Understanding antibiotic resistance
Understanding antibiotic resistance

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Understanding antibiotic resistance

1.3 Preventing entry, increasing exit

Antibiotics are only effective if they can reach their target. Preventing antibiotics from reaching their target is the final mechanism of antibiotic resistance that you will look at this week.

As you should recall from Week 2, the cell wall protects bacteria from osmotic and mechanical damage. To reach their targets inside the cell, antibiotics must cross this cell wall. In Activity 1 you will look at the mechanisms that antibiotics use to cross this bacterial cell wall.

Activity 1 Transporting antibiotics across the bacterial cell wall

Allow 15 minutes

First, watch the following animation which describes how antibiotics are transported across the bacterial cell wall.

Download this video clip.Video player: Video 1
Skip transcript: Video 1 Animation of the mechanisms of transport of antibiotics across the membrane.

Transcript: Video 1 Animation of the mechanisms of transport of antibiotics across the membrane.

INSTRUCTOR:
In this activity, you'll look at how altering the transport of antibiotics across the membrane can result in antibiotic resistance. The cell walls of gram-positive bacteria are permeable to most antibiotics, represented here as blues spheres and triangles. gram-positive bacteria are susceptible to these antibiotics because the antibiotic can cross the membrane and reach their targets, here shown in dark green inside the bacterial cell.
However, the outer membrane of gram-negative bacteria, like e. coli, forms a permeability barrier that prevents antibiotics from entering the bacterial cell and reaching their target. To reach their target inside gram-negative bacteria, antibiotics must overcome this permeability barrier. Embedded in the outer membrane of gram-negative bacteria are proteins that form channels known as porins, shown here in light green. Antibiotics cross the outer membrane of gram-negative bacteria by diffusing through these porin channels. Porin channels are fairly nonspecific and can transport many antibiotics across the membrane. The presence of porin channels in the outer membrane makes bacteria susceptible to antibiotics.
Some antibiotics can be efficiently removed from bacteria by efflux. Efflux is the movement of molecules out of the cell. Antibiotics are transported out of the bacterial cell by efflux pumps in the membrane, shown here in purple. Removing the antibiotic from the cell prevents it from binding to its target, so bacteria expressing efflux pumps are resistant to antibiotics. Some efflux pumps are specific and only transport one class of antibiotics, but many transport a wide range of molecules. These efflux pumps are known as multi-drug-resistant efflux pumps.
Porins and efflux pumps have opposite effects on the concentration of antibiotic inside the cell. In the following animations, the concentration of antibiotic inside the cell is shown by the brown colour. As the concentration of antibiotics increases, the colour becomes darker. The number of porins and efflux pumps on the outer membrane of bacteria can be altered, and these changes can affect the concentration of antibiotic inside the cell, and therefore, the susceptibility of bacteria to antibiotics. Watch what happens to the concentration of antibiotics as they enter the cell via porins and are removed by efflux pumps, and then answer the following questions.
End transcript: Video 1 Animation of the mechanisms of transport of antibiotics across the membrane.
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Video 1 Animation of the mechanisms of transport of antibiotics across the membrane.
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Now answer the following questions.

1 Decreasing the number of porin channels on the outer membrane:

a. 

(a) decreases the amount of antibiotic entering Gram-negative bacteria


b. 

(b) increases the amount of antibiotic entering Gram-negative bacteria


c. 

(c) has no effect on the amount of antibiotic entering Gram-negative bacteria.


The correct answer is a.

a. 

Your answer is correct. Most antibiotics cannot cross the outer membrane of Gram-negative bacteria and therefore enter the cell via porin channels. Decreasing the number of porin channels will decrease the amount of antibiotic entering the bacteria.


2 Bacteria that are resistant to penicillin are likely to have:

a. 

(a) very few porin channels on their outer membrane or have replaced their porin channels with channels that exclude penicillin


b. 

(b) numerous porin channels on their outer membrane


c. 

(c) replaced their porin channels with channels that selectively transport penicillin.


The correct answer is a.

a. 

Your answer is correct. If an antibiotic cannot reach its target, bacteria will be resistant to its action. Decreasing the expression of porins, or replacing them with channels that cannot transport the antibiotic, will prevent the antibiotic from crossing the outer membrane and reaching its target, therefore these bacteria will be resistant.


3 Increasing the rate of active transport of penicillin through the efflux pump would:

a. 

(a) increase the amount of penicillin in the bacterial cell


b. 

(b) decrease the amount of penicillin in the bacterial cell


c. 

(c) have no effect on the amount of penicillin in the bacterial cell.


The correct answer is b.

b. 

Your answer is correct. Efflux pumps actively transport antibiotics out of the bacterial cell. Therefore, increasing transport through these channels will decrease the amount of antibiotic inside the cell.


4 Bacteria that are resistant to penicillin are likely to have:

a. 

(a) efflux pumps that are unable to transport penicillin


b. 

(b) efflux pumps that transport penicillin


c. 

(c) no efflux pumps.


The correct answer is b.

b. 

Your answer is correct. If an antibiotic cannot reach its target, bacteria will be resistant to its action. Actively transporting antibiotics out of the cell decreases their concentration inside the cell, so that they cannot build up to a high enough concentration to exert the effect on their target.

Increasing active transport by expressing more efflux pumps that can actively transport the antibiotic out of the cell decreases the amount of antibiotic inside the cell and prevents it from acting on its target.


As you should now appreciate, bacteria can prevent antibiotics from reaching their target by decreasing the permeability of their outer membrane or by actively transporting antibiotics out of the cell (Activity 1). Both decreased porin expression and increased efflux pump expression have been reported in antibiotic-resistant clinical isolates. For example, S. aureus that overexpresses multidrug-resistant efflux pumps, which transport a wide range of antibiotics, have been isolated from patients (Kosmidis et al., 2012).

You will look at an example of how altering porin expression contributes to antibiotic resistance in the case study at the end of this week.

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