Saturday, April 16, 2022

How serious is antibiotic resistance?

[This is a transcript of the video embedded below. Some of the explanations may not make sense without the animations in the video.]

Antibiotics save lives. But increasingly more bacteria are becoming resistant to antibiotics. As a result, some infections can simply no longer be treated. Just a few weeks ago an international team of scientists lead by researchers at the University of Washington published a report in the Lancet, according to which antibiotic resistance now kills more than a million people worldwide each year. And the numbers are rising.

How serious is the situation? What are scientists doing to develop new antibiotics? Did you know that bacteria are not the most abundant organism on earth? And what do rotten eggplants have to do with all of that? That’s what we will talk about today.

First things first, what are antibiotics? Literally the word means “against life” which doesn’t sound particularly healthy. But “antibiotic” just refers to any type of substance that kills bacteria (bactericidal) or inhibits their growth (bacteriostatic). Antibiotics are roughly categorized either as “broad spectrum”, which target many types of bacteria, or “narrow spectrum” which target very specific bacteria.

The big challenge for antibiotics is that you want them to work in or on the body of an infected person, without killing the patient along with the bacteria. That’s what makes things difficult.

There are various ways antibiotics work, and most of them target some difference between bacteria and cells, so that the antibiotic harms the bacteria but not the cell.

For example, our cells have membranes, but they don’t have cell walls, which is a rigid protective layer that covers the membrane. But bacteria do have cell walls. So one way that antibiotics work is to destabilize the cell wall. Penicillin for example does that.

Another thing you can do is to prevent bacterial cells from producing certain enzymes that the bacteria need for replication, or inhibit their synthesis of folic acid which they need to grow.

As you can see, antibiotics work in a number of entirely different ways. And each of them can fight some bacteria but not others. You also have to take into account w*here the bacterial infection is, because not all antibiotics reach all parts of the body equally well. This is why you need a prescription for antibiotics – they have to fit to the infection you’re dealing with, otherwise they’re in the best case useless. In the worst case you may breed yourself a tough strain that will resist further treatment.

This problem was pointed out already by the Scottish physician Alexander Fleming who discovered the first antibiotic, penicillin, 1928. Penicillin is still used today, for example to treat scarlet fever. According to some estimates, it has saved about 200 million lives, so far.

But already in 1945, Fleming warned the world of what would happen next, namely that bacteria would adapt to the antibiotics and learn to survive them. They become “resistant”. Fleming wrote
“The greatest possibility of evil in self-medication is the use of too-small doses, so that, instead of clearing up infection, the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out which can be passed on to other individuals.”
To some extent antibiotic resistance is unavoidable – it’s just how natural selection works. But the problem becomes significantly worse if one doesn’t pull through an antibiotic treatment at full force, because then bacteria will develop resistance much faster.

The world didn’t listen to Fleming’s warning. One big reason was that in the 1940s, scientists discovered that antibiotics were good for something else: They made farm animals grow faster, regardless of whether those animals were ill.

On average, livestock that were fed antibiotic growth promoters grew 3-11% faster. So farmers began feeding antibiotics to chickens, pigs, and cattle because that way they would have more meat to sell.

Things were pretty crazy at the time. By the 1950’s the US industry was “painting” steaks with antibiotics to extend their shelf life. They were washing spinach with antibiotics. Sometimes they even mixed antibiotics into ground meat. You could buy antibiotic soap. The stuff leaked everywhere. Studies at the time found penicillin even in milk and some people promptly developed an allergy to it.

It wasn’t until 1971 that the UK banned the use of some antibiotics for animal farming. But it’s only since 2006 that the use of antibiotics as growth promoters in animals is generally forbidden in the European Union. In the USA it took until 2017 for a similar ban to come into effect.

Using antibiotics for meat production isn’t the only problem. Another problem is over-prescription. According to the American Center for Disease Control, about 30 percent of prescriptions for antibiotics in the USA are unnecessary or useless, in most cases because they are mistakenly prescribed against respiratory infections that are caused by viruses, against which antibiotics do nothing.

A 2018 paper found that the global consumption of antibiotics per person has increased by 39% from 2000 to 2015 and it’s probably still increasing, though the increase is largely driven by low and middle income countries which are catching up. And with that, antibiotic resistance is on the rise.

Already in 2019, the World Health Organization (WHO) declared that antimicrobial resistance (which includes antibiotic resistance) is currently one of the top 10 global public health threats. They say that “antibiotics are becoming increasingly ineffective as drug-resistance spreads globally leading to more difficult to treat infections and death”.

According to the recent study from the Lancet which I mentioned in the introduction, the number of people who die from treatment-resistant bacterial infections is currently about 1.27 million per year. That’s about twice as many people who die from malaria. They also estimate that antibiotic resistance indirectly contributes to as many as 4.95 million deaths each year. The Lancet article also found that young children below 5 years are at the highest risk.

So the situation is not looking good. What are scientists doing?

First there are a couple of obvious ideas, like bringing back old antibiotics that have gone out of use, because bacteria may have lost their resistance to them, and keep looking for new inspirations in nature. For example, in 2016, a group of researchers from Denmark reported they’d found that leaf-cutting ants use natural antibiotics. The next one you probably guessed: Artificial Intelligence to the rescue.

2 years ago, researchers from MIT published a paper in the magazine Cell in which they explain how they used deep learning to find new antibiotics. They first trained their software on 2500 molecules whose antibiotic functions are known and also taught it to recognize structures that are known to be toxic.

Then they rated 6000 other molecules with scores from 0 to 1 for how likely the molecules were to make good antibiotics. Among the molecules with high scores they focused on those whose structure was different from that of the known antibiotics because they were hoping to find something really new.

They found one molecule that fit the bill: halicin. Halicin is not a new drug, they just renamed what was previously known under the catchy name c-Jun N-terminal kinase inhibitor SU3327. They called it halicin after HAL from the Space Odyssey, I am guessing because their Artificial Intelligence is exploring a big “chemical space” or otherwise I’m too dumb to get it.

They did an experiment and found that indeed halicin worked against some multiresistant bacteria, both in a petri dish and in in mice. Then they repeated the process but with a much bigger library of more than ten million molecules. They identified some promising candidates for new antibiotics and are now doing further tests.

It’s a long way from the petri dish to the market, but this seems really promising, though it has the usual limitations of artificial intelligence: software can only learn if there’s something to train on, so this is unlikely to discover entirely new pathways of knocking out bacteria.

Another avenue that researchers are pursuing is the revival of phage therapy. Phages are viruses that attack bacteria. They are about 100 times smaller than bacteria and are the most abundant organism in the planet. There are an estimated 10 million trillion trillion of them around us, that’s ten to the 31. And phages are everywhere: on surfaces, in soil, on our skin, even inside our body. They enter a bacterium and replicate inside of it, until the bacterium bursts and dies in the process. You can see the potential: breed phages that infect the right bacteria and you’ve solved the problem.

One great benefit of phages is that they target very specific bacteria so they spare the beneficial bacteria in our body. The question is, where do you get the right phage for an infection? The first successful phage treatment was done in 1919, however, the method was never widely adopted because breeding the right phages is slow and cumbersome and when antibiotics were discovered they were just vastly more convenient.

However, with antibiotic resistance on the rise, phage treatments are getting new attention. Researchers now hope that genetic engineering will make it faster and easier to breed the right phages. The first successful treatment with genetically modified phages was reported in 2019 in Nature Medicine by a group of researchers from the United States and the UK. They bred a cocktail of three phages, one of which they found on a rotting eggplant from South Africa.

The group around Dr. Strathdee at the University of California San Diego hopes that one day we will have an open source library for genetically engineered phages which is accessible to everyone and she’s currently raising funds for that. Strathdee and her team don’t think that phage therapy will ever replace antibiotics altogether but that it will be an important contribution for particularly hopeless cases.

Another new method to fight bacteria was proposed in 2019 by researchers from Texas. They have found a way to kill bacteria while they are passive, so while they are not replicating. This can’t be done with normal antibiotics that usually target growth or replication. But the researchers have found substances that open a particularly large channel in the membrane on the surface of the bacterium. The bacterium then basically leaks out and dies. Another good thing about this method is that even if it doesn’t kill a bacterium it can make it easier for antibiotics to enter. They have tested this in a petri dish and seen good results.

To name one final line of research that scientists are pursuing: Several groups are looking for new ways to use antimicrobial peptides. Peptides are part of our innate immune system. They are natural broad spectrum antibiotics and earlier studies have shown that they’re effective even against bacteria that resist antibiotics.

Problem is, peptides break down quickly when they come into contact with bodily fluids, such as blood. But researchers from Italy and Spain have found a way to make peptides more stable by attaching them to nanoparticles that fight off certain enzymes which would otherwise break down the peptides. These peptide nanoparticles can for example be inhaled to treat lung infections. They tested it successfully in mice and rats and published their results in a 2020 paper. And just last year, researchers from Sweden have developed a hydrogel that contains these peptides and that can be put on top of skin wounds.

It is hard to overstate just how dramatically antibiotics have changed our life. Typhus, tuberculosis, the plague, cholera, leprosy. These are all bacterial infections, and before we had antibiotics they regularly killed people, especially children. During World War I more people died from bacterial infection than from the fights.

As you have seen, bacterial resistance is a real problem and it’ll probably get worse for some more time. But scientists are on the case, and some recent research looks quite promising.

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