Antibiotic resistance 101

Discussing the recent coverage of increasing drug resistance among gonorrhoea infections made me realise that a lot of people don’t really understand how antibiotic resistance happens or spreads. This is an attempt at a 101-style explainer. I suspect most people already have 90% of the knowledge needed to make sense of this, they just haven’t put it all together yet. I’m going to start with an example from animals which I think will make intuitive sense to people, and then move onto the bugs.

Antibiotic resistance develops through a process of evolution, through natural selection. Most people are familiar with how natural selection works in animals. Our DNA is subject to a constant process of mutation, both during our lives and from one generation to the next. Some of these mutations are harmful, like the BRCA mutations that put women at high risk of breast cancer. Some are beneficial, like the development of the ability the digest lactose that arose in European populations after the domestication of cattle. And some are neutral, like the mutation for red hair, which looks nice but doesn’t really do much for you either way.

Mutations happen at random, but whether they are harmful or helpful determines how effectively they spread through populations. For example, acacia trees, which are common in parts of Africa where giraffes live, are covered in huge thorns, making them a very unattractive food source unless you happen to be a giraffe with a very tough mouth. This doesn’t really matter, provided there are other things to eat if you have a soft mouth. But say there is a terrible drought, and all the easier-to-eat plants die off – suddenly a giraffe with a tough mouth has a big advantage over other giraffes. It’s more likely to survive a drought and have children, and those children will probably also have tough mouths, enabling them to survive and reproduce during droughts in their own lifetimes.

Now, a giraffe with a tough mouth that breeds with a giraffe with a soft mouth may not pass on its tough-mouth gene to its offspring – its partner’s soft-mouth gene might override its tough-mouth gene. Because (most) animals reproduce sexually, which involves mixing the genes of two different animals together, some useful genes get lost between generations. This is not a problem for lifeforms like bacteria that produce asexually. Bacteria don’t need other bacteria to reproduce with – they just split themselves in half, cloning themselves. One bacteria splits in half to form two, they split in half to form four, they split in half to form eight, and so on – all clones of the original, except for any new mutations that occur along the way.

This has a big impact on the survival of useful mutations in bugs. Prior to the discovery of antibiotics in the mid 20th century, bacteria were just going about their business, infecting humans, and being transported from one place to another. My favourite bacteria, the tuberculosis (TB) bug, was being carried around and transmitted by people all over the world.

In the late 1940’s, doctors in the US realised that the antibiotic streptomycin killed TB bugs. Suddenly, being a bug that was immune to streptomycin was the equivalent of being a giraffe with a tough mouth – it meant particular bugs could survive circumstances that were a disaster for everybody else. By the time someone with TB gets to a doctor, their lungs are absolutely chock-full of bugs – millions upon millions of the little blighters. When they start taking streptomycin, all of those bugs get exposed to the antibiotic, and most of them die. But if a few bugs have a random mutation that makes them resistant, those bugs survive and continue multiplying while all the bugs around them die. Eventually, only resistant bugs remain in the person’s lungs, and the person may then cough those bugs onto someone else before the TB kills them.

In this way, antibiotic resistant bugs can spread from person to person, and in the modern age, from country to country. This is what we’re currently seeing with TB, gonorrhoea, and other bacterial diseases. Drugs that came into use provided a strong advantage for bugs that could resist them, and those bugs survived and spread around the world. As newer drugs get introduced in specific places, the bugs infecting the patients on those drugs become resistant to those as well. The streptomycin resistant TB bugs from the 1950s have continued circulating around the world, picking up resistance to more and more antibiotics, and some strains of TB are now resistant to basically all of the drugs we have.

Remember though that bacteria, like humans, are undergoing constant evolution. There are unimaginable squillions of individual TB bacteria around the world, and even though they are all clonal descendants of previous bugs, they are constantly evolving. This is what gives rise to different “strains” of various bacteria – like humans have a variety of lineages. We’re all the same species, but we have different characteristics. Most TB bugs are still vulnerable to all drugs, some are resistant to one or two, and some are resistant to many or all drugs.

When you read that “TB is becoming drug-resistant”, this doesn’t mean that all TB bugs in the world are acquiring resistance to the same drugs at the same time – this would be like if somehow, overnight, everybody in the world became a redhead. Drug resistance, like hair colour, is a characteristic that is mostly passed down from one generation to the next.

However, bacteria have an additional trick up their sleeves that animals like us do not – they can actually swap genetic material with one another within their own lifetimes. Human genes are all contained on chromosomes, and the 46 you’re born with are the ones you’re stuck with – you have 46 identical copies in every cell in your body. Bacteria, however, are a single cell – and they are capable of trading small individual chromosomes (called “plasmids”) with one another. What this means is that not only does one drug resistant bug divide to create two drug resistant clones of itself (who then divide to create four, and so on) – it can also simply give a copy of its drug resistance genes to a friend!

But to give something to a friend, you have to meet the friend in person – bacteria are yet to develop a postal system. Someone with TB will have millions of individual bacteria in their lungs, some clones of one another, some very different. Those bugs that get close enough to touch one another can swap copies of their plasmids, but a bug in my lungs can’t give a plasmid to a bug in yours, unless the bug itself gets transferred over.

So that’s the mechanics of drug resistance in bacteria. Individual bacteria develop a mutation that makes them resistant, and they can pass that mutated gene to their clonal children, and to friends in their immediate environment. But the gene still has to spread through the population basically the same way different characteristics do in humans – mutations for red hair have arisen several times in several different places, but not everybody in the world has red hair. Even if I could make other people into redheads by touching them, the way bacteria can swap genes between friends, I would still have to chase people around and lay hands on them.

Bugs that are resistant to common antibiotics have a big advantage, and we have to make sure we expose them to other drugs that will definitely kill them – for example by treating streptomycin resistant bugs with penicillin, and vice versa. This is difficult, but not impossible. Drug resistance is on the rise and is cause for concern, but bacteria are subject to most of the same genetic laws as the rest of life on earth, and the antibiotic era is not over just yet.

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