ANTHRAX, botulism, cholera, meningitis, diphtheria鈥ome of our worst illnesses are caused by bacteria. And until now, modern medicine鈥檚 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 鈥� one the greatest threats to health today. So perhaps it鈥檚 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鈥檛 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 鈥渓ast resort鈥� antibiotics 鈥� 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鈥檚 infection. All antibiotics that either kill microbes or stop them reproducing inevitably 鈥渟elect鈥� for resistance in this way.
The solution, according to some microbiologists, lies in developing a completely new kind of drug 鈥� one that takes advantage of something called 鈥渜uorum sensing鈥�. 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 鈥渜uorum鈥� part of the name reflects the bacteria鈥檚 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鈥檚 defences by sheer force of numbers.
This is surprisingly sophisticated behaviour for such seemingly simple life forms, but it makes good strategic sense. 鈥淚f your army鈥檚 going into battle you need to know your numbers,鈥� says British-based researcher Paul Williams, an immunologist at the University of Nottingham who is one of the world鈥檚 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鈥檛 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鈥檛 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鈥檚 immune system to see off the invaders by itself.
The real beauty of quorum-sensing blockers, though, is that because they don鈥檛 kill bacteria, but just disrupt their signalling systems, they should exert very little 鈥渟elective pressure鈥�. The blockers won鈥檛 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鈥檛 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 (New 杏吧原创, 4 March 2000, p 8). Some 20 years later researchers noticed the role of quorum sensing in plant diseases (New 杏吧原创, 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鈥檚 Nottingham research group has focused is Staphylococcus aureus, the organism responsible for many wound infections and cases of blood poisoning in hospital patients. It鈥檚 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 鈥� but last year saw the first case of MRSA resistant to this antibiotic too.
One of S. aureus鈥檚 quorum-sensing chemicals is an oligopeptide, a short string of amino acids. Williams鈥檚 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鈥檚 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 鈥� that bacteria are pacified rather than killed 鈥� is also an obstacle to wider acceptance. 鈥淲hat the pharmaceutical industry wants,鈥� says Williams, 鈥渁nd what most clinicians want, is an antimicrobial agent that kills everything, and kills it right now.鈥�
Where big pharma fears to go, small biotech firms are usually willing to tread, and it鈥檚 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鈥檚 attack (New 杏吧原创, 31 August 1996, p 32). New biofilm can鈥檛 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鈥檛 reveal anything of their structure beyond saying they are small and 鈥渘ot peptides鈥�. But he is confident of their effectiveness and their safety. 鈥淲e鈥檝e tested them not only in bacteria but in mammalian cells,鈥� he says. 鈥淭hey work and they are not toxic.鈥�
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鈥檚 immune system. 鈥淲hen 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,鈥� 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. 鈥淧seudomonas in humans often grows inside a biofilm because this is the only way it can survive the actions of the immune system,鈥� says Givskov. 鈥淥ur furanone compounds seem to soften the biofilm, and this allows the antibiotics to penetrate it and reach the bacteria.鈥�
Lingua franca
Drugs such as these could well revolutionise the way we treat certain diseases 鈥� 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. 鈥淏acteria can speak in multiple languages,鈥� she says. 鈥淭hey have species-specific languages, and they have a general language, which we think is universal.鈥�
Bacteria use a signalling molecule termed autoinducer-2, or AI2 鈥� and possibly others like it 鈥� to monitor the presence and number of other species. 鈥淚t鈥檚 not good enough only to be able to count yourself,鈥� Bassler explains. 鈥淵ou have to be able to count everybody else who鈥檚 around.鈥� 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. 鈥淚f you鈥檙e an intestinal pathogen and you make the transition from an outdoor puddle into someone鈥檚 intestine, you are surrounded by zillions of other bacteria,鈥� says Bassler. 鈥淭his will tell you that you are inside a host.鈥� It is through AI2 signalling, Bassler believes, that many species decide when to turn nasty.
A year ago Bassler鈥檚 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. 鈥淚t was thrilling to realise what a role it could play in medicine,鈥� she says.
Bassler鈥檚 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 鈥渟oon鈥�.
The discovery of a universal language among bacteria, a sort of microbial Esperanto, has meant quorum sensing is now considered one of medicine鈥檚 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 鈥渏aw-jaw鈥� being preferable to 鈥渨ar-war鈥�, the conflicts he had in mind were military rather than microbiological. But the aphorism is equally apt. Smart doctors, like smart statesmen, don鈥檛 use brute force unless they have to. It鈥檚 better to talk.