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In the battle between humans and bacteria, antibiotics are one of our most important weapons. But, bacteria can fight back! In this lesson, learn about the strategies that some bacteria use in order to avoid being killed by penicillin.

Drugs vs. Bacteria

Imagine you’re outside playing soccer and you get a cut on your leg. You put a bandage on it and wait for it to get better. But, within a few days, you notice that the skin around the cut is getting red, swollen and painful to the touch, so you decide to get a doctor to look at it.

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The doctor suspects that you have a staph infection, an infection caused by bacteria in the genus Staphylococcus. These bacteria often live on our skin without causing any symptoms, but if they get into a wound, they can cause infections. Your doctor decides to give you antibiotics. But, let’s hope she chooses the right one.

..Let’s take a closer look at the infection on your leg. If you took a sample and looked at it under the microscope, you’d see lots of tiny bacteria growing and dividing and your immune cells trying to gobble them up.

You’d think those little critters wouldn’t have a chance of surviving, especially when antibiotics are there to help your immune system get things under control. But, don’t be fooled; bacteria have lots of tricks up their tiny little sleeves.If we imagine an infection as a battle between humans and bacteria, antibiotics would be one of our most important weapons. But, those sneaky little bacteria have evolved ways to survive even in the face of antibiotics.

There are many antibiotics available today, but almost as soon as they begin to be used in the clinic, resistant bacteria are found. In this lesson, we’ll take a closer look at an example of antibiotic resistance, penicillin resistance, which is when bacteria can avoid being killed by penicillin. We’ll explore how this works and how drug developers try to fight back.

Mechanisms of Penicillin Resistance

Remember that penicillin kills bacteria by weakening their cell walls. Penicillin specifically targets the enzymes that cross-link the peptidoglycan layer in the cell wall. Since the cell wall is so important for bacteria, how could a bacterium possibly survive penicillin treatment? Well, there are a few different ways, actually.

Penicillin Resistance: Restrict Transport

One strategy that some Gram-negative bacteria have evolved is to restrict transport of penicillin molecules into the cell wall.

This first strategy is analogous to reinforcing the walls of a fortress so that invading armies can’t get in. Remember that penicillin can diffuse easily into Gram-positive bacteria because they don’t have an outer membrane. However, penicillin and other drugs must enter Gram-negative bacteria through channels called porins on their outer membranes.

This is why some types of penicillin are ineffective against Gram-negative bacteria; they can’t get through the porins. However, there are related drugs called ‘broad-spectrum penicillins’ that can enter the bacteria through these porins. Amoxicillin is one of these broad-spectrum penicillins.Some Gram-negative bacteria, such as E. coli, which can cause various kinds of illnesses, including bladder infections and food poisoning, are resistant to the broad-spectrum penicillins.

These resistant strains can have mutations that make them produce fewer porins or that make the openings of the porins smaller. In either case, less antibiotic can get through to the peptidoglycan layer, where it needs to be to do its job.

Penicillin Resistance: Modify Target Molecules

Another impressive penicillin resistance mechanism is to modify penicillin’s target molecules, the enzymes that cross-link peptidoglycan. These target molecules are called penicillin-binding proteins because, well, they bind to penicillin. Some bacteria, like Streptococcus pneumoniae, which can cause illnesses like bronchitis, pneumonia and ear infections, use this second mechanism to resist penicillin. Resistant strains often have mutated penicillin-binding proteins that penicillin can’t bind to anymore.

Let’s imagine this concept in a larger size. Say there’s a targeted missile that specifically destroys the mortar that holds stone walls together. This second penicillin-resistance strategy would be like designing a whole new type of mortar that the missiles can’t recognize and then using this mortar to build all new walls.

Penicillin Resistance: Beta Lactamases

The third mechanism of penicillin resistance is really important. It’s the one that a lot of biologists think about when they hear the phrase ‘penicillin-resistant.’ Bacteria that use this third mechanism secrete enzymes that break penicillin down so that it’s ineffective. This mechanism would be analogous to releasing a substance that would dismantle missiles in midair before they can even hit anything. Pretty impressive.So, how does this third strategy work? First, we need to look at the structure of the penicillin molecule. Penicillin is a beta-lactam antibiotic, meaning it’s a member of a class of antibiotics that all have a beta-lactam ring in their structure.

The beta-lactam ring is essential for penicillin’s activity.Bacteria that can destroy penicillin do so by secreting enzymes called beta-lactamases. These enzymes cleave the beta-lactam ring of penicillin so that the drug becomes inactive. Many bacteria, such as the Staphylococcus that might be in that cut on your leg, express beta-lactamases, so penicillin doesn’t work to treat these bacteria.

Resisting Penicillin Resistance

Since so many bacteria express beta-lactamases now, drug developers have their own strategies to fight back.

One strategy is to modify penicillin by making it semi-synthetically. This means that the core molecule of penicillin is produced by the Penicillium mold as usual, but then chemists modify the molecule in the lab.For example, big, bulky side chains may be added to penicillin to make the beta-lactam ring harder for beta-lactamases to access and cleave. The penicillin-related drug methicillin was designed in this way so that it would be less easily cleaved by beta-lactamases. Another modification that can be made to the penicillin molecule is to change the structure of the beta-lactam ring itself.Drugs in the carbapenem family, such as imipinem, have a double bond in the neighboring ring, making the molecule very resistant to beta-lactamases.

And, monobactams, such as aztreonam, have only a single beta-lactam ring, not the neighboring ring that is present in penicillin. This also reduces the effectiveness of beta-lactamases against these drugs.Another strategy that drug developers use is to combine an antibiotic with a beta-lactamase inhibitor. A drug called Augmentin is the combination of amoxicillin and clavulanic acid. Clavulanic acid is not antimicrobial by itself, but it inhibits any beta-lactamases that a bacterium might be secreting. In this way, it improves the effectiveness of amoxicillin.All of these strategies definitely help in the battle against penicillin-resistant bacteria.

However, time and time again, bacteria have rapidly evolved resistance to every new drug that comes onto the market. Antibiotics must be used properly to reduce the extreme selective pressure that they put on bacteria to evolve antibiotic-resistance mechanisms.

Lesson Summary

Let’s go back to the infected cut on your leg. If your doctor prescribes you penicillin, will it work? Well, without testing the particular bacteria that are causing your infection, she won’t know for sure. But, since she thinks that the culprits may be Staphylococci, which often express beta-lactamases, she’ll probably prescribe you something other than penicillin just in case.In this lesson, we’ve learned about three mechanisms that bacteria can use to resist penicillin. The first is to restrict transport of the penicillin molecules into the cell.

Certain strains of Gram-negative bacteria, like E. coli, can express fewer or mutated porin channels, making them resistant even to the broad-spectrum penicillins that are designed to penetrate better into Gram-negative bacteria.The second strategy is to modify the target molecules of penicillin. Penicillin’s targets are the enzymes that cross-link peptidoglycan, which are called penicillin-binding proteins. Some bacteria, such as Streptococcus pneumoniae, have evolved mutated penicillin-binding proteins that penicillin can’t bind to anymore.

The third, and very important, strategy is to express enzymes that destroy penicillin. Bacteria that use this mechanism of resistance secrete beta-lactamases that cleave the beta-lactam ring, making penicillin ineffective. Staphylococcus species are notorious for using this mechanism, but many other bacteria use it as well.Finally, we learned that drug developers fight back against penicillin resistance by making drugs semi-synthetically, which allows them to modify penicillin so that it is less easily cleaved by beta-lactamases. The second major strategy is to treat patients with a combination antibiotic + beta-lactamase inhibitor.

This way, the drug will be more effective, because any beta-lactamases that the bacteria are secreting will be inhibited.

Learning Outcomes

After completing this lesson, you might be able to:

  • Note three ways bacteria resist penicillin
  • Classify the ways in which drug developers have attempted to overcome these penicillin resistances
  • Recall the reason that treatment with an antibiotic plus a beta-lactamase inhibitor can be effective against resistant bacteria strains

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