Drug repurposing - finding new indications for existing therapeutics - has been happening in medicine for decades, with an ever-growing list of success stories. Of course, no write-up about drug repurposing is complete without mention of the infamous ‘little blue pill’, sildenafil, one of the world’s most successful products of repurposing. Originally developed by Pfizer to treat hypertension and angina, sildenafil’s true calling became apparent during clinical trials, from which it moved on to become one of the highest grossing drugs in history. Sildenafil has been the leading example of serendipitous drug repurposing and inspirational in helping rejuvenate drug discovery for various indications, including infectious diseases.
The advantages of repurposing are clear - the potential is to deliver new treatments much more quickly and inexpensively compared to developing drugs from the ground up. As such, drug repurposing has become an important pipeline for academic researchers and pharmaceutical companies alike, who are exploring drugs on the market or salvaging assets that were shelved due to poor efficacy and testing them for alternative clinical applications. Such compounds have already gone through rigorous clinical testing, with safety data from these studies permitted as support for new regulatory approval thus reducing the time to transition from bench to bedside.
Yet, in the reviewed literature, one glaring observation is that, to date, not a single drug has been repurposed and approved for use as an antibacterial drug, a field where languishing drug pipelines are a colossal frustration. Nevertheless, it is also clear that there is considerable interest in drug repurposing for antimicrobial therapeutics and many potential candidates have been investigated for new indications, including antiparasitic, antiviral, antifungal and antibacterial purposes. We ourselves jumped on the repurposing bandwagon about a decade ago, seeking to discover new antibacterials by means of screening FDA-approved drugs. To our delight, we found cryptic antibacterial activities for drugs like the anti-diarrheal, loperamide; the fertility drug, clomiphene; and the antiprotozoal drug, pentamidine. It was evident for us, and many others, that the rate of success in finding hidden antimicrobial activities for known drugs was high. Yet, we have also witnessed – first-hand and in scouring the literature – that a common challenge often emerged: much higher concentrations of bioavailable drug are needed for antimicrobial efficacy than the effective doses of repurposed compounds for their human target(s). Indeed, when it comes to antimicrobial repurposing, the most common obstacle is a clinical pharmacology issue. Limitations in the pharmacokinetic profiles of existing drugs, more often than not, hamper the potential of these repurposed drugs for clinical applicability.
Our take-home from the reviewed literature is that the devil is in the details and in looking under stones unturned; innovative strategies may be the key to repurposing success in the infectious diseases field. For instance, combinatorial strategies can be valuable approaches in offering dose-sparing capabilities so as to remain in an applicable clinical range for the non-antimicrobial drug. Rationally designed screening platforms may also lead to successful repurposing opportunities, finding new drugs through unique phenotypic assays. Ever-improving in silico-based methods will also certainly aid in the discovery process. In all, it is clear the hunt is still very much on for more repurposed drugs to treat infectious diseases. With new strategies, and just a hint of serendipity, researchers may uncover the next repurposed antimicrobial agent. And perhaps, we will witness an overnight success like the sensational ‘little blue pill’.
The review published in Nature Microbiology can be found here: https://www.nature.com/articles/s41564-019-0357-1
Written by: Maya A. Farha and Eric D. Brown