Lecture 4 - Evolution of antibiotic resistance

Question 1

Evolution

Answer 1

The change in the heritable characteristics of biological
populations over successive generations

Question 2

Antibiotic resistance

Answer 2

The absence of susceptibility to the killing or growth-inhibiting properties of an antibiotic

Question 3

Antibiotic origin

Answer 3

Antibiotics are evolutionarily ancient

Occurred near the split between
Gram-negative and Gram-positive
bacteria (>3200 mya)

Question 4

How does antibiotic resistance form?

Answer 4

Heritable:
* Random mutations,
* horizontal gene transfer (in various forms)

• Antibiotics impose natural selection for resistant organisms (antibiotics do not cause resistance but they do select for it)

Question 5

Genomic mechanisms of antibiotic resistance

Answer 5

Horizontal gene transfer (HGT):
● Conjugative plasmids
● Mobile genetic elements
● Transformation

Spontaneous mutation:
● Errors occurring during DNA replication
● May alter binding site of antibiotic, alter gene expression, or change drug influx or efflux

Intrinsic resistance:
● Absence of e.g. specific antibiotic target
● Differences in permeability (e.g. between
Gram‒ vs. Gram+)

Question 6

Combination therapy: what is it, when is it typically used, and why is it good?

Answer 6

Treatment that uses two or more drugs

• Primarily used in cancer & HIV
• Increasingly against microbial infections

Can be more effective than one drug on its own (synergy), also helps to prevent resistance

Question 7

Where is antibiotic combination therapy in use?

Answer 7

• Standard practice against tuberculosis & other mycobacterial diseases

● Routine for some ‘common’ infections (e.g. trimethoprim/sulfamethoxazole for UTI)

● Second-line treatments for resistant infections (e.g. beta lactam/beta lactamase inhibitors)

Clinical trials ongoing for other conditions (e.g. Crohn’s Disease, MS)

Question 8

Key assumptions of combination therapy: why does it work in theory?

Answer 8

Acquiring multiple independent resistance mechanisms (multi-resistance) should be exceedingly rare

Multi-resistance should not emerge without selection for resistance to multiple antibiotics

Question 9

Experiments

Answer 9

Go over this if doing this lecture

Answer 10

Scope of the antimicrobial resistance problem
In 2019:
● 4·95 million deaths associated
w/ AMR
● 1·27 million attributable to AMR