Lorne 2012: The war on superbugs

Once considered mainly a ‘developing-world’ problem, bacterial infections that cannot be easily cured now account for increasing rates of hospitalisation and mortality throughout the world.

The reason is the increasing incidence of drug resistance by microbes to pharmaceutical treatment combined with our decreasing ability and lack of back-up drugs to do much about it.

Deep pockets are needed to produce and market a drug once the active molecule is discovered and validated in the research laboratory. Thus, judgments on what gets made, and for whom, lies partially in the hands of an entity whose activities might be well intentioned, but whose primary goal is to turn a profit.

And in the case of pharmaceutical companies, these days when it takes a billion or more dollars to take a drug from ‘invention to ingestion,’ the profits have to be huge.

According to Dr Mark Butler, a senior researcher in Professor Matt Cooper’s group at The University of Queensland’s Institute for Molecular Bioscience (IMB), the whole picture of drugs and drug marketing changed in the 1980s and 1990s with the rise of Big Pharma companies and the release of a few blockbuster drugs that made an awful lot of money in treating mostly chronic and lifestyle diseases.

“The first of these was probably Zantac, followed by Omeprazole and, of course, Lipitor, which has now made more than any other single drug in history.”

Zantac was introduced by GlaxoSmithKline in 1981 for the treatment of heartburn and ulcers, Omeprazole is a proton pump inhibitor and was released by AstraZeneca in 1989, and Lipitor is Pfizer’s 1997 drug to lower cholesterol. Current estimates suggest the yearly income from Lipitor alone is around $11 billion per year.

So, over that 10 to 20 year period, the pharmaceutical industry became all about trying to find that next blockbuster drug. Unfortunately, around the same time, antibiotics started to look less and less attractive to the big companies as an investment.

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Too hard basket

For a start, antibiotics in the 1980s were not really the problem they are now, with recalcitrant bugs like methicillin-resistant Staphylococcus aureus (MRSA) only just beginning to appear.

The big companies were also doing so well in developing broad-spectrum agents that they didn’t concern themselves much about looking for other, narrow-spectrum antibiotics with activity against these emergent ‘superbugs.’ And so the pipelines began to empty.   According to Butler, another disincentive is that discovering brand new types of antibiotics is much more difficult than it used to be.

“Nearly all of the main classes were discovered before 1970, and only about three classes since then have been launched, so there is also a lot of effort needed to find new gaps in the market.”

Antibiotics are large and complex molecules that are time-consuming and expensive to develop and produce. The other factor scaring companies off to a certain extent is that the clinical trials enforced by the U.S. Food and Drug Administrator (FDA) to get a drug into the clinic are becoming less and less tenable and virtually impossible economically for most companies to achieve.

In fact, there have been some recent examples of antibiotics getting almost to the market when the FDA changed its mind, resulting in a few good companies going bankrupt.

“A big scare in America is that any new antibiotics that work will start being produced just for the Asian and European markets where getting to the market is a bit easier and economically worth it, and so the U.S. might be left behind in terms of drugs available to the clinician, some of whom are getting very worried.”

The final nail in the antibiotics coffin, lies in the problem itself, says Butler. “Even if companies find a fantastic compound that works on resistant organisms, their use, and thus the company’s profits, might be restricted to keep as a last-line drug for certain patients to avoid the bugs finding ways to overcome them.”

This would preclude the drug being exposed to a wide market and act as a further disincentive to antibiotic development.

So, the purely profit-driven approach to drug discovery is not working, and research into antibiotics is drying up. At the same time, bacterial resistance has surged and antibiotics continue to be compromised by inappropriate use.

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“Antibiotic-resistant ‘superbugs’ in hospitals alone kill an estimated 500,000 people each year globally”, says Cooper. And there are now some organisms in clinical practice that are resistant to everything doctors can throw at them. Annually, 8 million people become ill with the tuberculosis bacterium, and 2 million people die from the disease worldwide.

And as the doctors’ bag empties of options, the scenario becomes more and more grim for patients with drug-resistant infections, especially those who are critically ill or immunocompromised.

Indeed, antibiotics are routinely used to keep cancer patients alive. “Thus, even infections that are easily treated now could prove fatal in the future without new antibiotic options being developed,” says Cooper.

A Wellcome hand

An ongoing research stream in Cooper’s group at the IMB centres on chemically modifying existing antibiotics to overcome bacterial resistance mechanisms. This approach potentially allows for an accelerated drug design process based on existing knowledge of how the antibiotics work, instead of screening for new structures.

One such antibiotic is the naturally occurring glycopeptide, vancomycin, which was first produced in the late 1950s to work against difficult-to-treat Gram-positive organisms such as Staphylococcus and Enterococci. Although it remains in widespread use, the increasing emergence of vancomycin-resistant organisms is a growing worry for clinicians.

Helping in this strategy will be the Wellcome Trust’s $5 million Seeding Drug Discovery funding awarded to Cooper and his team in 2011. The aim to improve the potency of vancomycin involves appending a chemical constituent to the backbone structure of the drug.

“This modification will help to specifically target the antibiotic to bacterial membranes in preference to mammalian membranes,” says Mark Blaskovich, project manager on the Wellcome project.

“By better targeting the vancomycin to the bacteria, you effectively increase its concentration at the surface of the bacteria through the additional interaction and so improve potency.”

Some of the major resistance mechanisms used by bacteria against vancomycin involve weakening the effectiveness of binding to its surface or increasing the cell wall thickness.

An extra and more specific binding motif on vancomycin should help to overcome both of these examples of resistance. The chemical modification was originally invented by Cooper when he was working at the University of Cambridge in collaboration with a UK-based biotechnology company.

“So far, the increase in potency with this simple addition of an extra targeting site is up to 1000-fold, with no measurable haemolytic or cytotoxic activity, and we are now trying to improve on that,” says Blaskovich.

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“Then we will work on making the new agent into something that is more drug-like (stability, bioavailability, low cytotoxicity, etc.), whilst trying to also optimise the potency and antimicrobial activity. So, basically, we take all of our earlier proof-of-concept work showing that the drug could potentially work and develop it into an actual drug that does work.

“On the chemistry side of things, we are trying to make analogues of the modified vancomycin compounds to look at different positions on this binding appendage in what are called structure-activity relationship studies,” says Blaskovich. “So, what changes do you make here and what effect does that have on the potency or on the cytotoxicity, etc.”

The team also has a bunch of microbiologists doing antimicrobial activity assays on the compound using a panel of drug-resistant bacterial strains available in-house. Then, another sub-group of scientists on the project will study the drug’s mode of action.

“This will confirm whether our new compounds are acting at the same bacterial target as vancomycin or whether the new agent has additional potential mechanisms for killing off the bacteria that will help improve its activity even further compared to vancomycin.”

Blaskovich predicts that if the planets align, they could be looking at setting up their first clinical trials of the modified vancomycin in three to four years. One good thing about the antibiotic space, and which might help speed their path to drug development, is that people have been developing these drugs now for about 70 years.

“We are lucky in that respect, that the actual package that you need to put together to get the drug out is quite standard and a lot of people know what to do.”

Cooper acknowledges the unrealistic prospect of pharmaceutical and biotech companies choosing less lucrative drug options for their R&D dollars. “We can’t change capitalist behaviour and drug companies need to make money to survive. What we can do, however, is look at different types of business models.”

In a recent commentary in Nature, Cooper suggests new public-private enterprise strategies for governments to work with companies on the antibiotics issue to the benefit of all parties; especially for those patients with recalcitrant and often deadly infections.

He proposes hybrid models of push-pull incentives, patent extension for new antibiotics to delay the impact of generic substitutes, and government-subsidised clinical trials as just some of the alternative ways forward in the push for new antibiotics.

“We need to encourage companies to invest in antibiotics again, before one of the most valuable discoveries of the 20th century is lost in the 21st century.”