ANTHRAX, botulism, cholera, meningitis, diphtheria…some of our worst illnesses are caused by bacteria. And until now, modern medicine’s answer has been to try to obliterate them. We zap the bugs with a chemical blitzkrieg of antibiotics. We breach their cell walls with penicillin and foul up their metabolism with streptomycin. Whatever the chemical, we show no mercy.
This has been our standard approach for the past century. But it is not going to work for much longer. Bacteria are increasingly developing resistance to antibiotics – one the greatest threats to health today. So perhaps it’s time to try a completely different tack. Instead of trying to kill bacteria, some scientists claim we should be trying to talk to them. We don’t need to eliminate disease-causing bacteria from our bodies, they say,just make peace with them. If it sounds crazy, it is because the new way of dealing with deadly bacteria tears up the rule book.
Blasting bacteria with antibiotics is certainly no longer a cure-all. Around the world, microbes are winning the fight against the standard antibiotics we use to tackle illnesses such as pneumonia, wound infections and tuberculosis, and the only option is to roll out drugs previously kept in reserve for more serious conditions. And resistance is even starting to emerge to some of these “last resort” antibiotics – much faster than we can develop new ones.
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This worrying trend occurs because one or two bacteria in a genetically diverse population may be able to withstand assault by a particular antibiotic. As the rest of the bacteria die off (or, in the case of some antibiotics, are stopped from reproducing), the impervious individuals multiply, passing on their genes for antibiotic resistance. Soon the drug is useless against the patient’s infection. All antibiotics that either kill microbes or stop them reproducing inevitably “select” for resistance in this way.
The solution, according to some microbiologists, lies in developing a completely new kind of drug – one that takes advantage of something called “quorum sensing”. First studied in relation to marine bacteria as long ago as the 1960s, it is only now being investigated in human pathogens. It could well change our whole approach to infectious disease.
Quorum sensing is a chemical signalling mechanism that bacteria use to find out ifthey are by themselves or one of a crowd. Each individual secretes into the environment a low level of a certain chemical, for which it has surface receptors. The more bacteria that are around and pumping out this chemical, the higher its local concentration and the more the cell surface receptors are stimulated. Lots of receptor activity means you are with lots of your mates.
The “quorum” part of the name reflects the bacteria’s need to be present in sufficient numbers to make it worthwhile to behave in a particular way, just as a political meeting needs to be quorate to take decisions. The decision bacteria need to make is whether or not to turn virulent.
Nearly all disease-causing bacteria have Jekyll-and-Hyde characters. In their benign mode, they keep a low profile and do us no harm. But when enough of them get together, as gauged through their quorum-sensing systems, the bacteria snap into virulent mode, and start attacking their host.
Bacteria benefit from ganging up for the assault because their virulence provokes an increased response from our immune system. White blood cells will gobble up bacteria, given half a chance, or secrete lethal chemicals that break down their cell walls. If only a few bacteria are present they will be polished off swiftly. But if there are enough of them, they may be able to overwhelm their host’s defences by sheer force of numbers.
This is surprisingly sophisticated behaviour for such seemingly simple life forms, but it makes good strategic sense. “If your army’s going into battle you need to know your numbers,” says British-based researcher Paul Williams, an immunologist at the University of Nottingham who is one of the world’s leading researchers on quorum sensing. An army should only mount an attack when it is strong enough. If it is too weak, it will do far better by lying low and waiting for reinforcements.
The practical significance of quorum sensing is its promise of an alternative way of controlling microbes: not killing them, but lulling them into a false sense of impotence. There may well be enough bugs to launch an attack, but if they don’t know this because their lines of communication have been jammed they will simply sit tight. A rampaging army is transformed back into a peace-loving community.
Because this approach doesn’t rely on killing bacteria, you might imagine that the infection would take off again once the drug is withdrawn. But initial research is suggesting that quorum-sensing blockers will often buy time for the host’s immune system to see off the invaders by itself.
The real beauty of quorum-sensing blockers, though, is that because they don’t kill bacteria, but just disrupt their signalling systems, they should exert very little “selective pressure”. The blockers won’t polish off vulnerable bacteria and leave a few resistant ones to take over and eventually defeat the drug. Bacteria that happen to be resistant to a particular blocker probably won’t have much advantage over their peers, and so should be less likely to predominate within the patient. Quorum-sensing blockers could be one new class of antimicrobial drug that lasts for a long time to come.
No compounds have yet been tested in humans, so it may be 10 years or so before any new medicines reach the market. But the potential is enormous. Some experts believe that nearly all disease-causing bacteria use some kind of quorum-sensing system to control their virulence.
Interest in quorum sensing has had a slow burn. It first surfaced in the 1960s in relation to bioluminescence, after the observation that certain marine bacteria would only start to emit their faint eerie light once they had reached a minimum population density (żěè¶ĚĘÓƵ, 4 March 2000, p 8). Some 20 years later researchers noticed the role of quorum sensing in plant diseases (żěè¶ĚĘÓƵ, 13 May 2000, p 34). Only more recently has quorum sensing been touted as a way of treating human infections.
One of the organisms on which Williams’s Nottingham research group has focused is Staphylococcus aureus, the organism responsible for many wound infections and cases of blood poisoning in hospital patients. It’s a big problem.In England alone, hospitals report about 18,000 cases annually.
The long-standing war against this bacterium illustrates the declining potency of antibiotics. For many years the standard treatment for S. aureus infections was penicillin. Then, as resistance to this drug kicked in, doctors had to use the newer antibiotic, methicillin. But strains of methicillin-resistant S. aureus (known as MRSA) are increasingly rearing their ugly heads in hospitals around the world. In Britain, for example, the proportion of S. aureus infections resistant to methicillin rose from 5 per cent at the beginning of the 1990s to 42 per cent by the end of the decade. As a last resort, doctors tackle the superbug with vancomycin – but last year saw the first case of MRSA resistant to this antibiotic too.
One of S. aureus’s quorum-sensing chemicals is an oligopeptide, a short string of amino acids. Williams’s group has investigated three different ways to disrupt the signalling system: interfering with oligopeptide production, breaking down the oligopeptide, and blocking its surface receptors. They have made the most progress with the receptor strategy route. Chemist Weng Chan, one of Williams’s colleagues, has produced a modified version of the oligopeptide that binds to the receptors without activating them. Add this to S. aureus in culture and it stops producing at least two toxins that contribute to its virulence, confirming the potential of this therapeutic strategy (Molecular Microbiology, vol 41, p 503). The group now plans to test the receptor blockers in animal models.
Despite the apparent promise of this approach, Williams has had limited success in persuading drug companies to invest in his research. One reason is that most of the quorum-sensing systems discovered are species-specific, so any new agent developed would work only against that type of bacterium. And paradoxically, the chief advantage of quorum-sensing blockers – that bacteria are pacified rather than killed – is also an obstacle to wider acceptance. “What the pharmaceutical industry wants,” says Williams, “and what most clinicians want, is an antimicrobial agent that kills everything, and kills it right now.”
Where big pharma fears to go, small biotech firms are usually willing to tread, and it’s this type of company that has been forging ahead in quorum sensing. The Munich-based firm 4SC started working in this area 18 months ago. It is targeting the bacterium Pseudomonas aeruginosa, which causes disease in several ways, including infections of wounds, burns and implanted medical devices such as heart valves. Another vulnerable group are cystic fibrosis patients:one of their main health problems is lung infections with P. aeruginosa.
This bacterium uses quorum sensing to gauge when it is present in sufficient numbers to form a biofilm, a slimy layer of polysaccharide that glues the microbes together and protects them from the onslaught of the immune system’s attack (żěè¶ĚĘÓƵ, 31 August 1996, p 32). New biofilm can’t form if you block the quorum-sensing system and existing films break down.
Still under wraps
The quorum-signalling molecules P. aeruginosa employs belong to a family called the acylhomoserine lactones. 4SC has identified three classes of chemical that interfere with the system. With patents not yet granted, the microbiologist in charge of the project, Aldo Ammendola, won’t reveal anything of their structure beyond saying they are small and “not peptides”. But he is confident of their effectiveness and their safety. “We’ve tested them not only in bacteria but in mammalian cells,” he says. “They work and they are not toxic.”
P. aeruginosa is a common target for quorum-sensing researchers. Mike Givskov, an associate professor at the Technical University of Denmark in Lyngby, is working with quorum-sensing blockers based on furanones, compounds that an Australian seaweed uses to stop bacteria overrunning its fronds. In studies yet to be published, Givskov has tested furanones in mice whose lungs are infected with P. aeruginosa. With their virulence suppressed, the bacteria become vulnerable to attack by their host’s immune system. “When we treat them for just four days and then check their lungs seven or eight days later, we find that they have successfully cleared the bacteria,” says Givskov.
To protect a burn or suppress other wound infections caused by P. aeruginosa, treatment could stop once the tissues healed. But cystic fibrosis patients, by contrast, might need treatment for life, so the quorum-sensing blockers would have to be relatively free of side-effects.
From lab tests, Givskov and Ammendola see a case for combining quorum-sensing blockers with antibiotics, which could then work faster and at lower doses. “Pseudomonas in humans often grows inside a biofilm because this is the only way it can survive the actions of the immune system,” says Givskov. “Our furanone compounds seem to soften the biofilm, and this allows the antibiotics to penetrate it and reach the bacteria.”
Lingua franca
Drugs such as these could well revolutionise the way we treat certain diseases – at least, the ones caused by bacteria whose quorum-sensing systems have been characterised. But one group of researchers recently made a breakthrough that has implications for all bacterial infections. Bonnie Bassler of Princeton University in New Jersey has discovered a single quorum-sensing system that she says many different species use, perhaps even all of them. “Bacteria can speak in multiple languages,” she says. “They have species-specific languages, and they have a general language, which we think is universal.”
Bacteria use a signalling molecule termed autoinducer-2, or AI2 – and possibly others like it – to monitor the presence and number of other species. “It’s not good enough only to be able to count yourself,” Bassler explains. “You have to be able to count everybody else who’s around.” This is because the activity of other species could be one of the factors that decides whether or not it is time to switch on the virulence genes. “If you’re an intestinal pathogen and you make the transition from an outdoor puddle into someone’s intestine, you are surrounded by zillions of other bacteria,” says Bassler. “This will tell you that you are inside a host.” It is through AI2 signalling, Bassler believes, that many species decide when to turn nasty.
A year ago Bassler’s team announced they had determined the structure of AI2 (Nature, vol 415, p 545). Unusually, the compound contains boron, an element rare in biological molecules. So far, AI2 systems have been found in about 50 species, including some of our deadliest foes, such as the bacterium that causes cholera and Escherichia coli 0157, which can cause severe food poisoning. Bassler says her team got more and more excited as the number of species using A12 began to mount up. “It was thrilling to realise what a role it could play in medicine,” she says.
Bassler’s success was recognised in October when she received one of the prestigious MacArthur awards, a no-strings-attached $500,000 research grant. Efforts to develop AI2-based antimicrobials will now be led by the biotech firm Bassler has co-founded, Quorex Pharmaceuticals in Carlsbad, California. The company has developed a compound that blocks AI2 receptors in the test tube, and another that inhibits the enzyme responsible for making it. For commercial reasons Bassler declines to give more details, other than to say animal tests should start “soon”.
The discovery of a universal language among bacteria, a sort of microbial Esperanto, has meant quorum sensing is now considered one of medicine’s next great hopes in the battle against infectious diseases. And as more and more of our existing antibiotics lose their potency, species-specific quorum blockers may also become increasingly valuable. Our whole approach to disease-causing bacteria, it seems, may become a much more peaceable one.
When Churchill spoke almost 50 years ago of “jaw-jaw” being preferable to “war-war”, the conflicts he had in mind were military rather than microbiological. But the aphorism is equally apt. Smart doctors, like smart statesmen, don’t use brute force unless they have to. It’s better to talk.