Facilitator: I have a few visitors with me and the first one is this. So this guy's responsible for a 1,000,000,000 deaths, human deaths. A third of the population right now has this guy inside themselves inactive, in a latent form. This bug is TB. Is TB normally this big?
Facilitator: No, okay, so at least I know that you know that. Is TB normally green? No, okay, so you get what the students get as well. So the problem with this at the moment as with a lot of bugs, same with a lot of bugs, is that there are multi resistant TB strains around. With the advent of Aids many years ago TB was activated in a lot of Aids patients because their immune system is compromised and whenever we did use antibiotics for TB, the bacteria - we always knew that there was resistance. What I want to explain tonight really is the huge amount of antibiotic resistance there is and why there's such a huge amount; how does it happen and what can we do about it.
So I'm going to start by introducing you to the normally invisible world of bacteria and then I'm going to explain what they are, where they live, what good they do and then the bad ones and concentrate on those. You'll understand what a Superbug is. You'll understand a little bit about antibiotic resistance, how it came about and what can we do about it, because there are things that not just hospitals or physicians like Tom can do about it, or scientists. There are also things that all of us can do and I think as a community it's really our voice that matters most.
So what are bacteria? Bacteria come from the Latinisation of the Greek word bakterion, which means staff or cane and that's to describe rod shaped bacteria which were the first bacteria to be observed. They're small, they're only one cell and you call one bacterium a bacterium. If you get more than one you call it bacteria. They have a simple organisation, basically a bit of DNA, a few other molecules inside a cell envelope, but it's much more complex than that in terms of how they regulate their life.
The usually have one chromosome - we have 46 - and they can grow and multiply very quickly. Some of the bacteria that we study can double their number in 10 minutes. Unlike viruses which they often get confused with, they can live and replicate outside the human body. Viruses cannot do that and they're not to be confused with parasites or fungi, or yeast or worms. All of those cells of those organisms actually are more similar to humans, so bacteria are quite different.
They're very small, absolutely tiny, so we're talking about one micron in diameter or length, up to a few microns. Now the easiest way of - if you're not familiar with those sorts of lengths, it's basically take a millimetre and divide that by 1000, so you can really only see them under a microscope and so I think the problem of infection is something that we can't always see. That's what makes it quite difficult for people to understand the enormity of the problem.
So if you look at - I might come down here because it's a bit easier. So normally a lot of you would be used to seeing bacteria on an agar plate where they just grow. We call these single colonies where you take a little bit of this with a sterile stick, you can put it into some water, disperse it into the water, put it on a microscope slide and that's what you'll see. So again that's a rod shape type bacterium so that's 1000 times magnified.
Another technique that people have used for quite a long time is one where you use electrons in an electron microscope, which is a big machine - basically you take bacteria, slice it up with a machine so that it's tiny slices and you can have a look at it side on, so this is a rod shape that you've sort of cut side on. This is magnified 10,000 times. To give you a better idea, if you take a household pin which is magnified quite a few times and then you look at the bacteria on that, you can only see them when you magnify it enormously and then you finally see the rod shape there. This is using scanning electron microscopy. So that just gives you a sense of how little they are.
They're also diverse and I've got a few more friends down here as well. So here we have a rod shape, TB, bacillus, clostridium. This is E. coli - looks a bit like a rock star with long hair but basically it's a short rod and it has little appendages called flagella. Bacteria have lots of little appendages to help them swim and sense things, move around and attach to various surfaces. This is a spiral shaped one. It's called campylobacter jejuni or campy it's known for short. It causes diarrhoea, particularly in infants - and this is our famous super star, so it's called MRSA or Superbug and it's a cocci, so you can see all these little bits. It forms little clusters of round cells, so this is a spherical one.
The shape is actually really important for bacteria as to how they causes disease as well as how they survive, so basically that just is a diagram of those things but I think the fluffy versions are much more interesting. So bacteria are fascinating. They've been here longer than any living thing on this earth. They've been here for three to four billion years. Humans have only been here for a few million years so they're 1000 times older than us and they live everywhere. Most people associate bacteria with infections or dirty germ things. Most of them aren't like that at all and they're already here. They've been here for billions of years. Don't ever think about getting rid of them. The reason for this is because we need them.
I got this slide from someone - Bo Barker Jorgensen is an ecologist/marine microbiologist. We've known for quite some time now that there's about [six by 10 to the 30] bacteria that exist in the world. Where are they? And what of course we thought was that all of them would be above the surface. It turns out that now with the advent of being able to sequence whole communities of bacteria and using things like oil drills to get right down to the seabed and below the soil, that most of the bacteria, in fact 90 per cent of the bacteria, live underneath the surface down to about 500 metres.
Until we had the technology to sequence that DNA we had no idea that there were so many there. It turns out that that's a third of the earth's biomass, okay. Biomass is important because it provides life, okay. The other thing - this is a very complicated slide, but all I want you to do is know that this is basically the flow of energy and materials in the living earth and what you can see with these round, these red rings is this is all microbe activity. So the sediments that release all these different elements, you've got all these different reactions going on, photosynthesis providing oxygen and most of it is done by microbes - a lot of it by bacteria, not all by bacteria but a lot of it by bacteria - so you can see how important they are.
So simply, they make half the oxygen we breathe. They provide 80 per cent of the nitrogen that we use where we ingest amino acids and proteins. What they're capable of doing here is providing, taking the nitrogen in a gas form - 80 per cent of the nitrogen is in the gas form - and bacteria are responsible for putting that into a solid form because we can't use it as a gas form. They are necessary for digestion of some foods in our gut. They provide protection, for example skin bacteria; there was a paper just the other day saying that the skin bacteria that live on our skin provide protection to stop our skin from becoming inflamed.
They're pollution busters as many of you would know, they're used in waste water treatment and bioremediation to convert toxic materials into materials that are safe for us to be exposed to. They're found in food. These foods aren't essential for our survival, but they're very nice - and I didn't know they were involved in chocolate but the fermentation process is used for separating the cocoa bean from the pod - and biological factories, so they're used to produce things like vitamins and they're used in bio fuels of course. So I've convinced you that they're essential for us and we'll never get rid of them.
So the other thing is that I said they live everywhere. They can live in very hot thermal vents. They can live on ice. They can live where there's not much oxygen or none. They can live where there's high salt, low pH, all sorts of places - and humans are one of their environments. Not all bacteria live on us but there are certain ones that do. There are more bacteria on a person's hand than there are people on the entire planet. They're just everywhere. They live on us so on our skin and they live in us. They produce 100 times more protein in our body than human cells do, so most of our cells are actually microbial cells and the stuff that we produce, all the molecules that we produce, is mainly microbial.
So only a very few types of bacteria cause disease and you would be familiar with a lot of these, so there's really not an accurate estimation of how many cause disease but certainly a lot less than one per cent and probably fractions of that. So from the air, tuberculosis I've mentioned a few times and meningitis; from insects, lime disease is an emerging disease started off in Connecticut from a tick. It's transferred to humans by tick bite, from direct contact. Anthrax you've heard about before. It's not that prevalent in humans but it's obviously in the news a lot as used in bio warfare or possibility to be used in bio warfare.
Leprosy is still very much with is in the developing world. It's caused by something similar to the organism that causes tuberculosis. Food and water, recent cholera outbreak in Haiti. It's caused by an organism that's usually living in the water. It's the most abundant marine microbe and every now and then it gets a gene that causes this pandemic, okay and I'll talk a bit about how it gets that gene. Typhoid - and from our skin and a lot of us, anyone who's had surgery would know that the risk of wound infections is significant and if you've been in the garden and you cut yourself or put your hands in the soil when you've had broken skin, that that's where you might get infections as well, so they're very common.
So how do bacteria cause infection? I just put this slide in just to really complete the story. So bacteria attach to a host and colonise, so they multiply and establish. You may have heard that sometimes we have colonisations of staph aureus in our nose - it's called nasal carriage in hospital terms. They just sit there. They're not really doing any harm, but they're there and it's important that they're there because if they get an opportunity to go somewhere where they shouldn't go or the immune systems compromised, they'll enter cells and tissues, end up in the circulatory system. That's where they grow and multiply causing infection very quickly.
They can produce toxins that alter the host cell and its functions and then they can invade the host defences and spread around the body. Bacteria are capable of putting coats of armour around themselves in molecular terms and preventing our immune system from seeing them. They have all sorts of molecular ways of doing this. The reason they have all this is because they've been around for four billion years. They've done it outside our body. They do it with plants, they do it with bees, they do it with all of them. So the important concept to know here is that every organism has a defence mechanism of molecules.
So bacteria have already used a lot of defence molecules before and that becomes important later. So why aren't we all infected? We've got staph aureus on our skin. Why aren't we sick? What are we doing here? The reason is because they need to be. They're on our skin and they're very safe on the skin, so we have an immune system. That keeps us healthy in many ways. It keeps bacteria from getting out of whack so you've got a whole lot of different bacteria in your body and on your body. The immune system is there to make sure that one type of bacteria doesn't start to multiply and go out of control.
The other thing that's happening though is that the human body is an ecosystem, so as much as you've got bacteria on a coral or on a sponge in the marine environment, that's what we are. We're like that marine environment. We have an ecosystem of bacteria, fungi and viruses inside us and in fact the human microbiome project was started a few years ago with lots of money from lots of different countries because it's important to know what we have in us. Our health relies on that good ecosystem.
So the populations of micro-organisms inhabit specific regions of the body. You have staph on your skin, it's not in your gut in general and they keep each other in check, so the immune system keeps them in check and they keep each other in check. So infections occur when our immune system is compromised in some way, so we have a disease where the immune system is weakened. Age will do that as well, just getting older will decrease the function of your immune system. Diabetes will do that, lots of things will do it; chemotherapy and a lot of interventions actually.
When other mechanisms are less functional, cystic fibrosis is an example where it's a mutation that causes a lot of liquid to reside in the lungs, so it changes the environment of the lung and this enables an organism called pseudomonas aeruginosa. It likes that environment so it goes down there, it forms these biofilms and it causes infection so when you change - it's just like the marine environment or wherever, outside our body - if you change that environment you're going to get an upset balance and you're going to get an infection.
Bacteria introduced into an area of the body that they don't normally inhabit, so if you have surgery and some of your staph from your skin get into the wound; you have a catheter insertion, some of the bacteria that are in faecal material may get inserted accidentally, so that's where they're introduced to places they're not normally found is where you'll get an infection. Eating contaminated food or water of course, normally that wouldn't be in our body or at least it's such a high inoculum. If it's contaminated we get a nice dose of it, so it's like inoculating yourself with the disease, with an infection.
So I probably don't need to go and tell you that really bacterial infections were the major cause of child and infant death, as well as adult death but particularly in children and infants, before antibiotics. And really it's still hailed as the miracle of modern medicine, the biggest miracle and it was really discovered in 1928 by Alexander Fleming and, as usual, a lot of discoveries in science occur just by somebody being very observant and curious about something. A person who saw that after taking a holiday he had staph aureus on a plate and the fungi were on the plate and realised that the staph was sort of cleared where the fungi was growing.
It turned out that the fungi was producing penicillin which was killing the staph aureus on the plate. Those antibacterial properties were demonstrated by Howard Florey. He's an Australian person and in 1943 there was mass production of penicillin and there's a few Nobel Prizes for infectious diseases treatments, discovery of treatments for infectious diseases. This is one of them, 1945, Fleming, Florey and Chain won the Nobel Prize. So what is an antibiotic? Okay, it's from the Greek word anti, meaning against, and biotic, fit for life okay, so it kills life. I've just read a book called Tuberculosis, a Story Never Told. It's fantastic for learning about scientific discovery and why the problem of antibiotic resistance is so big right now.
It talks about lots of different scientists. Selman Waksman was a very bright soil microbiologist. In 1942 he coined this word antibiotic, any substance produced by a micro-organism that at low concentrations inhibits the growth of other micro-organisms. So initially antibiotics were molecules that were taken from bacteria that used them in their own defence, okay. That's a clue to why we have resistance now. So that's what he defined them as and he identified streptomycin. It was produced by bacteria in the soil called streptomyces. He won the Nobel Prize for that in 1952 and it was the first antibiotic effective against tuberculosis and saved many, many lives.
So in general they're small molecules that target larger molecules essential for bacterial survival. They're specific for bacteria and as I told you, bacterial cells are quite different to all the other - our cells, fungi, parasites, all of those, so that means that you can get small molecules that effect bacterial survival that don't effect in general our health or our survival and that's important. These days there are antibiotics that are - they're not all from bacteria so nowadays people can make synthetic molecules that might be similar to ones that are released by bacteria, or they can be other natural products from organisms other than bacteria.
So people use the word antibiotic to describe just any small molecule that can kill a bacterium pretty much. So what happened? Two words; antibiotic resistance. You hear about it in the news all the time so as I said, when people did discover - in particular I read about streptomycin with TB, scientists and people knew that there was resistance to it, that you could get resistance to it. This was known at the time and it was known at the time really with penicillin. This is a history and it goes over two slides of what happens over time with resistance coming about and when it says resistant staph or it's resistant to penicillin, what it means is it's recorded in a hospital and there are a number of cases - but what we did know at the very time there was resistance.
What we didn't - because you might then ask well why did you use them? Firstly, because people were going to die without them and they weren't going to die from the resistance. They were actually going to die from the disease. The second thing was - it's most important - is that the enormity of the problem wasn't totally underappreciated that time. You realise at this time we didn't even know about DNA, so we had no idea how resistance came about, right. So we used them and I would still say that this is still the miracle of modern medicine. So they saved a lot of lives. They were used clinically in 1942, these penicillins - staph aureus resistant to penicillin. This is mainly mentioning staph aureus because it comes from a person who is illustrating this but there's a lot of other organisms involved here.
Tetracyclines which block - penicillins actually block growth of the bacterium. It blocks the elongation of the envelope of the cell. Tetracyclines block protein synthesis so how the cell makes proteins. It blocks this. Tetracycline resistance. You'll notice with some of these, for example, methicillin, you get methicillin resistance in the clinic pretty much straight away - so for all antibiotics you'll get resistance, okay. There isn't an antibiotic that you won't get resistance to eventually and here you have multi drug resistant TB. This is called vancomycin resistant enterococcus. They're just different types that you'll come across in the papers and perhaps you know people that have been infected by these.
So this is the story and it just keeps going. The other thing that's happening is that there are very few new antibiotics being discovered or being produced and I'll come back to this in a minute. Okay, so this is the problem; most of the antibiotics target four different pathways in bacteria, only four, because once they had a few and making lots of money and saving lots of lives we didn't need any more. Then, when some of the started not to work because of resistance, you could just modify those molecules just a little bit without spending too much time and too much money, then give them again back into the clinic. Well then you'll get resistance to those because they're not very different.
So that's why you'll see first generation cephalosporins and then there'll be second generation and third generation and that just means that they keep changing them slightly so that you keep ahead of the bacteria, but very soon the bacteria become resistant. Okay, so there's lots of these graphs. This is just one to say that there is a lot of surveillance going on in hospitals and by various groups funded by governments now, to show the increase in the incidence of antibiotic resistant infections. This is just in the US. It's to a particular drug to staph aureus MRSA, so a methicillin resistant staph aureus, in an intensive care unit and there is no question, no matter what data you look at, that those numbers are increasing significantly all around the world.
So it's a major world problem, so much so that WHO on its annual World Health Day this year identified that combating antibiotic resistance is one of the world's most pressing public health threats. The Australian Society for Microbiology President at the time in 2008, Keryn Christiansen, who is a physician at Royal Perth Hospital, has put out some quotes in The Age in 2008; Large numbers of people are dying from resistant organisms but I'm starting to wonder if you have to line body bags up in front of Parliament House to get any action. I think some action's happening now, but it's a problem because bacteria are invisible and because we really can't see it, I don't think people are aware of the enormity of the problem.
So for some organisms we have absolutely nothing in the antibiotic pipeline. We're not facilitating the development of any new antibiotics for these, so the drying up of the antibiotic pipeline is a major concern. These people see this every day in the hospitals. So why is there no antibiotic pipeline? So why aren't we producing more antibiotics? I said that antibiotics normally target four different pathways, only four. There's a lot more pathways than in bacteria. One of the reasons for that is it's very expensive to make drugs. It costs about a billion dollars.
From the very start to the end you really don't know whether you're going to get any profit from that at the end and now, as you know, there are drugs that we can take for cardiac disease. Viagra's one. You take them for a lot longer than you do to treat an infection, so there's a lot more money to be made from other drugs, not antibiotics, okay. So that's one of the major reasons and while I said there's first and second generation, third generation drugs, drug companies have been involved in doing that. They don't have to spend as much money, but to go right back to the discovery stage, all the way up 20 years later trying to get a drug, it's a big ask and if you're a shareholder of a pharma company you'll understand why.
It's a whole society issue, okay. Pharma has always made big profit and that's what their shareholders expect, so it's part of that issue of we need the whole of the community to really work on this issue together. So how does antibiotic resistance come about? For many years it was not really known how it came about, so bugs are very clever. They've been on this earth for a long time and they've always had their own defence mechanisms, so if you make an antibiotic from a bug that defends itself against other bugs, you're going to get resistance. So they've evolved these ways of doing things, so they make an enzyme that inactivates the antibiotic so it's completely inactive.
They change the target so they have ways of modifying the target so that that antibiotic can't recognise its target and get rid of it. They change the permeability, so they change the ability of that antibiotic to get access into the cell, so don't let it in. There's a lot of efflux pumps as well and they are pumps that exist for bacteria to get rid of things they don't like and they're pumps that pump out lots of different types of molecules so they just get rid of it before it can do any damage. I should say that some of the first antibiotic resistance genes that were identified are ones that actually act on disinfectants to pump them out, so disinfectants, biocides, different to antibiotics but they kill bacteria and bacteria has resistance to them as well.
The other thing is to bypass the function targeted by the antibiotic, so this sounds interesting but there's more and this is the real key to why it can happen so quickly and why it is quite frightening and quite amazing. So we didn't even know about genes when antibiotics were discovered. Then we knew about genes and a person who now works in I3 at UTS called Hatch Stokes, in partnership with Ruth Hall whose at University of Sydney, discovered that there is a way of which genes can move from one bacteria to another without reproduction so without division. They identified these what they call mobile genes and that was just the beginning.
There's lots of different types of mobile genes and they can carry all sorts of different genes - sorry, mobile - they're called cassettes and they can carry lots of different types of genes. So this is just a schematic diagram really, showing you that bacteria can exchange DNA, okay. So what this is called, it's called conjugation where this is an E. coli cell that sends out a little tube, a hollow tube to another bacterial cell that's, you know - it's the closest they get to sex and they transfer a piece of DNA from one guy to the next. That piece of DNA often contains antibiotic resistant genes, okay.
There's lots of different types of mobile elements that transfer these, so it can happen in minutes, so you don't need to multiply. You can just transfer it, so even if you add something that stops bacteria growing they can still do this. Okay, so in the meantime Hatch and Ruth and a few others around the world have done a lot of studies on these mobile genes and it turns out that first of all it doesn't require cell division, so they just don't have to reproduce to do it. The second amazing thing is that they can carry multiple antibiotic resistance genes, so four, five, six, seven, eight, nine, whatever, okay, so lots of them together.
The other thing that they do is they can transfer them between species, so you have a staph infection. You treat it with vancomycin. The staph then transfers its mobile DNA to all the other staph in the vicinity. They all become vancomycin resistant. That can also transfer to enterococcus so you don't even have to treat for an enterococcus infection to get it in there. Then someone comes in with an enterococcus infection and it's vancomycin resistant already, so that's why in those graphs things are going up so quickly, because these bugs have the ability to do this.
So the way in which bacteria actually evolve is partly through cell division and inheriting DNA to the daughter cells and so on, as happens with us. But now they have an ability to transfer all sorts of DNA. It's not just the antibiotic resistance, there's a whole lot of different sorts of DNA so it's all mobile. One of the major ways in which they evolve is actually through this lateral gene transfer, so it totally changes how we look at how bacteria has survived on this earth for so long and how we address the issue of antibiotic resistance.
So just to give you an idea of the antibiotics in the biosphere; there is not a bacterium in the world - there's not a colony or a pool of bacterium in the world that doesn't have antibiotic resistance. Because we've used so many antibiotics, particularly in agriculture, often for prophylaxis but also for growth promotion, we've used them for therapy and prophylaxis in humans and, of course, in plants. They go everywhere, so you can go to somewhere, a pristine environment where you have a tribe of humans who have never travelled anywhere and you test that water in the lake and you will find antibiotic resistant bacteria, so there's no getting away from them.
So what is a Superbug then? It always comes up in the paper. It's more a sort of a media term, but what it means is that it's acquired a whole lot of resistance genes through those mechanisms that I was talking about. It's associated with increased mortality and rate of incidence and there's a potential for untreatable infections. This is what a lot of the media stories are about, so you would have heard of multidrug resistant staphylococcus aureus. The MRSA really stands for Methicillin Resistant Staph Aureus, but what it means is that that bug is resistant to a lot of different antibiotics and it's in hospitals.
Now initially we just thought it would be hospital acquired. Why would it be found in hospitals? Because we use antibiotics in hospitals a lot, okay. We need to, but we also, because there are so much of them in hospitals and because we didn't think there was such a problem we used a lot of them. That means that all the bugs in the hospitals are transferring all these antibiotic resistance genes everywhere, so they're all there. Now they've come into the community as well because a hospital isn't a closed system. So initially they were found in hospitals, however it's now a thing called Community Acquired Staph Aureus and that is called that because you don't have to go to hospital to get it, okay.
They're mainly skin and soft tissue infections, so this was Centre for Disease Control in the US, this is found on their website. You may have heard that the grid iron team, there was a problem with Community Acquired Staphylococcus or MRSA infections here. They happen more when you've got lots of people together and personal hygiene may not be as good as it can be. Also you will find a lot of Community Acquired MRSA in indigenous populations in Australia and other countries, or in certain situations where people do not have access or the same level of hygiene that other people will have.
So you can see the importance of - apart from the obvious humane importance - of making sure that people in the world are healthy and have a good standard of living. So Community Acquired Staph Aureus was actually identified first I think in Western Australia in the 1990s, thanks to some good groups over there who actually did a lot of surveillance to see where it was coming from, because they suddenly found it in the hospitals and were quite alarmed by it. So you don't have to go to hospital to get resistant infection.
You would have heard of MDM1, which is the New Delhi metallo beta lactamase - don't have to know about the name, but basically that is a big problem because this gene is being transferred between organisms that are resistant to everything but one major antibiotic and the Indian one, it's actually a gene which encodes something that destroys this one antibiotic. So if all the normal safest antibiotics that doctors would use to treat these infections, all of a sudden this major one wasn't working. So this is a case where they're resistant to more antibiotics than any other situation, okay and some of them were resistant to everything of course and some people died as a result of that.
A multidrug resistant TB I've talked about already. Okay, so how many of us are reservoirs of antibiotic resistance genes? Well if I think I've told you enough now, it's 100 per cent. We all have them, so they're here. What can we do about it? So you might say well, game's up. I don't think so. You could say the same with climate change, but I think it's a similar problem in that it's something we don't really see every day. I think a lot of people have probably had antibiotic resistance or know somebody who's had antibiotic resistant infections, but it's not something we see. You don't always know what's going on, so what can we do about it?
First thing, in the 1930s washing hands was very important because we had no antibiotics. It's still the most important thing that we can all do, okay, because we - in some ways people just thought we've got antibiotics, we don't have to worry about disease, infectious diseases anymore and this is just not true anymore, so it's always a good thing to wash your hands - but very importantly to do that when you're touching animals as well and between patients. Obviously healthcare workers need to do this vigilantly and they've brought back the 1930s strict rules to do this, so this is again the Centre for Disease Control with the more modern advertisement of why you need to wash your hands.
Basically the washing, just the mechanical movement of hand over hand and you've seen how surgeons do it in movies if you haven't seen them do it in real life - basically just wiping off and getting rid of the high number of bacteria is the important part. Okay, so we need as I said strict control measures; isolation rooms in hospitals, washing hands. There's even a school Washing Hands Day this year or last year in Australia, so there's a lot of effort behind helping kids understand the importance of this.
Strengthen the global surveillance of resistant strains. We need to know where they are. We need to know the prevalence. We need to be able to type them, so there's lots of molecular studies that always goes on in hospitals and path labs to work out what sort of organism is this. Tom's part of this group. He's played a big role - Australian Group on Antimicrobial Resistance or AGAR started up quite a few years ago. They do a lot of surveillance. The Federal Government has supported them and they do this as a volunteer work so that they can just know what is out there, what's happening, because then they can change their - if they need to - antibiotic regimes, what they give patients and just be aware of what might be going on.
So manage the use and types of antibiotics; so there's a thing called Antibiotic Stewardship which means let's be careful in not overusing antibiotics and let's try to use the right ones. So when I mention that vancomycin before, you need to be aware if you're going to use an antibiotic to get rid of an infection of one type of bacteria, sometimes you can easily be aware of if you use that what might happen in the future. Are you going to end up having antibiotic resistance in other - the same antibiotic resistance in a different organism? So you can also use less antibiotics in agriculture and this has worked in Denmark.
The world's been pretty slow to move to this because it's quite a big change and of course agricultural industry is saying well we're going to lose money and this is the same with a whole lot of environmental issues, a whole lot of issues where one industry's saying but we're going to lose money but we have to make these changes if we're going to save our own lives. But I don't think we necessarily have to make agriculture pay for that. We have made sure that we all pay for that because it's worth it. So identify new treatments for prevention and treatment of infections by research and I'm going to give you a little bit of a flavour of what we're doing in I3 to address this issue.
So what are we doing about it at I3 at UTS? I just want to say that most of the discoveries for treatments for infectious diseases are from people that are doing basic biology, so Saksman was a soil microbiologist and he realised and other people that worked with him, they realised that if - they were ecologists and they realised that you have an ecosystem, bacteria and there's going to be some interplay between them to try and defend themselves, so they knew to look into the soil for streptomycin. So I think this is important because I think we need to go back to ecologists, we need to go back to basic biology again to say okay, now that we know about mobile genes let's try and find out what new antibiotics there are.
So I3 takes a basic biology approach. We're a group of people that know quite a lot about the organisms that become multi resistant and that cause problems with infections and we translate that to new drugs, so I'll just give you a few stories about how we do that. One of the reasons why Big Pharma are not creating new drugs as well is that people are now looking to academic researchers more and more because, because of our extended knowledge of the biology of the organisms we're able to identify new ways of killing bacteria - hopefully at the same time reducing the amount of resistance.
So one of the things I've worked on for a long time is bacterial cell division, so this is basically multiplication of bacteria. As you can imagine that's essential for infection. It hasn't been targeted before. There are no drugs out there that target division, so we need antibiotics with new modes of action clearly and this is just a simple diagram to show that normally a bacterium with one chromosome replicates that chromosome. They get segregated and you get a division and one of the key molecules that's involved in determining where bacterial cells divide and when they will do it is this thing called - it's a green ring and it's a green ring of a protein called FtsZ.
What my lab works on is how the cell knows to regulate this process, because if you dis-regulate this process then you can cause cell death. So basically what we discovered was there was a connection between this process of replicating the DNA and segregating the chromosomes and actually laying down this division ring. So we identified some molecules that we could develop antibiotics that would affect this process and make a ring form over the one chromosome, so make it form too early in which case you'll have two daughter cells with half a chromosome each and neither of them will survive.
So mucking up this process of their multiplication is really what we wanted to do and we've moved on to working from rod shaped cells to the little round ones, the staph aureus. What you can see here is we use a lot of microscopy so bacterial cells have proteins inside them. They are very organised in terms of proteins and where proteins go, so this is showing you a z ring. If you look at it in two dimensions you'll basically just see a band. What we can do with this type of microscopy - it's called fluorescence microscopy - this is a protein that's been labelled with something that actually fluoresces if you shine a particular light, a type of light on it, but it doesn't give us a lot of information in a round cell because it's hard to sort of look around it, yeah.
So UTS has bought this very expensive, very impressive microscope which shows us a level of resolution that we've never had before and it shows it in 3D, so for round organisms that are sort of one micron in diameter you can actually see that the ring is far easier to have a look at and you can have a look at it in a lot more detail. So this microscope is housed in the I3 institute over at the science building at UTS, so what you can see here is that the cell's moved around and you can actually just have a good look at it. This is the first time we've actually been able to take a bacterial cell and sort of turn it around.
So this is one protein. We can do this with lots of different proteins and we're just submitting a paper on this at the moment to show that this particular protein has a very discontinuous appearance. Now that may not mean much to you, but to us it tells us how this protein might be actually working to cause division and there are other proteins that join it. What we're now looking at is trying to identify where those proteins actually go relative to this one. So it gives us a bird's eye view finally and what we want to do with this is that if you are looking at any antibiotics that are affecting proteins inside cells, one easy way of looking at how the antibiotic affects those cells is how it affects where those proteins go.
That's just another window of opportunity for us to look at and as I say, there's lots of projects in I3 where we're collaborating with people outside the university as well, one on malaria where they've actually identified new structures of the malarial parasite that have solved some mysteries about how it causes disease as well. So we're also doing a drug screening program to target Superbugs, starting with MRSA, going on to all sorts of other types of organisms and because we are biologists we're going to follow that up with determining how those drugs work and then developing those compounds into proper drugs.
Obviously when we identify these compounds we'll also be looking at commercialising that and working with companies, biotech companies and Big Pharma, who are interested in doing that with us. Bacterial biofilms are a big problem and if you know anyone that's had recurrent bacterial infections it's no doubt due to a bacterial biofilm. I'd like to just talk a little bit about this and the fact that they are antibiotic resistant by nature and there's a lot of work done by Cynthia Whitchurch and Lynne Turnbull on biofilms. I also just want to tell you a little bit about Manuka honey which has been advertised in the papers, so I must tell you about that new work.
These are different ways, so we've got drug screening, we've got looking at biofilms as another way of killing bacteria from antibiotic resistant infections and we've got another way in which we're looking at something completely different. We're not looking at an antibiotic anymore, we're looking at honey which is a solution - like wine, there's a lot of different things in it and the secret to its success is really the fact that it's very complex. It's not just one compound, so biofilm - this is a very schematic diagram, but basically bacterial cells mainly live in communities, so very few of them live sort of freely swimming around.
For years - and still this is how we study them, because it's easy to do so and you can do certain experiments with free living bacteria - but most of them live this way, in our body, in drains, on boats, in showers, wherever you find a surface you'll find them. So what they do is they swim around, find a surface, attach to that surface, make a bit of slime, extra cellular material and build a scaffold basically. This is their way of bunkering down to protect themselves. They can protect themselves from the immune system and from antibiotics, so you have to add a 1000 times more antibiotic to a biofilm to actually kill the cells and in fact that's not practical to do so when you have an infection in the body.
What happens then to finish this cycle is that they detach, then you get free living forms again and so if most of the infection is in the biofilm like if you've had a catheter inserted or a pacemaker or whatever else, you can have a biofilm forming on that. Every now and then some free living bacteria will leave it, form an infection or you'll get high blood counts of bacteria. You take antibiotics, it dies down, the biofilm is still there, bacteria come out again, move around the system again, you take antibiotics, it goes down again. Some people take antibiotics all their life because this is what happens.
So how do we deal with that? Okay, so they're everywhere as well, but medical biofilms of importance here; they're thought to cause at least 80 per cent of infections. Implants, medical devices, they're persistent infections as I've just described and they're found in chronic wounds which in the aging population particularly is a big problem and also with diabetes sufferers. They're recalcitrant to antibiotics and the immune system, so all this time we've been dealing with antibiotics we haven't really addressed the issue of biofilms and so at I3 Cynthia Whitchurch and Lynne Turnbull have - they study a lot of different things, but basically one of the key organisms they're interested in - pseudomonas aeruginosa - I described that that's involved in cystic - well, it's a problem in cystic fibrosis.
These people with CF suffer from these infections in their lung and the reason for this is they form these amazing biofilms and I'm just about to show you a movie of this. So this is a movie that Cynthia and Lynne have put together and what you can see here in red is the bacteria. The green is actually DNA so they've stained the DNA with green and what you can see if I show this again is that the cells are travelling in a sort of a pattern around and every now and then you'll see these bright bits of green. Where you see those, they've observed that the cells move quite quickly along that and it turns out that this is extra cellular DNA, so Cynthia was really the first person to discover this and showed that that extra cellular DNA was essential for biofilm formation.
It now turns out that extra cellular DNA's essential for biofilm formation in pretty much all bacteria, so they use it as a scaffold. So you've got somehow these bugs producing this bacteria and laying it down for other bugs to move along. Again, quite a surprise; just studying, pure curiosity, leads you to these discoveries. DNA's released from cells. It provides an opportunity for preventing biofilm formation by adding an enzyme that actually cuts DNA up called DNase, so that's a way in which you can just make a basic biology discovery and come up with a new way of treating patients.
Okay, the final story I'd like to talk about is the honey story. We're now going back to a pre-antibiotic era. There is no question about it and before antibiotics were discovered there were lots of different things that people used for infection of course, some with mixed success. Honey has been used since the dawn of time. You will see drawings of Egyptians that have beehives and things, who've used it for a long time, mainly topically okay. It kills all bacteria and even the resistant ones, so I've been involved in some of those studies at Sydney University but there's a lot of studies showing that honey has potent antibacterial activity.
It can kill bacteria that have up to 14 resistances. We've done those experiments. Not just any honey works, it's all sorts of different honeys like there are different wines and so it's important to know. You can go onto the web and find out a little bit about the different types of honey. Manuka honey is quite special in that it's quite potent and a lot of studies have been done on it, a lot of chemical studies have been done on it and it's available as an approved dressing in Australia and in the USA and the UK and a few other countries now. It's very successful. I've talked to many people that use it. They like it and it does work, so they are a very good wound dressing.
It's ideal for chronic wounds that don't go away, so one of the reasons they don't go away is because you've got bacterial biofilm sitting in there and they don't go away. They smell. They are debilitating to people. Many people have them in the population and sometimes they will threat - obviously with diabetes sufferers you'll have an amputation as a result of a chronic wound, okay. So they're important and the only issue with them is that they're under-utilised, so often you'll read - I get emails. I got an email today where a person had diabetes. Her sister had diabetes. She's had it since she was eight - she's now 69 and she nearly lost her leg. The last resort was honey.
Someone just said maybe we should try honey. You hear that again and again and again and you think gosh, I wish they'd have tried it 30 years ago when this woman still had chronic wounds. So it's under-utilised. So how do we make it more utilised? We know it works in the clinic. One of the things is that every time we mention it to people they say but how does it work? Until we have some more data about how it works it's going to be difficult to get people to use it more often, so this is just an example of where antibiotics didn't work.
An 88 year old woman, a horrible open wound. It's very painful as well I should say. Five weeks with honey, lots of closure there. Honey doesn't just get rid of the bugs but it also helps in debriding the wound. It's thought to help with immune system boosting and also decreasing inflammation and there's some molecular evidence coming out for that - and in 10 weeks it's gone. So this is work funded by Australian Research Council. It's a linkage grant where the Government puts in quite a lot of money and a company called Comvita in New Zealand who make these dressings also put in some money, because they're interested in the science of it. They understand that that's important for people to know and for people to use it.
So no one knows how honey kills bacteria really. Until the last two or three years we didn't really know a lot of the components that were involved in killing them, so what we did was a big study - and I'm just showing you one example where if you have no honey, which is this dark blue curve on the left here, the cells grow up. They have a lovely exponential phase and then they always go into a stationary phase, so this is normal this blue curve. So what you do is you add increasing amounts of this Manuka honey. You go from blue to the green, to the pink and then you don't get any growth at all.
So if you increase the level of honey up to about something like eight per cent the cells will stop growing and you see this with a whole lot of different bugs. What we also see - and it's a bit hard to see this with the lights - but basically this is staph aureus. What's normal is that we've stained the DNA with red stain here. They're a round cell and what you might be able to see is there's two blobs. When you add the honey to these guys - and this is taken from the pink curve - you can see that the cells are a bit smaller. There's just one blob of DNA there and there are a few different theories as to why this is happening.
One theory is that you don't have DNA replication and another theory is that it's preventing the cell making protein synthesis because this is something that happens when cells don't make protein. So this is the first real evidence of an effect of honey on bacteria - just looking at them. So of course what we want to do now is find out what's actually happening. Now we've just finished a yearlong study that looks at 10 different chemically defined honeys. Almost all studies in the literature have used honeys but they don't tell you what's in it or what levels and they're all different, so you need to know exactly what's in them and what levels.
So the question was how do these different honeys affect bacterial cells and their growth? So we looked at 10 different honeys, four different bacteria, pseudomonas, staph, an E. coli and a bacillus type organism. The bacteria responded in different ways to the multiple components of honey that prevent their growth. What that means - and there was lots of data, about 160 growth curves, lots and lots of photos - basically it means that the bacteria are probably stressed in different ways. It's clear that they're being stressed and unlike an antibiotic that acts on a lot of different bacteria, that does the same thing to all those bacteria, it appears that honey not only has multiple components but it also acts on those bacteria in different ways.
So methylglyoxal is a component of honey. It's very effective on staph. It's not as effective on pseudomonas, but there are other components in honey that are more effective on pseudomonas. So what this suggests to us is that it's unlikely that a common mechanism - there's a common mechanism of resistance. Antibiotics work one pure compound - you're going to get the same gene for resistance for one organisms going to be the same for another, okay, so you get lateral gene transfer of that and they get resistant. With honey it's unlikely to be a common mechanism, so the mobilisation of resistance genes is probably not going to be an issue.
So even in the long-term, using honey on wounds, if it works to help the person lead a better life or helps save their leg or life, fabulous. The second thing is to think of lives in the future and I think that if you're not getting resistance to it then that's a good start, but it's only to be used for wounds and topical things. That's the important part. Okay, so bacteria are good for you. Very few are bad. Superbugs are very smart. Can we outsmart them? Not completely, no, but I think we can be much smarter than we are now.
Antibiotic resistance is an urgent issue. Yes, we can all do something about it. There are lots of resources and prevention is better than cure - so hygiene is really important because you won't get anything in the first place if you're careful - to some extent. So thanks to you for being so attentive, so thanks very much.
24 August 2011
Bacteria have been in existence for over three billion years. They will probably outlive the human race, and they support life on earth, yet we know very little about them. They usually come to our attention in dire circumstances with major repercussions on human health such as an outbreak of MRSA or the new super bug, NDM-1!
The miracle of human medicine occurred in the 1940s with antibiotics being used to treat infectious diseases and saved thousands of lives. However, with the alarming rise in antibiotic resistance, we can no longer rely on current antibiotics to successfully treat many fatal infectious diseases. The emergence of new bacterial strains such as the 'New Delhi metallo-beta-lactamase' (NDM-1) and MRSA has meant that they are resistant to almost all kinds of antibiotics; with little progress production of new antibiotics to treat these infections. Why?
Test Tags: biomedical science, bacteria, superbugs, antiobiotic resistance
About the speaker
Professor Liz Harry discusses the secret lives of bacteria. She explains the vital role that bacteria plays in sustaining life on earth; how some of these tiny unassuming creatures cause serious disease, what antibiotic resistance is, what we can do about it, the challenges facing science in reducing antibiotic resistance, and the latest research that is being done to find solutions to this serious threat to human health.
Liz Harry is principal researcher with the UTS iThree institute. After completing her PhD at the University of Sydney, she went to Harvard University as a postdoctoral fellow to revolutionise our understanding of bacterial cell structure by pioneering fluorescence microscopy techniques to see the location of proteins in bacterial cells.
After returning to Australia, Liz became an Australian Research Council Postdoctoral Fellow and then an ARC QEII Fellow at USYD before coming over to UTS. Liz works with industry to develop novel antibiotics targeting the process of bacterial cell division. In 2002, she was awarded the Australian Eureka Prize for Scientific Research, and in 2008 the Australian Society for Microbiology Frank Fenner Award.
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