Dear reader, I apologise for my absence. I was held captive to an examination, which is especially precarious for someone who doesn’t believe in the kinds of exams we are usually subjected to. Maybe a topic for another article. Regardless, we are now resurrected and shall resume with a fun, quick one.
In this one, let’s talk alternative medicine. Before our usual target audience tunes out, and the hordes of you-know-who flood this – we’re talking alternative uses for antimicrobials that don’t rely on their bug killing activity. Some leverage unwanted side effects, some leverage unintentional discoveries and all are quite amusing.
Since there are so many neat examples and brevity is not the soul of my wit or writing, this shall be done in two parts. This first part is a love letter to cross-disciplinary utility and drug repurposing. Initially developed as antimicrobials, these drugs are more frequently used for their alternative indications. In the next part, we shall cover the true-blue antimicrobials that also happen to moonlight as something else.
Before we begin, let’s have a moment of silence and respect for Streptomyces who have kindly uplifted humanity and are the sponsor for this episode of Myths and Maladies.
1 – Rapamycin (Sirolimus) and Cyclosporine (Ciclosporin)
Original Development: Anti-fungal agent
Additional Uses: Immunosuppressant, especially used in prevention of transplant rejection
The Story: The discovery of rapamycin is a nuanced and storied one, layered with historical context surrounding colonialism and Indigenous rights, which makes for fascinating reading if you’re so inclined. It began with a Canadian expedition to Easter Island (Rapa Nui, hence the name Rapa-mycin) in 1964 that involved collecting soil samples as part of an effort to find naturally occurring sources for antibiotics. A supposed fascination that birthed this was why the locals did not develop tetanus despite walking barefoot, leading to soil samples being of interest.
These samples were sent to a pharmaceutical company in the United States (Ayerst Pharmaceuticals) where it landed in the hands of Suren N. Sehgal. Here, Sehgal and team isolated the usual culprit for all antibiotic maladies – a Streptomyces species – from a soil sample and noted it to have broad anti-fungal activity, especially against Candida. Their development of rapamycin as a antimicrobial was dented by the finding that it had undesirable immunosuppressive side effects. The commitment of Sehgal to the cause led to his sending it to the National Cancer Institute for investigation of its anti-tumour properties, where it created excitement for its cytostatic (inhibiting dividing) over the usual cytotoxic mechanism of action. It wasn’t quite to be for rapamycin, as Ayerst Pharmaceuticals downsized, halting further development and leading to Sehgal to storing samples of Streptomyces hydroscopius in his fridge for six years before it was finally re-evaluated in 1988. A long 35 years since the initial expedition that led to its discovery, rapamycin gained FDA approval for use in 1999 as an immunosuppressant. In 1998, Sehgal was diagnosed with metastatic colon cancer that his physician perhaps fittingly treated him with rapamycin for.
Rapamycin being the peculiar drug that it is, is now gaining more attention recently for its anti-aging effects. The sun hasn’t quite set on this saga yet.
Ciclosporin shares a similar soil sample anti-fungal to immunosuppressive story, but it’s a lot less colourful so I won’t bore you with the details. Dear reader, it may also interest you to know that sirolimus, ciclosporin and tacrolimus are all macrolide compounds. Perhaps this explains one of the quirky immunosuppressive effects of azithromycin, which is covered in our second edition.
Recommended Reading:
A very readable article about Rapamycin in the BigThink. A discussion about the ethical controversies surrounding its discovery in The Conversation. A detailed historical rundown in journal article form. A letter about Dr Sehgal’s life’s work.
2 – Hydroxychloroquine
Original Development: Treatment of malaria
Additional Uses: Disease-modifying anti-rheumatic drug used in rheumatoid arthritis and lupus
The Story: Malaria is a disease as old as time. Enter World War II and the need for mass antimalarial prophylaxis for millions of troops. In this de facto mass public health experiment, it was noticed that the use of mepacrine (quinacrine, an antimalarial used by the Allied forces) led to alleviated rashes and inflammatory arthritis symptoms – paving the way for the first trials of quinine-derivates in rheumatic diseases.
Hydroxychloroquine was introduced with a small chemical modification (-OH) purported to reduce toxicity without compromising its efficacy, and is now ubiquitous in the treatment of systemic lupus erythematosus.
Recommended Reading:
A brief history of hydroxychloroquine and some further reading about mepacrine. Further historical context about hydroxychloroquine.
3 – Ristoceitin
Original Development: Antibiotic
Additional Uses: Diagnostic tool for platelet disorders
The Story: From the ribosomes of Nocardia lurida was born a glycopeptide antibiotic bearing the name Ristoceitin. In the 1950s, when initially developed, this was found to have the unwanted side effect of thrombocytopenia and other myelotoxicities that nearly sidelined this drug into obscurity. Enter the Australian duo of Margaret Howard and Barry Firkin who re-discovered ristoceitin for its current use – by identifying it was capable of differentiating platelet disorders through this platelet aggregation property. Today, ristoceitin is used for its thrombotic capabilities in diagnostic assays – particularly in the diagnosis of von Willebrand disease and related disorders where this is especially helpful.
As an aside, bleomycin (now used in chemotherapy) is also a glycopeptide molecule that was isolated from Streptomyces, specifically looking for compounds with anti-tumour activity. For a first-hand account of this, see this article.
Recommended Reading:
An early 1958 whistleblow regarding ristoceitin’s unwanted myelotoxicity. A history of the path towards the diagnosis of vWB, touching on ristoceitin’s paradigm shifting role.
4 – Demeclocycline
Original Development: Tetracycline antibiotic
Additional Uses: Induction of nephrogenic diabetes insipidus to treat SIADH
The Story: The tetracyclines seem to have some sort of a dispute with nephrons. For instance, a feared side-effect of expired tetracycline drugs is the induction of Fanconi syndrome due to degeneration into problematic metabolites (the renal one, whereby proximal convoluted tubular reabsorption is kaput).
In the case of demeclocycline, it was found that patients who were taking it for its original indication in the 1960s developed polyuria and polydipsia – which led to this targeted study in 1973 where it was isolated to an induced ADH-insensitive state at the collecting duct. Over time, as the antibiotic itself lost popularity, its use as an agent to induce nephrogenic diabetes inspidus as a treatment for SIADH was pioneered, though this is now increasingly obsolete with specific drugs like the vaptan class of medication and its unreliable efficacy.
Recommended Reading:
A 1965 clinical report identifying the association between demeclocycline and nephrogenic DI, complemented by a 1973 study identifying it was due to a defect in ADH responsiveness. A systematic review regarding the use of demeclocycline in SIADH.
And to end on, I thought I would share the converse. A medication that usually has nothing to do with infection being used for quite a disparate purpose.
Honourable Mention – Sertraline
Original Development: Anti-depressant
Additional Uses: Anti-fungal activity (best known against Cryptococcus)
The Story: Fungal infections are not particularly common. They often affect patients with significant immunosuppression (namely HIV/AIDS) and those with psychosocial barriers to accessing care, which further compound its high mortality and morbidity. Lucrative, however, it is not.
A means of combating this is drug repurposing whereby existing drugs are screened for alternative applications – think rituximab, initially developed for non-Hodgkin’s Lymphoma that is now used for seemingly everything down to a flu. It is through this process that sertraline was consistently found to have anti-fungal activity against Candida and Cryptococcus that was backed up with preclinical animal studies. Its ability to cross the blood-brain barrier and extensively documented safety profile was another appealing aspect for the treatment of CNS mycoses.
This anti-fungal property of sertraline caught enough steam to make it to primetime – a phase III RCT published in the Lancet Infectious Diseases though the findings were not supportive of its ongoing use.
Recommended Reading:
A recent review of sertraline’s anti fungal activity. The RCT of sertraline in cryptococcosis.
I hope this is enough armoury for you all to bore your colleagues into oblivion at your next ward round or party. I kid of course – if you’re reading this I don’t suppose you’re being invited to any parties.
I will see you at the next rodeo, allegedly in a fortnight, where we tackle the second part of alternative antibiotics.
Discover more from Myths & Maladies
Subscribe to get the latest posts sent to your email.
