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.