Drug rebels

Drug-resistant bacteria can mean that some treatments become ineffective over time

Aspirin works as well today as it did when launched. But drugs used to treat infections (and cancer) lose their potency, because of resistance.

The headlines send a chill down the spine. ‘Killer bugs’ or ‘superbugs’ have found a way around the drugs we use to destroy them. From MRSA (methicillin-resistant Staphylococcus aureus) to tuberculosis, resistant bacteria are on the rise. And the threat is not confined to bacteria. The malaria parasite, the human immunodeficiency virus (HIV) and even tumours can develop resistance to chemotherapeutic agents. What’s going wrong? Why are life-saving drugs losing their punch?

The answer is natural selection. Whenever microorganisms are placed under selective pressure, such as exposure to drugs, occasional mutant forms that are less susceptible to the drug survive and multiply.

There are many ways in which resistance to a drug may arise:

  • Pump it up (and out): A microbe may expel a drug before it has a chance to act, using protein pumps in their cell membranes. Interestingly, cancer cells use a relative of bacterial pumps, the P-glycoprotein, to expel anticancer drugs.
  • Chop it up: A common response is to metabolise a drug, breaking it down or chemically modifying it, rendering it ineffective.
  • All change: A drug will act on a specific part of a target protein; if a mutation alters that part of the protein, the drug may bind less well and be less effective. The mutant protein may not work as well either, but at least the cell survives. Other mutations may then act to improve the protein’s function.

In fact, resistance is rarely all or nothing. A bacterium typically first tolerates a drug – it survives but does not grow – before gradually becoming more resistant.

Resisting resistance

The development of resistance is simply natural selection in action, so it can never be completely avoided. But there are ways to minimise its impact.

One is simply to develop new medicines. This is more easily said than done, however. Developing a drug is expensive and takes years.

Another solution is to use drugs in combinations. If a microorganism acquires a mutation that makes it resistant to one drug, it will still be killed by another. It is extremely unlikely that the same cell will simultaneously acquire mutations protecting against all drugs being given together. Combination therapy is now used for tuberculosis, HIV/AIDS and some malaria treatments.

Another possibility is to rotate drugs, to allow them to lie ‘fallow’. Over time, use of drug X in a region could lead to the appearance of resistance. That region could swap to drug Y, then later to drug Z. By the time resistance to drug Z appeared, the microbe might be susceptible to drug X again. There is some evidence from Africa that resistance to some antimalarials drops away once a drug is no longer used.

Another option is to stop resistance spreading in the first place by treating anti-infective agents with respect and not misusing or abusing them. Taking recommended doses for the full course is essential. Otherwise, low doses may allow moderately resistant bacteria to survive and spread.

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About this resource

This resource was first published in ‘Drug Development’ in January 2008 and reviewed and updated in August 2014.

Microbiology, Medicine
Drug Development
Education levels:
16–19, Continuing professional development