Antibiotic Resistance

Question 1

Why is antibiotic resistance a concern?

Answer 1

Antibiotic resistance:

Increases mortality
challenges control of infectious diseases
threatens a return to the pre-antibiotic era
increases the costs of health care
jeopardizes health-care gains to society

Question 2

Describe some mechanisms of antibiotic resistance

Answer 2

1. Drug inactivation- beta lactamase is an enzyme acquired by bacteria that can destroy the beta lactam ring of penicillin and cephalosporins - so one way a bacterium may become resistant to beta lactams/penicillin etc is by production of a beta lactamase enzyme
2. A bacterium could acquire a new drug target, meaning that eg penicillin doesn’t bind, eg you could have an altered ribosome structure or you could have a mutation in the porin gene in gram negative bacteria so drug won’t enter the gram-negative bacteria as well and bacteria becomes resistant.
   so you can have a mutation in the porin that stops drugs getting in or you can have mutations in efflux pumps that pump out antibiotics faster than they can accumulate
3. Some bacteria can overproduce the target (eg an enzyme) or precursors
4. intrinsic impermeability- some bacteria are intrinsically resistant to some antibiotics

Question 3

What, overall, are the 3 main mechanisms of resistance?

Answer 3

Natural resistance

Genetic Mechanisms - acquired

Non-Genetic Mechanisms (growth phases)
tolerance

Question 4

Describe the main mechanisms of resistance.

Answer 4

1.Natural resistance- as opposed to acquired
Drug must reach target - natural barriers, porins, export pump
G+ve peptidoglycan - highly porous - no barrier to diffusion
G-ves outer membrane - barrier resistance advantage
Porins - single mutation - multiple resistance

2. Genetic mechanisms:
   A. Chromosome-mediated:

Due to spontaneous mutation:
in the target molecule
in the drug uptake system
Mutants are SELECTED (by misuse of antibiotics) ; they are NOT induced by taking antibiotics etc

or can have 
B. Plasmid-mediated
	gene exchange
Common in Gram-negative bacteria
Transferred via conjugation
Multidrug resistance

Bacteria can transfer DNA between them either by process of acquisition of DNA- called transformation or by being infected by a virus particle, called a bacteriophage which will infect a bacteria and transfer DNA from previous host to new host, thereby transferring DNA from one bacteria to another- known as transduction(very quick process)
Or some bacteria can conjugate together and transfer genetic information

Question 5

What is one way we can overcome antibiotic resistance?

Answer 5

We can use antibiotics in combination with other chemicals to overcome resistance eg clavulanic acid + amoxicillin (binds to and inactivates beta-lactamases)

Question 6

What are the mechanisms by which bacteria can become resistant to penicillin?

Answer 6

Mechanisms:

1. Produce penicillinases / beta lactamases that cleave the beta lactam ring
   - penicillin is inactivated
2. Acquire alternative forms of / or mutations in penicillin binding proteins (PBPs)
   - penicillin can’t bind
3. Acquire alternative forms of / mutations in porins,
   - penicillin cannot get into cell
4. Acquire alternative forms of / mutations in efflux pumps
   - penicillins are pumped out faster

Question 7

Summary of genetic mechanisms of Resistance

Answer 7

Production of drug-inactivating enzymes

Altered target structures – new or mutations

Alteration of membrane permeability

Altered influx or efflux - new pumps or mutations or altered gene expression

Question 8

What are the non-genetic mechanisms of resistance?

Answer 8

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

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