GOING to hospital these days has become a bit of a lottery. While your doctors are doing their best to solve the problem that took you there in the first place, nasty hospital bacteria are waiting to ambush you, and perhaps leave you sicker than ever. That happens to some 2 million people each year in the US alone, and about 90,000 of them die of such infections. Even worse, the bacteria that hang about hospitals have been exposed to so many antibiotics that more than half of hospital infections are resistant to at least one antibiotic, and a few can dodge them all. Clearly, antibiotic resistance is a serious threat.
The answer, according to a growing band of scientists, may be to stop trying to kill disease-causing bacteria. Taking inspiration from the gentlest of nature鈥檚 metaphors, mother鈥檚 milk, they advocate instead a kinder approach that merely tames the bugs. Their strategy is to try to prevent bacteria from clinging to the cells of the body. No adhesion means no infection, and hence no problem. Doing nothing more aggressive than turning bacteria away could help to prevent the evolution of antibiotic resistance, and might even get evolution on our side for a change and encourage less virulent strains that have lost much of their ability to attack humans. That鈥檚 the hope.
Most of the bacteria that invade our bodies and cause infections begin by adhering to the mucosal cells that line our respiratory, gastrointestinal or urinary tracts. For instance, proteins called lectins on the surface of the bacteria bind to carbohydrate fragments on the surfaces of host tissues. This prevents the pathogens from being swept away, allows them better access to nutrition and is an important aspect of their virulence. During the past two decades, it has been discovered that breastfeeding 鈥� well known to shield newborns from infections 鈥� works some of its protective magic because breast milk contains complex sugars that prevent lectins from binding.
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More recently, researchers have begun searching for other compounds that can bind to lectins and stop bacteria adhering to host cells. One striking success came three years ago in horses, which frequently become infertile as a result of uterine infections 鈥� often from antibiotic-resistant bacteria. Sheryl King, director of equine studies at Southern Illinois University at Carbondale, tried flushing a mare鈥檚 uterus with a solution containing mannose, a sugar that adheres to a broad variety of uterine bacteria. She hoped that the bacteria would cling to the mannose instead of the uterine wall and get flushed out too.
The results were spectacular. Mares that had previously been unable to get pregnant started to have foals. The most impressive example was a thoroughbred mare that had been barren for four years. 鈥淗er uterus was a mess,鈥� King says. 鈥淲e went about using the mannose on her and got her in foal the first year we started using it. And she鈥檚 been in foal every year thereafter.鈥�
The strategy works in people as well. Xylitol, a five-carbon sugar alcohol, has long been known to prevent dental caries in children, at least partly because it keeps cavity-causing Streptococcus mutans from sticking to the teeth. But in 1998, Matti Uhari of the University of Oulu in Finland and colleagues reported that xylitol also prevented Streptococcus pneumoniae, the bacterium responsible for most ear infections, from binding to epithelial cells. This may explain why children who regularly chewed gum containing xylitol had 40 per cent fewer ear infections than those who did not (Pediatrics, vol 102, p 879).
The same mechanism accounts for the success of cranberry juice in warding off urinary tract infections. The juice, which is a well-known folk remedy, contains anti-adhesive compounds known as proanthocyanidins. Last year, Amy Howell, of Rutgers University in Chatsworth, New Jersey, reported that urine samples taken from women after they drank cranberry juice prevented nearly 80 per cent of antibiotic-resistant strains of Escherichia coli from adhering to cells of the urinary tract lining, while none of the urine samples taken before the women drank the juice had any such effect. The anti-adhesive effect of cranberry juice was apparent within 2 hours, and remained for up to 12 hours (Journal of the American Medical Association, vol 287, p 3082).
This traditional remedy could have big medical benefits, Howell says. 鈥淲omen often get recurrent infections. They are on low-dose regimes of antibiotics, and they develop massive resistance,鈥� she says. 鈥淚f we could switch them to cranberry juice, we would solve a lot of problems. It could help to slow the pace of resistance development, because you do not have to take so many antibiotics.鈥�
The anti-adhesive strategy has attracted the attention of researchers trying to block infections ranging from whooping cough to stomach ulcers. For example, a team led by Torkel Wadstr枚m of Lund University in Sweden has been studying the bacterium Helicobacter pylori, known to cause chronic gastritis, peptic ulcers and stomach cancer. Two years ago, the researchers showed that glycoproteins extracted from cow鈥檚 milk can prevent adhesion of H. pylori in mice and reduce bacterial colonisation of the stomach. They are now working towards clinical trials in humans, Wadstr枚m says.
Plants are another source of anti-adhesives. Marjorie Cowan of Miami University in Oxford, Ohio, has found that the enzyme polyphenol oxidase, which is found in potatoes and apples for example, inhibits adhesion of many different kinds of bacteria, including disease-causing E. coli and Streptococcus sanguis. This could explain why in many south-east Asian countries, extracts of potato peel are applied to the skin of burn victims to prevent infection. 鈥淢aybe some of that is an anti-adhesive effect,鈥� Cowan says.
Not content with discovering naturally occurring anti-adhesives, some researchers are also designing them from scratch. The most ambitious effort so far has just begun to bear fruit after 14 years. Last month Cytovax, a Canadian biotechnology company based in Edmonton, Alberta, successfully completed preliminary human trials for a vaccine based on the principle of anti-adhesion. The company has been targeting Pseudomonas aeruginosa, one of the most rampant of antibiotic-resistant hospital bugs. This opportunistic microbe can infect the respiratory, urinary and gastro-intestinal tracts, and even the cornea. Infections can be fatal, particularly for people with severe burns or whose immune system is compromised by cancer treatment or HIV.
The bacterium has rod-shaped extensions called pili, the tips of which bind to host epithelial cells. Cytovax cofounder Robert Hodges, who is now at the University of Colorado Health Sciences Center in Denver, and his colleagues identified a 17-amino-acid peptide at the tip of each pilus that is responsible for adhesion, and they designed a vaccine against it. When they gave the vaccine to mice specially bred to be susceptible to P. aeruginosa, it prompted the mice to produce antibodies against the peptide. When the mice were exposed to P. aeruginosa, the antibodies bound to the pilus peptide, preventing the bacteria from attaching to mouse cells, and the mice remained healthy when they would otherwise have been expected to die.
To be useful in people, however, the vaccine needs to protect against a variety of strains of P. aeruginosa, each bearing a slightly different peptide on its pili. After studying many strains, Hodges and his team designed what they call a 鈥渃onsensus sequence鈥� peptide that was not identical to any single strain but was close enough to all to provoke an immune response to every strain. Their preliminary studies have shown that the Cytovax vaccine works not only for many strains of P. aeruginosa but also for a wide variety of other disease-causing bacteria, and even against the yeast Candida albicans. Animal trials of this consensus vaccine have been successful enough for the company to begin testing in humans. On 1 October, Cytovax announced that its vaccine is free of serious side effects in people and it appears to boost antibody counts. More extensive tests in humans are planned.
If these and other anti-adhesive strategies continue to show promise, they may offer a crucial advantage over antibiotics: the bacteria could be much less likely to evolve resistance to the treatment. 鈥淚f you are using an antibiotic, you are trying to kill the bug. The bug is under huge pressure to change, to survive the antibiotic challenge,鈥� says microbiologist Randall Irvin of the University of Alberta in Edmonton, who worked with Hodges on the Cytovax vaccine. 鈥淲ith an anti-adhesion therapeutic strategy, all you are saying to the bug is, 鈥楴o, you can鈥檛 stay here鈥�.鈥�
Most disease-causing bacteria have other options besides human hosts. The ubiquitous Pseudomonas, for instance, has such minimal nutritional requirements that it can even grow in distilled water. 鈥淎ll you are doing is restricting their environmental niche a little bit,鈥� Irvin says. That discouragement may be so gentle that the bacteria have little reason to find a way around it. Every anti-adhesion researcher contacted by 快猫短视频 reckons that most bacteria should not develop resistance to anti-adhesives.
While that may be true for generalist pathogens, some critics dismiss this reasoning as over-optimistic in the case of more specialised bacteria. Irvin himself points out that Neisseria gonorrhoeae, which causes gonorrhoea, and the related Neisseria meningitidis, which causes a form of meningitis, for example, require human hosts to survive. For such germs, says James Bull, an evolutionary biologist at the University of Texas in Austin, resistance remains a real threat. 鈥淭here is not much fundamental difference between failing to colonise because you are dead and failing to colonise because you get washed out,鈥� he says. 鈥淚n either case, a mutant 鈥榮urvivor鈥� will be able to invade and leave potentially billions of descendents.鈥�
But even if the evolutionary pressure exists, it may not be easy for bacteria to find mutations to overcome anti-adhesives. Ironically, Hodges says, the bacteria鈥檚 adhesion proteins may be too finely tuned for their own good. As it turns out, there are several ways to build a protein to bind to host cell receptors 鈥� hence the various adhesion proteins used by different strains of bacteria. But there is no easy way to get from one successful shape to another. That鈥檚 because the precise fit depends on the interaction of several amino acids within the adhesion proteins鈥� receptor binding domain. Change a single one of them 鈥� as would happen as a result of a random mutation 鈥� and the fit is destroyed. Only by changing several amino acids at once in just the right way 鈥� a highly improbable event 鈥� could the bacteria come up with ways to evade the anti-adhesives and still bind to the receptor, Hodges says.
If blocking adhesion really does sidestep the development of bacterial resistance as well as preventing infection, it would join a small group of other promising non-antibiotic approaches to disease control. They include the use of phage viruses to attack bacterial pathogens (快猫短视频, 5 April, p 36) and chemical means of preventing bacteria from sensing that they are numerous enough to attack the host (快猫短视频, 4 January, p 30). It remains to be seen which of these strategies will work best under which clinical conditions.
Anti-adhesive therapy, though, has one potential advantage over the others. It could push the evolution of bacterial pathogens toward gentler, less virulent forms 鈥� in essence, taming the germs. Debate is currently raging in academic circles about whether the virulence of pathogens can be managed in this way, using drugs, vaccines or other interventions to favour less virulent forms.
If enough people used anti-adhesive compounds or vaccines, proponents argue, then bacteria would be wasting their energy producing proteins for adhering to host cells. Non-adherent variants that used their energy for something else would be favoured by natural selection. 鈥淭he assumption that鈥檚 critical here is that the ones that don鈥檛 adhere are going to be less harmful,鈥� says Paul Ewald of the University of Louisville, Kentucky. 鈥淚t could be that you could get another virulence mechanism, rather than adherence. But, if everything else is the same, and if you could block adherence, and the ones that don鈥檛 adhere can still survive, then they would be milder.鈥�
While no one has yet studied whether anti-adhesives really do lead to decreased virulence, Ewald points to similar evolutionary changes that happened after the very successful vaccination programme against diphtheria. People given diphtheria vaccine develop antibodies not against the diphtheria bacterium itself, but against a toxin it produces which causes the disease symptoms. By neutralising this toxin, the vaccine put selective pressure on the bugs to avoid wasting their energy producing useless toxin. 鈥淭he key prediction is that whenever you introduce the toxoid vaccine you鈥檒l get an evolutionary change towards benign organisms that don鈥檛 produce toxin, or at least very little toxin,鈥� Ewald says. And everywhere studies have been done, that鈥檚 exactly what has been observed.
Bull agrees, though with a caveat. 鈥淚n the diphtheria case, it is true that the vaccine appears to have selected for loss of the toxin,鈥� he says. 鈥淏ut it is also true that the toxic form of the bacterium has reappeared in areas that no longer receive high levels of vaccine coverage. Virulence re-evolved if the selective pressure was removed.鈥� The payoff from anti-adhesive therapy, then, might be only temporary.
Even so, there is great hope among anti-adhesion researchers that they have an answer to infection by superbugs, without too much risk that bacteria would find a way around it. After all, mother鈥檚 milk still works. Bacteria, it seems, haven鈥檛 figured that one out yet.
