Waning of the Wonder Drugs
With bacterial resistance on the rise, where will we get the drugs of the future?
By Tyler Irving
In the face of reports of drug resistant strains of bacteria, like Staphylococcus aureus and Clostridium difficile, finding out exactly why the ‘wonder drugs’ of yesteryear appear to have lost their punch — and more importantly, what can be done about it — is critical. Gerry Wright, professor in the Department of Biochemistry and Biomedical Sciences at McMaster University, aims to answer these questions. Using tools like environmental genome sampling and high-throughput screening, he has gained new perspectives on how bacteria evolve resistance and has identified strategies that could lead to new drugs. ACCN spoke with Wright to find out how we will create the antibiotics of the future.
ACCN You've said that the current situation with regard to antibiotic resistance “approaches perfect storm characterization.” How so?
GW For over 70 years, we’ve benefitted from an ample supply of antibiotics. Today, that’s being eroded by an upsurge in antibiotic resistant strains of bacteria. At the very same time the pharmaceutical industry is looking elsewhere; they no longer see antibiotics as a profitable area of research. The end result is this ever-growing disconnect between clinical need and potential solutions, hence the ‘perfect storm.’
ACCN How have antibiotics been developed in the past?
GW Probably the grandfather of antibiotic discovery is Paul Ehrlich, who in 1909 systematically tested a series of chemicals — primarily dyes and arsenic-based compounds — for their activity against Treponema pallidum, the organism that causes syphilis. The result of this first high-throughput screen was Arsphenamine (also known as Salvarsan), a drug whose effectiveness was nothing short of stunning for its time. In the 1930s sulfonamides (sulfa drugs) were identified by Bayer AG and used to treat a wide variety of bacterial infections.
However, then as now, the most effective drugs came from natural products, which have consistently been of low toxicity and highly effective as drug molecules. The classic example is penicillin: Alexander Fleming identified the organism that produces it in the late 1920s, and by the early 1940s scientists had been able to purify and manufacture it. The time between 1940 and 1960 was really the golden era of antibiotic discovery. Small molecules produced by microbes, in particular fungi and soil-dwelling bacteria, were the source of the chemical scaffolds for almost all antibiotics in use today. Synthetic chemistry played a huge role in the elaboration of these natural scaffolds to create new drug molecules. The only significant antibiotic compounds that were completely synthetic were the quinolones and fluoroquinolones, identified in the 1960s and early 1970s.
ACCN Much of your work focuses on studying how bacteria develop resistance to antibiotics. What have we learned about this over the years?
GW Bacteria produce chemicals for almost every purpose, from signalling molecules to antibiotics that keep the competition down. If microorganisms produce antibiotics, they have to have a way of protecting themselves, so the evolution of antibiotic resistance goes hand in hand with the evolution of antibiotics. Now that we can sequence the genomes of these organisms, we can trace these resistance genes. And because bacteria can share genes between species, these resistance genes show up even in bacteria that don’t produce antibiotics.
In 2006 we had a paper in Science where we sampled the collection of all the antibiotic resistance genes in the genomes of non-pathogenic soil bacteria; we call this the antibiotic resistome. What we found is that these bacteria are resistant to many different antibiotics, on average somewhere between seven or eight of the 20 that we screened. Of course, there is the possibility that these microbes may have somehow been exposed to man-made versions of the antibiotics we were looking at. So last year some of the same people did a similar screen of the genomes of organisms that had been frozen in permafrost 30,000 years ago. And a few months later, we did the same for bacteria isolated from Lechuguilla Cave in New Mexico, where the bacteria had been cut off from the surface for at least 4 million years. In all cases, the result was exactly the same; they are all intrinsically multi-drug resistant.
What this shows is that we have failed to understand the chemical ecology of antibiotics. We are lucky that the bacteria that cause disease have, by and large, been highly drug-sensitive, at least for the last 70 years or so. But our work shows that the resistance genes are out there in the genomes of non-pathogenic bacteria. On top of that, we’ve created a massive selection pressure to move those genes around.
ACCN You’re referring to the use of antibiotics in everyday products?
GW Absolutely. The organisms that produce antibiotics have been doing so on a microgram scale, in very confined environments. Even so, resistance has spread around the world among bacteria that live in those environments. But a situation like we’ve had over the last 70 years, where compounds like penicillin get applied on gram or kilogram scales, is unprecedented in the history of this planet. Human use of antibiotics has provided an evolutionary pressure to move resistance genes from organisms that don’t cause disease into those that do. The fact that we have this problem of antibiotic resistance in what were almost universally sensitive organisms 70 years ago is the proof of this.
ACCN Why haven’t drug companies kept up with the problem of resistance?
GW Let me use an example: The first penicillin-resistant organisms were actually discovered before penicillin was made into a drug. These organisms produce enzymes called beta-lactamases that destroy penicillin. They were never really that much of a problem until the 1950s, when those beta-lactamase producing genes started to spread around. So medicinal chemists began tinkering with the structure of penicillin to render it impervious to these enzymes. The bacteria responded by evolving point mutations in those enzymes, and the cycle continued; it’s been a real arms race.
By the 1990s, we ended up in a situation where we had basically exhausted our ability to tinker with existing scaffolds. There are only so many ways that you can differentiate drug molecules before they start becoming lousy drugs, with issues of toxicity, bioavailability and so on. What we need at this point is new scaffolds, and that’s really what’s been lacking. The last really new scaffold was a lipo-peptide called daptomycin, discovered in the early- to mid-1980s. So we’ve exhausted our ability to make new derivatives and at the same time we haven’t discovered any new scaffolds.
Gerry Wright, shown here in his lab at the Michael G. DeGroote Institute for Infectious Disease Research, suggests that previously discarded chemical scaffolds might be one potential source of new antibiotics. An example is daptomycin, shown above. Originally discovered in the mid-1980s but rejected due to toxicity issues, the compound was finally commercialized in the 2000s, when new experiments showed that toxicity could be controlled with careful dosing.
ACCN If that’s true, where are the antibiotics of the future going to come from?
GW There are scaffolds that have been looked at but were discarded because we already had better drugs around. Daptomycin is a good example; when it was first discovered by Eli Lilly in the 1980s, early studies found that it was associated with toxicity, so it was dropped. Later, a new company called Cubist felt that they could deal with the toxicity by changing the dosing. They bought the rights and showed that, using appropriate dosing, it was perfectly viable; it’s now making something on the order of $700 million to $900 million a year. So that’s one possibility.
I also think there’s always a great opportunity to keep looking to natural products. During the 1990s, a lot of drug companies worked very hard on using computer models to make synthetic antibiotics and that unfortunately has not worked. We haven’t yet figured out the rules for making molecules that will get into bacteria and kill them. So I’m biased toward natural products, and here we can really benefit from our ability to sequence genomes.
Today we can sequence a bacterial genome in an afternoon for a thousand dollars, and that price keeps dropping. We’re no longer even limited to the species we can grow in the lab, which we know make up less than 10 per cent of the organisms that live in a gram of soil. Instead you can extract all of the DNA and sequence it directly, so you know everything that’s produced in there. Of course, you don’t necessarily know which genes will produce antibiotics, but you might find an interesting chemical scaffold worthy of investigation. I think there are tremendous opportunities there.
Finally, another route we’ve taken in my lab with my colleagues Eric Brown and Mike Tyers is combining molecules. That takes advantage of what we’re now beginning to understand from systems biology, which is that a single molecule usually can’t completely shut down an organism’s ability to grow; in other words, true antibiotics are rare. There’s a lot of redundancy in microbial metabolism, with biochemical pathways having all sorts of backups. It’s kind of like the internet; it’s very hard to shut down by unplugging one computer, but if you unplug two, three or four, you can at least start to affect the local networks. We can now do high-throughput screens for combinations of molecules, and we’ve been very successful in identifying some that can kill bacteria and fungi too.
ACCN What will these changes mean for the way chemists work?
GW I think chemists are going to have to get more comfortable dealing with natural products, since this is really where we’re going to find the new antibiotics. It’s tough because they are complex and challenging, with multiple stereocentres — not the kind of thing that is easy to work with. But more broadly I think this is going to really be an era of partnership. It has already been to some extent in the past, but the antibiotic field has not seen the level of co-operation between biologists and chemists that anti-hypertension or anti-cholesterol drugs have, for example. It will be medicinal chemists, analytical chemists and biological chemists working with geneticists who will help us find the new scaffolds.
Another aspect is making sure these things get from the lab to the clinic. I think it’s evident that if we wait for the pharmaceutical industry to do this, we’re going to be waiting for a long time. On the other hand, history has shown us that the large pharmaceutical companies are very receptive to acquiring bright technologies and moving them down the clinical pathway. I think a lot of this research is going to get done in academic labs and in small biotech companies. The critical element is to make sure that we get sufficient interest by funders, whether those are venture capitalists, angel investors, government or private sector. There are lots of reasons to be hopeful, but the pump needs to be primed.
ACCN Is this a war we can win?
GW I don’t like the war mentality much, and in fact it has been part of the problem. We’re not at war with these organisms, we’re just trying to control their growth. If we think of them as agents of evolution, as opposed to something we need to eradicate, we will have much better success in the future.
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