5. Anti-cancer drugs as broad-spectrum anti-infectives
Repositioning studies of anti-cancer drugs has led to the discovery that targeting certain host proteins yields broad-spectrum anti-infective activity, a further contribution away from the magic bullet paradigm77. Heat shock protein 90 (Hsp90) inhibitors and oestrogen receptor antagonists have unearthed therapeutic targets whose modulation may successfully treat malignancies as well as infection.
It has long been understood that microbes have exploited stress proteins as virulence factors for pathogenesis in their hosts78. Owing to its ability to sense and respond to the stress conditions, the molecular chaperone Hsp90 is one of the key stress proteins utilised by parasitic microbes79. There is growing evidence for the critical role played by Hsp90 in the growth of pathogenic organisms like Candida, Giardia, Plasmodium, Trypanosoma, among others80. The attractiveness of Hsp90 as an anti-cancer drug target has driven much research at laboratory, preclinical and clinical levels for several Hsp90 inhibitors as potential anti-cancer drugs81. Similarly, data pertaining to toxicity studies, pharmacokinetics and pharmacodynamics studies, dosage regime, drug related toxicities, dose limiting toxicities, and adverse drug reactions (ADRs) are available for Hsp90 inhibitors, making them attractive repositioning candidates82.
The triphenylethylene class of selective oestrogen receptor modulators related to tamoxifen (TAM) has also shown activity against a range of pathogens including bacteria, fungi, parasites, and viruses83-85. It has been suggested that the broad spectrum of activity of TAM may be related to its amphipathic chemical properties: a hydrophobic aromatic core linked to a basic amine function86-89. Indeed, a TAM analogue lacking the amine function is rendered completely inactive as an antifungal90. In consideration of TAM’s relatively low safety profile, medicinal chemistry-based optimisation of this pharmacologically attractive biologically-privileged scaffold may yield analogues with a balance of activity and toxicity useful within the anti-infective space.
While novel host-modulating properties of antimicrobials such as azithromycin and nitazoxanide are still being elucidated, host-directed anti-cancer drugs are emerging as antimicrobial treatments in their own right. The shared novelty of these therapeutics is the increased range of infection types able to be treated relative to pathogen-targeting antimicrobials, which are limited by the lack of conserved targetable moieties across pathogen types. Indeed, it is unsurprising to find that potential pan-pathogen antimicrobials may be repositioned to treat cancer. Niclosamide, for example, exhibits activity suggested for several cancer types, including acute myelogenous leukaemia, colon, and ovarian cancers by high-throughput screening. Similarly, ivermectin has been shown to induce immunogenic cancer cell death (ICD) and robust T cell infiltration into breast tumours. Ultimately, repositioning studies, both of anticancer drugs and antimicrobials, are the sole source of discovering clinically-viable pan-pathogen antimicrobials, and can therefore be used as a metric for formally characterising such drugs.