Question

Exposure to antimicrobial drugs act as a selective pressure on bacteria. This ultimately selects for bacteria that are resistant to the antibiotic. Describe four mechanisms a bacteria can use to be resistant to an antimicrobial drug.

Answer 1

There are two main ways for bacteria to withstand the effects of an antibiotic:

1. To stop the antibiotic from reaching its target at a high enough concentration
2. To modify or bypass the target that the antibiotic acts on

Over time bacteria have evolved many different antibiotic resistance strategies to accomplish this.

Antibiotic resistance mechanisms

1. Stop the antibiotic from reaching its target

• Pump the antibiotic out from the bacterial cell. Bacteria can produce pumps that sit in their membrane or cell wall. These so-called efflux pumps are very common in bacteria and can transport a variety of compounds such as signal molecules and nutrients. Some of these pumps can also transport antibiotics out from the bacterium, in this way lowering the antibiotic concentration inside the bacterial cell. In some cases mutations in the bacterial DNA can make the bacteria produce more of a certain pump, which in turn increases resistance.
• Decrease permeability of the membrane that surrounds the bacterial cell. Certain changes in the bacterial membrane make it more difficult to pass through. In this way, less of the antibiotic gets into the bacteria.
• Destroy the antibiotic. There are bacterial enzymes that can inactivate antibiotics. One example is β-lactamase that destroys the active component (the β-lactam ring) of penicillins, extremely important antibiotics for treating human infections. In later years, bacteria that produce extended-spectrum β-lactamases, so called ESBL-producing bacteria, have become a major problem. They can degrade a wide spectrum of β-lactam antibiotics, sometimes also the last resort drugs available for infections with these bacteria.
• Modify the antibiotic. Bacteria can sometimes produce enzymes that are capable of adding different chemical groups to antibiotics. This in turn prohibits binding between the antibiotic and its target in the bacterial cell.

Antibiotic resistance strategies in bacteria

2. Modify or bypass the target of the antibiotic[

• Camouflage the target. Changes in the composition or structure of the target in the bacterium (resulting from mutations in the bacterial DNA) can stop the antibiotic from interacting with the target. Alternatively, the bacteria can add different chemical groups to the target structure, in this way shielding it from the antibiotic.
• Express alternative proteins. Some bacteria are able to produce alternative proteins that can be used instead of the ones that are inhibited by the antibiotic. For example, the bacterium Staphylococcus aureus can acquire the resistance gene mecA and produce a new penicillin-binding protein. These proteins are needed for bacterial cell wall synthesis and are the targets of β-lactam antibiotics. The new penicillin-binding protein has low affinity to β-lactam antibiotics and is thus resistant to the drugs, and the bacteria survive treatment. This type of resistance is the basis in MRSA (methicillin-resistant Staphylococcus aureus).
• Reprogram target. Sometimes bacteria can produce a different variant of a structure it needs. For example, Vancomycin-resistant bacteria make a different cell wall compared to susceptible bacteria. The antibiotic is not able to interact as well with this type of cell wall.

Some bacteria are naturally resistant to certain antibiotics. Imagine for example an antibiotic that destroys the cell wall of the bacteria. If a bacterium does not have a cell wall, the antibiotic will have no effect. This phenomenon is called intrinsic resistance. When a bacterium that was previously susceptible to an antibiotic evolves resistance it is called acquired resistance.