Lecture 35: Antibiotics II

Question 1

How has antibiotic resistance evolved over time?

Answer 1

It has risen over the past 20 years.

Question 2

What type of antibiotic resistance has risen the most in the last 20 years?

Answer 2

Fluoroquinolones

Question 3

What type of antibiotic resistance is most concerning? Why?

Answer 3

Resistance to carbapanems, as they are our last resort antibiotic if the microbe is resistant to other drugs.

Question 4

What is antibiotic resistance?

Answer 4

The ability for bacteria to grow in the presence of antibiotics.

Question 5

What is multidrug resistance?

Answer 5

The resistance of a microbe to multiple compounds

Question 6

Antibiotic resistance is defined by what metric?

Answer 6

A high MIC (minimal inhibitory concentration)

Question 7

In a disc diffusion assay, what type of result indicates antibiotic resistance?

Answer 7

A small zone of inhibition indicates high resistance.

Question 8

How does human behaviour affect antibiotic resistance?

Answer 8

It accelerates the emergence, selection, and spread of antibiotic resistance.

Question 9

What are the two origins of antibiotic resistance in microorganisms?

Answer 9

Advantageous mutations (by chance) or expropriating genes

Question 10

Explain how advantagenous mutations can lead to antibiotic resistance in microorganisms. What is required for an advantagenous mutation to be successful?

Answer 10

A mutation takes place that is selected for. If the mutation becomes fixed, it can be passed down to daughter cells and the resistance can be passed on.

Question 11

Explain how expropriating genes can lead to antibiotic resistance.

Answer 11

Certain resistance mechanisms or plasmids encoding resistance genes can be shared among microorganisms. Bacteriophages can also contribute to gene sharing.

Question 12

What is the difference between vertical gene transfer and horizontal gene transfer of antibiotic resistance?

Answer 12

Vertical = trait passed from one generation to another within a given species, with clonal expansion.
Horizontal = trait transferred to different bacteria, potentially of a different species, by conjugation or plasmids, by transformation, or by bacteriophage integration.

Question 13

Antibiotics can have [one/multiple] mechanism(s) of resistance, and specific mechanisms can confer resistance to [one/multiple] class(es) of antibiotics.

Answer 13

Multiple, multiple

Question 14

Name the 7 major mechanisms of antibiotic resistance.

Answer 14

1. Low permeability
2. Drug efflux
3. Target mutation
4. Target modification
5. Drug modification/degradation
6. Overproduction of target mimic
7. Factor-associated protein

Question 15

What is intrinsic resistance?

Answer 15

It is an antibiotic resistance property that is not unique, but is instead shared by many bacteria based on a morphological property, such as the structure of the membrane.

Question 16

What type of antibiotic resistance property is primarily responsible for intrinsic resistance?

Answer 16

Low permeability due to presence of outer membrane.

Question 17

What types of bacteria use low permeability as a resistance technique? Why?

Answer 17

Mainly gram negative bacteria and mycobacteria, as both have an outer membrane that is highly hydrophobic and impermeable.

Question 18

Describe how low permeability works as a resistance mechanism.

Answer 18

Since the outer membrane of gram negative and mycobacteria is so hydrophobic, it is a naturally selective barrier. In addition, since many antibiotics have to enter through pores, there can be size limitation or mutations that prevent them from entering effectively.

Question 19

What types of bacteria use drug efflux as an antibiotic resistance technique? Why?

Answer 19

Gram negative bacteria, as efflux pumps are located in their outer membrane. However, sometimes they can be present in gram positive as well, but less often.

Question 20

Describe how antibiotic resistance due to drug efflux works.

Answer 20

The bacteria recognizes the entry of an unwanted compound and will pump it out using an efflux pump. The bacterium can sometimes code for alterations in the pumps to exclude antibiotics.

Question 21

Are drug efflux pumps specific or nonspecific? Explain.

Answer 21

They are nonspecific, and pump out molecules based on their charge and size. So, they can confer multi-drug resistance.

Question 22

What are the main 2 types of antibiotics that drug efflux targets?

Answer 22

Macrolides and tetracycline.

Question 23

Describe how target mutation works as a resistance mechanism.

Answer 23

The bacteria mutates the genes of the target of the antibiotic so that it can no longer be recognized and bound to.

Question 24

Describe how target modification works as a resistance mechanism.

Answer 24

The bacteria adds sugar chains to the target to prevent the antibiotic from recognizing or binding to it.

Question 25

Give an example of resistance by genetic mutation of the target gene, including the antibiotic involved.

Answer 25

gyrB (topoisomerase) mutations and quinolone resistance

Question 26

Give an example of resistance by enzymatic modification of the target structure, including the antibiotic involved.

Answer 26

Erm (methyl transferase) modification of the 50S subunit and macrolide resistance.

Question 27

What type of antibiotic is mainly associated with resistance due to drug modification or degradation?

Answer 27

Betalactams.

Question 28

Describe how drug modification/degradation works as a resistance mechanism.

Answer 28

If the bacteria can't modify the target of the drug, they can modify the drug itself by metabolizing or rendering it nonfunctional.

Question 29

Give 2 examples of drug modification or degradation.

Answer 29

Beta-lactam degradation by beta-lactamases and aminoglycoside modification.

Question 30

Describe how beta-lactam degradation by beta-lactamases works.

Answer 30

Enzymes are secreted that are effective in cleaving beta-lactam rings, rendering drugs like carbapenems (which are beta-lactams) ineffective.

Question 31

Cephalosporins can be cleaved by [...], while carbapanems can be cleaved by [...]

Answer 31

ESBL, metallo-beta-lactamases

Question 32

Describe how aminoglycoside modification works.

Answer 32

Aminoglycosides gets inactivated via the addition of other molecules (AMP adenylyl transferases, -PO3 by phosphoryl transferases, acetyl by acetyl transferases). This prevents proper binding of aminoglycosides to the 30S subunit.

Question 33

What are superbugs?

Answer 33

Bacteria which have resistance to a variety of compounds.

Question 34

What are the 6 main superbugs (incl. acronym)?

Answer 34

ESKAPE: Enterococci faecium Staphylococcus aureus Klebsiella penumoniae Acinetobacter baumannii Pseudomonas aeruginosa Enterobacter sp.

Question 35

Name 3 reasons why antibiotic resistance is increasing.

Answer 35

1. Global antibiotic consumption increased 65% from 2000-2015. 2. 30% of antibiotics prescribed per year are not necessary to treat the infection. 3. In low income countries with less clean water, they might have more interaction with biofilms, which are inherently resistant to antibiotics.

Question 36

Name 2 ways in which human behaviour promotes antibiotic resistance.

Answer 36

Antibiotic overuse in health/food/animal industries and antibiotic misuse, including not following treatment indications.

Question 37

Explain why antibiotic overuse in food/animal industries is problematic for human health.

Answer 37

If animals are overfed with antibiotics, they can end up being excreted by animals and travel through the soil and environment, exposing the bacteria in the soil to antibiotics and making them resistant. These resistant bacteria in the soil will then end up in the food we grow and in our bodies.

Question 38

How has the discovery of new antibiotics evolved in recent decades? Why is this?

Answer 38

Extremely few new drugs have been approved since ~2000, with no new classes approved and no new targets. This is because synthesizing new compounds is a long and expensive process.