by Saadia Basharat, PhD, Consultant and Ashley Clark, Consultant Intern at Alacrita

 

An interaction not often considered in the drug development process is that of a therapeutic compound with no intentional antibiotic activity interacting with the vast array of bacteria living in the human gut. However, recently the importance of this has been gaining much more appreciation. A large-scale study by Japanese and German researchers that screened over 1000 marketed drugs, from anti-psychotics to chemotherapies, against common gut bacteria showed that more than 24% of drugs screened inhibited growth of at least one bacterial species in vitro. This finding is both exciting and worrying – on the one hand it provides a whole new avenue for antibiotic drug discovery; on the other hand, it suggests an imminent need for a new arm of toxicity screening in the drug development process.

Unsurprisingly, 78% of the antibacterials in the group of 1000 drugs screened demonstrated activity against the gut microbiota. Even among the other anti-infectives specifically targeted against viruses or eukaryotes it was found that 50% also have activity against our gut microbiome.  While this may not be a huge shock, it is disquieting. The adverse effects of some antibiotics have been well documented in the past. It is understood that it is often the non-absorbed part of orally administered systemic antibiotic drugs that reaches the colon and can lead to diarrhoea, opportunistic C. difficile infections and an enhanced presence of other antibiotic resistant microorganisms. Yet it is only relatively recently that drug companies have seriously started to consider how antibiotics in development may influence gut bacteria. The 2011 GSK safety study for the antibiotic GSK1322322 is an example of how studies have started to incorporate microbiome analyses in to standard drug development. The data shows that oral GSK1322322 produces a shift in study participants’ microbiomes, but interestingly the intravenous version of the drug does not have this affect. As the gut microbiome is increasingly considered in drug development, the next stage for companies will be to work out how best to measure the effects of trial drugs on a patient’s microbiome, and whether they are harmful to human health in the short and long term.

However, not only should the effects of drugs on gut bacteria be explored, but also the influence of the gut microbiome on the efficacy of drugs. As far back as the 1980s, it has been reported that gut bacteria could metabolise digoxin, a plant derivative for heart failure, and reduce its efficacy. Further exploration found that the effect was down to one particular species (E.lenta) and that only some bacterial strains have the genes required to metabolise digoxin, suggesting a future role of the gut microbiome in the development of personalised medicines.

Another interesting angle is that the gut microbiome can have a beneficial and even essential role in patient response to cancer immunotherapy; one of the most exciting areas of drug development today. Recent reports suggest that the lack of certain bacteria present in the gut can reduce the efficacy of immunotherapies.  For example, one study showed that the absence of Ruminococcaceae in metastatic melanoma patients correlated with non-response to immunotherapy. These patients were treated with immune checkpoint inhibitors targeting the PD-1/PD-L1 axis, and it is suggested that the presence of a favourable gut microbiome i.e. the presence of Ruminococcaceae actually enhances antitumor immune responses by increasing antigen presentation and improving effector T-cell function.

Much work has yet to be done of course in terms of developing new screening assays to detect drug-microbiome interactions, and better understanding the clinical implications associated with these interactions.

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