Run to stay put
How Big Pharma intends to win the race with super-microbes
Nikita Lavrenov, Forbes, 11.07.2019
While 700,000 people die each year from drug-resistant infections, the structural problems of the pharmaceutical industry prevent the rapid development of new antibiotics. This forces researchers to look for workarounds.
Antibiotics are a special category of medicines that underlie most approaches of modern medicine. They are used not only for the treatment of bacterial infections, but also for the prevention of sepsis, for example during surgical operations. They are also used as auxiliary drugs for suppressing the immune system, which is required after organ transplantation or during chemotherapy.
The World Health Organization regularly makes alarming statements about new cases of resistance of dangerous microorganisms to antibiotics. According to scientists, at the current rate of development of new drugs and the nature of the use of existing ones, by 2050 the number of victims of "superbugs" will increase from the current 700,000 per year to 10 million. WHO calls for more active search for new compounds with antimicrobial action and to develop new approaches in the treatment of bacterial infections.
Why no one wants to develop antibiotics
The cost of developing a new drug doubled from 2002 to 2014 and now averages $2.5 billion. Taking into account the costs of testing in accordance with FDA standards, the cost can reach almost $3 billion. The largest pharmaceutical companies – with the exception of Roche – refused to develop new antimicrobial drugs. The cost of their development is the same as that of anti-cancer or anti-rheumatic drugs, while the return on investment (ROI) is significantly lower. The antibiotic market is already saturated with a sufficient number of cheap drugs.
Small biotech companies also do not seek to find solutions to the problem of antibiotic resistance. In addition to the high cost of development, there is a high risk of not recouping the investment. The example of the American company Achaogen is indicative. She developed the antibiotic ZEMDRI (the active ingredient is plasomycin), brought it to the market in 2018, and in April 2019 declared bankruptcy. This case highlights that the problem of antibiotic resistance can in principle be solved (the drug has proven its effectiveness in the fight against multi-resistant gram-negative bacteria), but at the same time shows that it is not so easy to build a successful business on this.
For both large and small companies, the development of antibiotics in modern realities is not profitable. They are trying to change the existing model at the state and international levels. So, according to the former chairman of Goldman Sachs, British financier Jim O'Neill, it is necessary to return large pharmaceutical companies to the industry using the play or pay method. For companies that do not finance antimicrobial development, in his opinion, additional fees should be introduced, and those who have successfully brought a new drug to the market should be encouraged by paying from $1 billion to $1.5 billion.
Other strategies are proposed by the governments of the United States, Great Britain and the European Union at the state level. Thus, the FDA facilitates the procedure for testing new antimicrobial drugs, considers applications for their registration as a priority and grants an additional 5 years for the exclusive right to manufacture the drug. However, such measures are clearly not enough to change the situation – it is necessary to change the market. In the USA, it is proposed to change the model of the use of antibiotics in hospitals (from direct purchases of drugs to licenses for the use of antibiotics), in the UK – to encourage developers of new antimicrobial drugs by setting prices for antibiotics based on perceived value.
Finding workarounds
Research teams from all over the world are engaged in fundamental developments to combat antibiotic resistance (or the search for ways to circumvent resistance). Biotechnologists from France and Spain have proposed an extraordinary approach to selectively "kill" only pathogenic bacteria. They developed a plasmid, that is, a small fragment of DNA that bacteria can exchange with each other, and sewed into it the genes of the toxin and the antidote to it.
The approach was tested on resistant strains of the cholera pathogen – Vibrio cholerae. The gene system sewn into DNA works in such a way that the toxin becomes active only in the absence of an antidote, and this scenario develops only in resistant strains of vibrio cholerae. If the strain is sensitive to antibiotics, then an antidote is also synthesized that prevents the toxin from passing into the active form. The "blocking" of the gene encoding the antidote occurs due to the presence of the SetR protein in resistant strains, which, in fact, provides resistance to antibiotics.
The toxin, the gene of which was sewn by bioengineers into the plasmid, acts very quickly and accurately. In order to give a head start in time for the action of the antidote, the genetic sequence of the protein-intein is sewn into the toxin gene: after the synthesis of the toxin-intein-toxin construct, some time is needed to cut out the "middle" and activate the active substance. During this time, the antidote manages to interact with the "dangerous ends" of the structure. Such an elegant genetic construct, developed as part of a fundamental study, demonstrates a fundamentally new approach to combating resistant microbes.
On test objects – arthropod larvae and danio-rerio fish – the technique proved to be effective. The safety mechanism makes it difficult to develop resistance to such treatment. Modern methods of genetic engineering allow us to develop similar designs for almost any resistant microorganism. However, it may take more than a dozen years before the first drugs based on this principle appear.
Another approach that the scientific community is looking towards is the killing of bacteria with the help of bacteriophage viruses. This approach is not new, it was successfully applied in the USSR back in the 1960s, and the first, less successful attempts were made even before the discovery of penicillin, in the 1920s and 1930s. However, antibiotics have become a more effective and cheaper solution in the fight against bacteria, and phage therapy was forgotten – before the appearance of superbugs resistant to all known antibiotics.
For systemic infections caused by several pathogenic microorganisms at once, this approach is not used even now, since it is necessary to develop a unique bacteriophage for each strain of the pathogen using genetic engineering methods. However, if the infection is caused by only one strain that is resistant to all known antibiotics, phage therapy may be effective. Just such a case was described recently in the journal Science: 15-year-old Isabel Carnell from London has been struggling with a lung infection caused by Mycobacterium abscessus for most of her life. After the lung transplant, the infection resumed against the background of artificial suppression of the immune system.
Scientists from the University of Pittsburgh, where a collection of more than 15,000 bacteriophages has been collected, came to the rescue. After studying the cultures from the patient's lung, the researchers selected three types of phages that showed effectiveness against the infection of the girl. Three days after the first drip with a cocktail of phages, signs of improvement appeared, and after 6 weeks the symptoms almost disappeared. It was not possible to finally overcome the infection, and Isabel is still undergoing treatment, but the patient was able to attend school again and return to normal life.
Evolutionary biologists fell in love with the metaphor of the "Black Queen" from Lewis Carroll's fairy tale, according to which "you have to run as fast as you can to stay in the same place." It is also applicable to the situation with the evolutionary race of bacteria and the pharmaceutical industry. The modern system of new drugs entering the market is designed in such a way that more than 10 years may pass from the moment of discovery of a potentially effective molecule to the release of a commercial drug on the market. The evolution of bacteria is going on everywhere and with much more rapid steps, which is the reason for the alarming statements of WHO and the disappointing forecasts of researchers.
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