While 700,000 people die each year from drug-resistant infections, structural problems in the pharmaceutical industry are hindering the rapid development of new antibiotics. This forces researchers to look for workarounds.
Antibiotics are a special category of drugs that are the basis of 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 agents for the suppression of the immune system that is required after organ transplantation or during chemotherapy.
The world health organization regularly performs with alarming statements about new cases of threat resistance of microorganisms to antibiotics. Scientists project that at the current pace of development of new drugs and the nature of existing by 2050, the number of victims of "superbugs" will increase from the current 700 000 per year to 10 million who calls for actively looking for new compounds with antimicrobial activity and to develop new approaches in the treatment of bacterial infections.
Why nobody wants to develop antibiotics
The cost of developing a new medicine from 2002 to 2014, has doubled and now stands at an average of $2.5 billion including the cost of testing in accordance with FDA standards the cost could reach nearly $3 billion in the Largest pharmaceutical companies — with the exception of Roche abandoned development of new antimicrobials. The cost of their development is the same as anticancer or Antirheumatic means, while the return on investment (ROI) is much lower. The antibiotics market is already saturated with a sufficient amount of cheap drugs.
Small biotech companies are not eager to find solutions to the problem of antibiotic resistance. In addition to high development cost, high risk not to pay back the investments. An illustrative example of an American company Achaogen. She developed antibiotic ZEMDRI (active ingredient — platonicien) in 2018 brought it to market, and in April of 2019 declared bankruptcy. This case highlights that the problem of antibiotic resistance can in principle be solved (the drug has proved its effectiveness in the fight against multi-resistant gram-negative bacteria), but at the same time shows that to build a successful business is not so easy.
Both large and small companies development of antibiotics in the current situation is not favorable. To change an existing model trying on the national and international levels. Thus, according to the former Chairman of the British Goldman Sachs financier Jim O"Neil, you need to return to the industry a large pharmaceutical company method of play or pay. For companies that are not sponsoring the development of antimicrobial, in his opinion, it is necessary to impose additional fees, and those who successfully brought to market a new drug, to encourage payment from $1 billion to $1.5 billion.
Other strategies offered by the US government, UK and EU at the state level. So, the FDA facilitates the process of testing new antimicrobial agents, processes applications for registration in the priority order and provides an additional 5 years for the exclusive right to manufacture the drug. However, such measures are not enough to change the situation, it is necessary to change the market. In the United States offer to change the pattern of antibiotic use in hospitals (direct procurement of drugs to licences for the use of antibiotics) in the UK — to encourage developers of new antimicrobial drugs by setting prices for antibiotics on the basis of perceived value.
A fundamental development to combat antibiotic resistance (or find ways to bypass the resistance) are engaged in scientific teams from around the world. Innovative approach for the selective killing only pathogenic bacteria suggested that biotechnologists from France and Spain. They have developed a plasmid, i.e. a small fragment of DNA which bacteria can exchange with each other, and sewed in her genes toxin and an antidote to it.
The approach was tested on the resistant strains of the causative agent of cholera, Vibrio cholerae. The system of genes encoded in DNA works in such a way that the toxin becomes active only in the absence of a cure, and this scenario only develops in resistant strains of Vibrio cholerae. If the strain is sensitive to antibiotics, it is also synthesized and antidote, preventing the transfer of the toxin to its active form. "Lock" the gene encoding the antitoxin is due to the presence of resistant strains of protein SetR, which, in fact, provides a resistance to antibiotics.
Toxin, the gene of which are sewed bioengineers in the plasmid, acts very quickly and accurately. To give leeway to the operation of the antidote, the toxin gene is sewn genetic sequence of a protein intein: after synthesis of the design of toxin-intein-toxin, it will take some time to cut out "the middle" and activate the active substance. During this time with the "dangerous end" of the design manages to communicate the antidote. So graceful the genetic structure developed through fundamental research, demonstrates a fundamentally new approach to the fight against resistant microbes.
On test objects — the larvae of arthropods and fish-zebrafish — methods proved 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 micro-organism. However, until the first drugs based on this principle, it may take more than a decade.
Another approach, the looks, the scientific community, is killing bacteria with viruses-bacteriophages. This approach is not new, in the Soviet Union began to successfully apply even in the 1960s, and the first, less successful attempts were made before the discovery of penicillin, in the 1920s and 1930s. However, the antibiotics became more effective and cheapest solution to fight bacteria, and about phage therapy was forgotten — until now resistant to all known antibiotics superbugs.
For systemic infections caused by several pathogenic microorganisms, this approach is not used now, because every strain of the pathogen necessary genetic engineering techniques to develop a unique bacteriophage. However, if the infection is caused by only one strain, which is resistant to all known antibiotics, phage therapy may be effective. This is the case described recently in the journal Science: 15-year-old Isabelle Carnell from London most of my life struggled with pulmonary infection caused by Mycobacterium abscessus. After lung transplant infection resumed on the background of artificial suppression of the immune system.
Came to the aid of scientists from the University of Pittsburgh, where a collection of more than 15 000 of bacteriophages. After studying the crops of the lung of the patient, the researchers picked three types of phages, showed efficacy against infection girls. Three days after the first dropper with a cocktail of phages showed signs of improvement, and after 6 weeks the symptoms had almost disappeared. Finally to fight the infection failed and Isabel is still undergoing treatment, but the patient was able again to attend school and return to normal life.
Biologists-evolutionists liked the metaphor "the Black Queen" from Lewis Carroll's tale, according to which "we have to run to stay in the same place". Apply it to the situation of the evolutionary race with bacteria, and the pharmaceutical industry. The modern system of release of new drugs on the market is designed so that, since the discovery of potentially effective molecules to yield a commercial drug to market may take more than 10 years. Evolution of bacteria is everywhere and much more rapid steps, which causes disturbing statements from the who and the disappointing forecasts of researchers.