What comes after antibiotics?

With decades of misuse gradually ruining the life-saving drugs, science is searching for new ways to kill dangerous bacteria.
Written by John Rennie, Contributor


The three greatest boons to public health in history have been public sanitation (clean water), vaccines, and antibiotics. Misguided parents groups aside, vaccines are still mostly recognized as crucial for preventing many infectious diseases, and nobody is clamoring to eliminate sewers. But the future existence of antibiotics is seriously in jeopardy: not from any effort to stop using them but from the consequences of their misuse.

Antibiotic resistance is fast on the rise among bacteria, including some of the most dangerous varieties such as tuberculosis and staphylococcus. (The journalist Maryn McKenna, author of the book Superbug, reports brilliantly on this subject and makes her identically titled blog compulsory reading for staying current on it.) Some small portion of that resistance is the inevitable result of using antibiotics at all: natural selection will favor strains that are even marginally less vulnerable to the drugs. And in places like hospitals, bacteria of different species can sometimes pass the genes for resistance back and forth, increasing their spread.

Yet the greater share of the problem results from the overuse and inappropriate use of the drugs. The culprits are everything from doctors' inappropriate prescription of antibiotics to treat viral infections, to patients' failure to take all their pills as directed, to the non-therapeutic addition of huge quantities of antibiotics to farm animal feed to make the animals grow bigger, as I've discussed previously here. (On that latter point, the FDA has recently taken some welcome steps to restrict such farm uses, but as Maryn has explained, they leave serious loopholes unclosed and concerns unaddressed.)

Capsules of the antibiotic amoxycillin. (Credit: Sheep purple, via Flickr)

The ominous possibility remains that all classes of antibiotics could become medically useless in years to come. Experts such as Thomas Frieden, director of the Centers for Disease Control and Prevention, and Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, testified to that effect in 2010 before Congress. Antibiotics, which are typically based on fungal compounds, generally interfere with bacterial reproduction or crucial aspects of their metabolism or damage their cell walls. The pharmaceutical development pipeline does not hold many new drug formulations with similar antibacterial effects.

If antibiotics do completely fail, what alternative treatments might science cultivate as replacements? And can they be made ready in time?

Interfering nanotechnology

The U.S. Department of Defense takes the potential loss of antibiotics highly seriously, which only makes sense given the range and severity of injuries for which the military needs to prepare. To that end, last November in its solicitation for small business innovation research proposals, the Defense Advanced Research Projects Agency (DARPA) called for a versatile replacement to antibiotics based on nanotechnology.

The "Rapidly Adaptable Nanotherapeutics" title that DARPA used might conjure up images of microrobots killing bacteria in the bloodstream, but in this case it has a more prosaic and biochemical meaning. DARPA is interested in the development of nanoparticles linked to small interfering RNA molecules (siRNAs). Inside cells, siRNAs live up to their name by very precisely interfering with the ability of specific active genes to make protein. In principle, siRNAs on nanoparticles could be designed to bollix up genes active only in pathogenic bacteria, leaving the human host's cells alone. Such an approach could be highly versatile: so long as researchers can find unique features in the genomes of bacteria to target, they ought to be able to create nanoparticles to destroy them.

But as the DARPA call for proposals makes clear, the agency is looking for contractors prepared to undertake a potentially lengthy, complex, multistage development process, from the definition of the needed basic technologies through testing of the platform's capabilities and securing FDA approval. A system that could fully live up to the desired goals of creating useful therapeutic nanoparticles on demand within a week or so could be a couple of decades away.

Assisting the immune system

Of course, when it comes to versatility, it's hard to beat a claim that a technology can "cure everything," but that's been said about a brainchild of Nobel laureate Kary B. Mullis. Mullis first won fame as the inventor of polymerase chain reaction (PCR) technology, a mainstay of modern molecular biology. He has gained no little notoriety since then for his unconventional views (the chapters in his book Dancing in the Mind Field that deny the HIV-AIDS connection, cast doubt on global warming, defend astrology, and describe adventures with extraterrestrials and on the astral plane speak for themselves). But he also now holds a patent for "chemically programmable immunity" that might have promise.

Credit: Altermune, LLC/www.karymullis.com

Mullis's technique involves an artificial molecule with two parts. One is called a DNA aptamer -- a long, highly folded single strand of DNA that can grab onto a unique target, not unlike an antibody. For the purposes that Mullis has in mind, that target would be a pathogenic bacterium or virus. The other part is a carbohydrate structure called the alpha-Gal epitope -- a structure that human cells do not make and that the human immune system instantly recognizes as foreign.

The idea is that this artificial molecule can tag pathogens that would normally evade the immune system and thereby make them easy targets. Aptamers could be designed to stick to pathogens; the linked alpha-Gal epitope would then draw down an immune attack. Mullis has said that in tests, his molecules provided 100 percent protection against anthrax in rodents. Last September his company, Altermune Technologies LLC, entered into a joint venture to develop the approach with Loxbridge Research LP, which is putting up $7 million in seed funding.

At this point, no one can say how well Mullis's approach will work in practice. Much will depend on how rapidly bacteria might be able to change the features to which the aptamers would stick -- and on how long it takes to create aptamers against a particular pathogen. Another unknown is whether in humans the immune system might clear the molecules and their alpha-Gal epitopes from circulation too quickly to be of use. Hence the need for many more tests.

Magainins and more

Clawed frog, Xenopus laevis. (Credit: NIH)

Antimicrobial peptides (AMPs) made by animals have both excited and frustrated developers for years. Part of animals' defense against invaders is the innate immune system, which consists of purely chemical defenses embedded in their epithelial and mucosal membranes. AMPs fall into several categories but typically, they act against bacteria's cell wall (a structure that animal cells lack).

The modern study of AMPs generally goes back to 1987, when Michael A. Zasloff (then at the National Institutes of Child Health and Human Development, and now at Georgetown University) observed that wounds in the skin of Xenopus clawed frogs healed quickly even though the animals were literally swimming in bacteria-infested water. He identified AMPs in their skin that he called magainins.

Since then, Zasloff and other researchers have identified more than a thousand AMPs in the skin, intestines, and mucosa of amphibians, mammals, sharks, and other creatures (as well as some plants). Part of the molecules' early appeal was that, because they had survived in nature for millions of years, bacteria might find it hard to become resistant to them.

Hard but, alas, not impossible. Researchers have now documented a variety of mechanisms whereby bacteria can protect themselves from magainins and other AMPs. Efforts to turn AMPs into drugs have moved slowly (to say the least). One magainin analog, pexiganan, showed promise in Phase III clinical trials as an alternative to antibiotics for treating mildly infected diabetic foot ulcers, but its development seems to have been discontinued in 2009.

Fight bad bacteria with good bacteria

One of the most innovative approaches to treatment that could work in some illnesses might be not to focus on killing the bad bacteria at all, but rather just to replace them with more benign ones. These treatments are based on taking an enlightened view of the importance of the microbiome, the ecosystem of microorganisms that lives inside all of us.

Intestinal bacteria, E. coli. (Credit: CDC)

Dangerous diarrhea can result from many types of bacterial infection, but antibiotics can cause it, too, precisely because they disrupt the healthy ecosystem of microorganisms in the guts. A diarrhea remedy that has worked amazingly well in select case studies is fecal transplant: deliberately infecting a patient's intestinal tract with a tiny amount of the contents of a healthy person's colon. (Does that sound revolting? Perhaps, but it isn't necessarily any more so than most medical procedures.)

What's amazing, as Maryn McKenna recently noted, is that the limited clinical data suggest that fecal transplants might even be more effective than antibiotics for treating many cases of diarrhea. Veterinarians have used fecal transplants routinely for many years with good results.

If fecal transplants still seem a bit much for you, consider a recent oral health study by researchers at the Colgate-Palmolive Technology Center in Piscataway, N.J. The scientists first killed all the Streptococcus mutans bacteria, which cause tooth decay, in volunteers' mouths. (They did so with an antimicrobial peptide, C16G2, interestingly enough.) They found that subsequently the number of S. mutans in the mouths stayed low even though the total number of bacteria returned to normal: the S. mutans were displaced by other bacterial species that didn't damage the volunteers' enamel.

What are needed for such microbiome approaches to make headway in medical practice are proper clinical trials to test their safety and efficacy. And that's the problem, as Maryn notes: the FDA and similar authorities elsewhere don't yet know how to organize such trials and test the treatments rigorously. (There's no such thing as standard, laboratory-grade, certified-healthy poop, for one thing.)

Save what works now

Nanotech constructs based on siRNA, immunity boosters, novel antibacterial proteins, and microbiome manipulations are only a few of the possibilities to which we might turn if we lose antibiotics. Others include treatments based on bacteria-killing phage viruses, or ways of chelating the nutrients that bacteria require, or therapeutic vaccines. They could all turn out to be valuable additions to the pharmacological war kit, no matter what.

But antibiotics work as therapies now, while the usefulness of those other remedies won't be known, at best, for years. We need to be better stewards of the antibiotics left to us or we risk waking up one day with no relief from infection at all.

Image: An agar plate supporting colonies of drug-resistant bacteria. (Credit: NIGMS/NIH)

This post was originally published on Smartplanet.com

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