“We will not be able to do without conventional antibiotics”

Mark Brönstrup and Till Strowig — Mark Brönstrup, head of the research group "Chemical Biology" and Till Strowig, head of the research group "Microbial Immune Regulation"

Interview

11/04/2019

Mark Brönstrup, head of the research group "Chemical Biology", and Till Strowig, head of the research group "Microbial Immune Regulation", talk about the current antibiotics research and how it is related to microbial research.

Antibiotics are often the only treatment option for bacterial infections. Generally, however, they have the unfortunate side effect of also killing useful bacteria – for example in the intestine – and thus sometimes disrupting digestion for weeks. For some years now, research into microbiomes, the bacterial communities in and on the human body, has been gaining momentum. It is now known that an intact microbiome strengthens the immune system, influences the course of many diseases and can also protect against infections. With this in mind, the drug researcher Mark Brönstrup and microbiome researcher Till Strowig from the Helmholtz Centre for Infection Research (HZI) discuss whether antibiotics are still relevant today and which findings about the microbiome can be used for treating infections.

What can antibiotic and microbiome researchers learn from each other?
Mark Brönstrup: In the search for new drugs that treat infections, we can learn from the microbiome which mechanisms bacteria use to communicate with each other and to keep each other under control. Bacteria are able to prevent one population from excessive growth and from overwhelming all others in the communities. The strategies to control growth by members of the microbiome could perhaps be used for therapeutic purposes.
Till Strowig: We are interested in how microbial communities affect people, but we also need to understand how members of these communities communicate and compete with each other. Some of the principles used by conventional antibiotics also apply to the microbiome. This is why there are attempts in microbiome research, as an interface to antibiotic research, to identify from DNA sequences of the microbiome how bacteria form their own antibiotic substances. The dominant topic in conjunction with antibiotics is, however, their undesired side effect of damaging the microbiome.

Do antibiotics always damage the microbiome?
TS: There are only a small number of clinical studies that describe the effect of antibiotics on the microbiome in healthy people. Mostly, the side effects of antibiotics on the microbiome were observed in patients, meaning that interrelations with the infection and the disease symptoms cannot be ruled out. New research on healthy mice has shown that many factors, such as certain diets, can have an effect on the dynamics of microbiome recovery after antibiotics are administered. However, the effects of antibiotics are not easy to generalise, because it also depends on how well the drugs are absorbed and how they are excreted, for example via the gall bladder or the kidneys. This varies considerably between the different substance classes. For example, increased stability of an antibiotic in the metabolism may be good for its availability in the body, but at the same time can result in a higher excretion in the intestine and thus lead to a stronger effect on the microbiome. Ultimately, there are currently only limited indications where the microbiome could replace treatment with antibiotics, for example a recurrent infection with the intestinal pathogen Clostridioides difficile. In the next ten to 20 years, we will not be able to forego antibiotics for systemic infections, because the microbiome itself cannot perform a protective function.

MB: I agree. We will not be able to do without conventional antibiotics for now. In acute situations such as bloodstream infections, we must quickly and reliably reduce the amount of pathogenic bacteria. Until we have fast diagnostics that can precisely characterise the germ, this can only be achieved with a broad-spectrum antibiotic. The negative effect on the microbiome must simply be accepted. With improved diagnostics, however, we could use antibiotics in a more targeted manner in such cases.

TS: In the future, microbiome and antibiotic researchers should collaborate even more closely. On a small scale, we are already doing that: One example is an early drug candidate for Clostridioides difficile, where we are investigating at any early stage the effect of this drug on the microbiome. This means we can see whether the drug might have a lower risk for the microbiome than the antibiotics currently used to treat Clostridioides difficile.

Can the effects on beneficial bacteria be considered during drug development?
MB: In general, drug development is already so complex that optimisation for effects on the microbiome is not considered as particularly critical. But in specific cases, it is possible: Some new drugs that target Clostridioides difficile actually have a very narrow spectrum of activity. The typical intestinal microbiome should only be minimally affected.

Can the regeneration of the microbiome be accelerated after treatment with antibiotics?
TS: A study has shown that supplementing with probiotics can actually delay the recovery of the microbiome. The conclusion of this research was that it is better to allow the microbiome recover naturally. But this was just one study with only a few subjects. For the future, it is important to develop medicines that act quickly, especially against multi-resistant germs, and to repair the damage to the microbiome with new probiotics or bacterial cocktails, whose effectiveness has also been scientifically proven. This does not only apply to the intestinal microbiome, it also applies to the bacterial communities in the bladder or the lungs, for example.

Till Strowig, head of the research group "Microbial Immune Regulation"

Can the microbiome, where bacteria are constantly in competition with each other, be a source of new antibiotic agents?
MB: That is a promising area of research that we are also pursuing. The technologies needed to discover which small molecules bacteria of the microbiome use to communicate with each other are exactly the same as those we use in natural product and metabolome research. That is why we are bringing our expertise together to investigate “microbiomic natural products”. Monocultures are conventionally used in natural product research, but there are highly complex microbial communities in the microbiome. Therefore, we want to find molecules that, for example, are only formed in interaction with other microorganisms.

Is research also being conducted into ways of reducing the use of antibiotics?
TS: A major topic in microbiome research is phages, because they can intervene quickly in bacterial communities and can kill off bacteria in a targeted manner. However, treating infections using phages is still difficult.

MB: Another interesting approach looks at pathoblockers. They do not kill the bacteria; they just disarm them and are designed to keep the microbiome intact. We attempt to inhibit specific mechanisms that only occur in pathogenic bacteria, in order to weaken pathogens. Although pathoblockers cannot completely replace antibiotics, they can be used as an adjunctive therapy to improve treatment outcome.

Can antibiotics be optimised so that they only act at the site of the infection, in order to protect the microbiome in other parts of the body?
MB: The topic of drug transport is very important for all medications, not just antibiotics. The drugs should accumulate at the target organs or, in the case of antibiotics, at the site of the infection. We are currently working on releasing and activating antibiotics only where the bacteria are located. The Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) also investigates innovative approaches to transport drugs to specific locations.