The empire strikes back
A contribution by Dr. Hannelore Meyer
Resistance to antibiotics became alarming
During the 1940s antibiotics were first discovered. They were and are used to fight bacterial infections successfully ever since. This is the first instance where the cause of bacterial infections could be tackled, which led to an unprecedented increase in life-span as well as to the development of modern medicine.
Infections caused by bacteria that developed resistance against (almost) all existing antibiotics represent a massive threat jeopardizing health and life of many people. Media report 33,000 deaths caused by antibiotics-resistant bacteria in Europe every year. This number has doubled since 2007 and now equals the fatal crash of a Jumbo jet carrying 400 – 500 passengers every five days. Deaths caused by multi-resistant bacterial strains are globally expected to grow from currently 700,000 to approximately 10 million by 2050. This would exceed the current number of cancer-related deaths, which is standing at 8.2 million / year. On top of that, medical achievements such as transplantations, tumor-therapies, complex surgeries, or intensive care for prematurely born infants may be jeopardized. All of these treatments require effective antibiosis for success as the immune system of these patients is compromised. Therefore, they cannot effectively overcome bacterial infections without the help of powerful antibiotics. This already resulted in a drastic increase of the cost of medical care to about 20 to 35 billion US $ by 2013 in USA. By 2050 the global loss of productivity may equal today’s gross domestic product of Great Britain.
Figure 1: Death cases by disease. Blue: 2013 data; orange: 2050 projection
Multi-faceted strategies against bacterial antibiotics resistance
The threat posed by AMR receives worldwide attention and was recognized in the declarations of the G7 and G20 summits during the last years. Due to the rapid global dissemination and inter-bacterial transfer of resistances against antibiotics will essential to implement monitored number of measures: i) monitoring the development of antibiotics resistances, ii) targeted and restrictedapplication of antibiotics in the clinic, iii) reduction of the use of antibiotics in farming, iv) improvement of hygiene, v) development of novel diagnostic tests allowing for identification remaining treatment options. Furthermore, the development of new therapeutic options is pivotal in that respect. The WHO published a list of bacteria in 2017 against which development of new therapies is most urgent. This list allows streamlining multiple approaches in order to speed up development of therapies against the most dangerous bacterial pathogens.
Complementary, novel and personalized therapy concepts
There are multiple developments augmenting the classical range of antibiotic therapies. “Prevention is better than therapy” is the motto inspiring the development of vaccines against malicious bacteria. The best weapons are prophylactic vaccinations preventing infections later on. Such vaccines are usually well tolerated, cost-effective and avoid the problem of subsequent development of resistances.
Innovative antibody-therapies (i.e. utilizing specifically induced immune agents) are currently developed to enable application of antibiotics not yet used. The idea is to chemically link particular antibiotics to an antibody, which is supposed to shuttle to the target location, where it is enriched. This way a rather high local concentration of the antibiotics can be achieved, while much lower systemic concentrations are needed, which avoids side effects and toxicity. In addition, this approach is also feasible for antibiotics that would not reach the target sites upon oral or intravenous application.
So called ‘lytic peptides’ are molecules, which only get incorporated into bacterial (but not into human) membranes and cause membrane perforation. These peptides are expected to be effective against a wide variety of bacterial pathogens, as they do not specifically block a particular cell function. Due to this unspecific mode of action, development of resistance is not expected.
Bacteria themselves fall prey to viruses like us. These bacteria-specific viruses are called “phages” and, fortunately, they are harmless to humans. However, so far the western world took little notice of this approach, which recently gained more attention. The production of phages, which are highly specific for the disease-causing bacterial strain, is straight forward and comparatively cheap. For the first time, it becomes possible to provide each patient with a personalized antibacterial therapy based on this technology. This raises great hopes, but we still need to see how to ensure and proof that each new phage product will meet all criteria regarding quality, safety and efficacy.
More than 1000 clinical trials have shown successful treatment of intestinal infections with antibiotics-resistant Chlostridia by transplanting the gut microbiome from healthy donors. This procedure restores the balance of the highly diverse bacterial community in the intestine which had been disturbed in previous antibiotic therapies.. However, our understanding of the interdependencies between the microbiome and certain diseases is currently rather limited. Therefore, microbiome transplantations are still restricted to patients, for who no other treatment options are left. Studies so far are very promising both regarding efficacy as well as avoidance of side effects.
The classical drug development is still a major part of our anti-infections arsenal, despite the multitude of ideas and concepts. Bacterial infections can be typed rapidly by the latest state-of-the-art diagnostics and technologies such as mass spectrometry, PCR-based or NGS-driven analyses. On top of that bacterial resistances to a host of antibiotics can be spotted paving the way for tailor-made drugs.
So-called pathoblockers allow personalization of therapies based on the respective specifc bacterial infection. Pathoblockers aim to interfere with the intercations between bacterium and patient, but - in contrast to classical antibiotics - do not aim to kill the bacteria. Pathological processes can be blocked without harming the bacteria. Spontaneously occurring resistances are, thus, no longer a selection advantage. Mechanisms responsible for adhesion, virulence, or immune evasion are very specific for each bacterial strain or group of strains. Any drugs interfering with such mechanisms will, therefore, affect only a few pathologic bacteria sparing our symbiotic gut bacteria. This is ecpected to substantially reduce potential side effects. Furthermoer, even if some resistances appear, the number of other bacteria acquiring and maintaining such resistances will remain small as these resistances cannot be transferred to other bacterial species. Thus, pathoblockers are personalized medicine against bacterial infections, personalized not with respect to the patients but the bacteria attacking them.
Innovative RNA- and immunology-based approaches are already used routinely in cancer therapies. Similar approaches will be applied both for diagnostics and therapy in infectious diseases. They will also provide the basis for more targeted personalized developments including anti-infection strategies.
Our enemies, pathological bacteria, will also in future develop means to neutralize our medical arsenal. In order not to lose this rat race, we need to come up with more and new weapons. This does require increased effort in research, including an increase in personalized concepts.