams and glycopeptides

E.coli is intrinsically resistant to vancomycin and Mupirocin as can’t get through outer membrane

Many g-ve species resistant to linezolid as actively effluvia out

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3
Q

What does O’Neil report say on Ab resistance?

A

By 2050 antibiotic resistance will be largest cause of death, taking 10 million a year

With economic impact of $100.2 trillion dollars

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4
Q

Consequence of antibiotic resistance

A

Increased mortality
- resistance can be more fatal

Increased morbidity

  • prolonged illness
  • great opportunities to for resistant organisms to grow

Increased cost

  • Longer stays in hospitals
  • newer, more costly drugs will be used
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5
Q

Mechanisms of resistance all the ways to alter target site

A

Mutation of target

Recombination

Modification of target

Target overexpression

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6
Q

Example of recombination resistance

Example of target modification resistance

A

Neisseria spp and Streptococcus spp can have beta lactam resistance by taking DNA from eDNA of intrinsically resistant species

Methylation of ribosomal RNA

Enterococci can confer resistance to vancomycin by switching out D-ala-D-ala for D-ala-D-lactate

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7
Q

Resistance mechanisms by decreased uptake?

A

Reduced permeability
Mainly feature of g-ve, by loss of porins( has fitness cost)

Active efflux
Several different families of efflux pump
May be specific or broad
Confer resistance to multiple classes of Antibiotics
May arise from upregualtion of endogenous pump or horizontal acquisition of new one

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8
Q

Structure of AcrAB/TolC system in E. coli

A

Tripartite pump
Efflux transporter connected to adaptor protein linked to OM channel protein

Drug crosses OM and or CM

Transporter pumps drug out bypassing OM

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9
Q

Enzyme inactivation or modification?

Example

A

Destruction of target
B-lactamases mediate resistance to beta-lactam Antibiotics

Cyclic amide bonds of beta lactam rings are hydrolysed
Open ring forms cannot bind to target site
Problem as g-ve produce several B-lactamases

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10
Q

What enzymes modifiy aminoglycosides ?

As form of resistance

A

Aminoglycoside adenyltransferase ANT
–catalysed ATP-dependant adenylation of hydroxyl group

Aminoglycoside acetyltransferases AAC
–Catalyses acetyl CoA-dependant acetylation of an amino group

Aminoglycoside phosphotransferases APH
–Catalyse ATP-dependant phosphorylation of hydroxyl group

Bulk up sites important for binding to the 16s ribosomal unit

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11
Q

Target bypass?

And example?

A

Acquisition of alternative target

MRSA has acquired MecA gene that encodes an alternative PBP2. It’s a transpeptidase resistant to B-lactam

Trimethoprim resistance by resistant dihydrofolate dedicates that can discriminate between the drug and dihydrofolate

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12
Q

Multiple mechanisms of resistance can operate for single drug class?

What drug classes have 3 mechanisms of resistance

A

B-lactams

Aminoglycosides

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13
Q

How long has Fusidic acid been in clinicl use

A

Since 1962

Systemically and topically

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14
Q

Fusidic acid hydrolyses

A

GTP

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15
Q

How does FusA resistance arise

A

Consequence of point mutations in gene that encode this protein

Huge diversion of mutation that can cause this

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16
Q

What is fusB type resistance

A

Less we’ll known or characterised

Associated to strains that’s carry plasmid associated with resistance of Fusidic acid

17
Q

How was genetic basis of fusB type resistance?

A

Shotgun cloning performs on plasmid responsible for Fusidic acid resistance and fragments were cloned into staph

Single small gene (FusB) was 642bp

  • –bioinformatics analysis shows encodes as small proteins that is cytoplasmic and hydrophilic
  • –no known homologues
  • -part of family of unknow functions

Homologise collectively know as FusB type proteins

18
Q

Number of resistance isolates in MRSA

And percentage

A

N=291

FusB=67%
FusA=13%
FusC=20%

Vast majority of strains horizontally acquire
Resistance emerges due to succesful clones spreading from one patient to another

19
Q

FusB binds to?

A

Ef-G
Binds to EF-g without need for other components

Highly affinity binds
1 mole of FusB bind to 1 mole of EF-G
FusB binds to EF-g whether or not in the presence of Fusidic acid

20
Q

What are the routes to Antibiotic resistance?

A

Spontaneous mutations to resistance
Depends on fidelity of DNA polymerase.

Horizontal acquisition by

  • natural competence
  • transposition

Most resistance is spontaneous event without need for Antibiotics
But are cases Antibiotics can cause mutations due to stress

21
Q

Mutation frequencies to Antibiotics

A

Mutation rare event but bacteria can increase their rate of mutation and become hyper mutable

Biofilms can become hypermutable due to oxidative stress

Adding catalase removes hydrogen peroxide and detoxifies biofilm lowering mutation rate
Best seen in CF infections

22
Q

How do Antibiotics cause mutations?

A

Due to stress
Bacteria initiate SOS response
This is DNA repair by low fidelity polymerase
Which increases rate of horizontal acquisition

23
Q

How can resistance be transferred horizontally

A

Plasmids
Transposons
Staph cassettes

Known as ICE integrative conjugating elements
By transduction(phages), conjugation and transformation
24
Q

Where do acquired resistance genes originate ?

A

Antibiotics used for under a century but bacteria millions of years

Many antibiotics are naturally produced metabolites. So bacteria would have encountered and and obtained resistance in nature.

Vancomycin resistance can be found in environmental strains

25
Q

Origins of B-lactamases

A

PBPs and b-lactamases very similar

Both have serine group in active sites and can perform nucleophilic attack on ring structure of the beta-lactam

Ring structure is broken and would covalently bind to PBP but with B-lactams those intermediates are released

FusB resistance could be due to resistance being conferred accidentally by household genes

26
Q

How do resistances spread?

A

Once emerged can grow and expand by

Global expansion
Horizontal dissemination of resistance genes

Antibiotic resistance is evolutionary process and antibiotic usage drives an increase to resistance frequencies. Survival of fitness

Inadvertent directed evolution

27
Q

Why is Enterobacteriacea current cause of concern

A

Has resistance to Aminoglycosides, beta-lactams and fluoroquinolones

Extended spectrum beta-lactamase ESBL. CTX-M enzymes –seriously threatens use of 3rd generation cephalosporins
Shift to carbapenems: cost, parenteral administration, destruction of commensal flora and selection for carbapenem resistance

International spread of NDM-1 beta-lactamases which confer resistance to all b-lactams

28
Q

Concerns over Pseudomonas aeruginosa and Acinetobacter baumannii?

A

Environmental bacteria have evolved vast methods of survival strategies, efflux pumps and large complex genomes

Are very adaptable

29
Q

Tuberculosis has three diff types of resistant strains. Which are?

A

mdr TB
edr TB
XDR TB

30
Q

Concerns about Neisseria gonorrhoea

A

Common Bacterial infection
Not fatal but can lead to sterility
People don’t pay attention to non lethal disease

Ciprofloxacin was common treatment

In 2011 3rd gen cephalosporin and azithromycin

Not proved effective new resistance gonorrhea first outbreak in Leeds

31
Q

How to address resistance. Problem

A

Better training of people prescribeing drugs

Better coordination of international surveillance of resistance arising in animals and humans

Better guideline
-cycling Antibiotics to reduce the selective pressure
Restriction on use of antibiotic as growth promoters

Improve infection control practice

Ultimately need new antibiotics drugs to circumvent the problem

Antibiotic Action amd Resistance (2 decks)

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