Antibiotic Resistance

Question 1

What are the consequences of antibiotic resistance?

Answer 1

• Increases mortality
• Challenges control of infectious diseases
• Threatens a return to the pre-antibiotic era
• Increases healthcare costs
• Jeopardizes healthcare gains to society

Question 2

Describe the pathogenicity of drug resistant bacteria

Answer 2

Drug resistant bacteria are NOT MORE pathogenic - We just have fewer antibiotic options for treatment as they’re resistant to antibiotics

Question 3

How do bacteria become resistant to ꞵ-lactams?

Answer 3

Beta-lactamase enzyme acquired by resistant bacteria to destroy antibiotic ꞵ-lactams ring - make it inactive

Question 4

How do mutations cause resistance?

Answer 4

If RNA pol undergoes a simple mutation, the drug is no longer able to bind (common in TB)

Question 5

How do drug targets become resistant?

Answer 5

Acquisition of a new drug target e.g. PBP2a in MRSA - no longer inhibited by ꞵ-lactams

Question 6

What are the effects of bacterial enzyme mutations?

Answer 6

Mutations in DNA gyrase and polymerase mean non-functional quinolins etc.

Question 7

What are the consequences of bacterial porin mutations?

Answer 7

Mutations in porins causes alterations to their transportation properties:

• Upregulation of efflux pumps
• Blockage of porins

Question 8

Explain how some bacteria are naturally drug resistant

Answer 8

Some bacteria are intrinsically impermeable - their membranes are so naturally impermeable, antibiotics have no effect (majorly in Gram -ve)

Question 9

Describe how metabolic changes cause resistance

Answer 9

Metabolic change D-ala-D-lac and vancomycin

Question 10

What are the 3 mechanisms of resistance?

Answer 10

• Natural resistance
• Genetic Mechanisms; acquired
• Non-Genetic Mechanisms (growth phases)

Question 11

What is the natural resistance within bacteria?

Answer 11

> not acquired
Natural barriers for drug reaching target: porins, export pump
G+ve peptidoglycan - highly porous; no barrier to diffusion
G-ves outer membrane; barrier resistance advantage
Porins; single mutation leads to multiple resistance

Question 12

What are the 2 types of genetic mechanisms of resistance?

Answer 12

• Chromosome-mediated

- Plasmid-mediated

Question 13

What causes chromosome mediated genetic resistance?

Answer 13

Due to spontaneous mutation:

• in target molecule
• in drug uptake system

Question 14

Describe plasmid mediated drug resistance

Answer 14

• Common in Gram-ve rods
• Transferred via conjugation
• Multidrug resistance

Question 15

How do bacterial mutants arise causing genetic resistance to antibiotics?

Answer 15

Mutants are SELECTED ; they are NOT induced

Question 16

How does antibiotic resistance cause selection for resistant bacteria?

Answer 16

Random mutation occurs - has no major effect as overpowered by many sensitive bacteria surrounding it

Antibiotic administered, killing all sensitive bacteria, leaving mutated bacteria - selection antibiotic resistance

Question 17

What are the 3 methods of gene transfer in bacteria?

Answer 17

• Transformation
• Transduction
• Conjugation

Question 18

What is transformation?

Answer 18

Uptake of naked DNA that is lysed from another bacteria (e.g. streptococci)

Question 19

What is conjugation?

Answer 19

2 bacteria come together and form pili where (chr./plasmid) DNA is exchanged - not all bacteria can do this

Question 20

What is transduction?

Answer 20

Phage infection takes fragment of DNA from one bacterial host to the next

Question 21

Outline how Gram +ve bacteria become resistant to ß-lactams

Answer 21

ß-lactamase (Penicillinase)

Alteration of transpeptidase enzyme (PBP)

Question 22

How do Gram -ve bacteria become ß-lactam resistant?

Answer 22

ß -Lactamase (Penicillinase)

Alteration of porins

Question 23

How do bacteria become penicillin resistant?

Answer 23

Penicillinase destroys active part of penicillin molecule so that it is no longer a competitive structural mimic of the enzymes involved

Question 24

What is augmentin / Co-amoxiclav?

Answer 24

Antibiotic combination = Clavulanic acid + amoxicillin

Question 25

What is the role of Clavulanic acid?

Answer 25

Clavulanic acid is an inhibitor of a ꞵ-lactamase enzyme but has no antibacterial activity alone

Question 26

Outline how beta-lactam resistance is acquired

Answer 26

1. Porin mutates / new porin type acquired - multiresistant
   Ꞵ-lactam unable to cross outer membrane
2. PBP mutates / bacteria acquires new PBP; even if ꞵ-lactam gets through porin, its unable to bind to PBP enzymes
3. Bacteria acquires (extended) ꞵ-lactamase enzymes that destroy ꞵ-lactams entering bacteria

Question 27

What are the different mechanisms of penicillin resistance?

Answer 27

Produce penicillinases / beta lactamases that cleave beta lactam ring

Acquire alternative forms of / mutations in

• efflux pumps
• porins
• penicillin binding proteins (PBPs)

Question 28

How is MRSA treated?

Answer 28

Only effective treatment is vancomycin, a 1.5 kDa glycopeptide

Question 29

How does vancomycin treat MRSA?

Answer 29

Vancomycin sits on top of the terminal D-ala-D-ala peptides to inhibit peptidoglycan cross linking from occurring

Question 30

How does vancomycin resistance arise?

Answer 30

Bacteria that are vancomycin resistant acquire van operon structure by transposition
Makes D-ala-D-lactate rather than D-ala-D-ala - prevents vancomycin binding

Question 31

What are the non-genetic mechanisms of antibiotic resistance?

Answer 31

Inaccessibility to drugs (e.g., abscess, TB lesion)

Stationary phase/vegetations and biofilms (non-susceptible to inhibitors of cell wall synthesis)