3. Host-modulating antimicrobials
The success of magic bullets and immunomodulatory therapies in the
20th century and the induction of the host-pathogen
interactome model have propelled convergent research into antimicrobials
with host-modulating properties over the last few
decades22. Such ‘host-modulating antimicrobials’ have
become a desideratum for all disciplines of modern antimicrobial
development due to lower probabilities of drug interactions (compared to
the use of immunomodulatory therapies in conjunction with
antimicrobials) associated with higher patient compliance, increased
therapeutic range, and reduced contributions to antimicrobial
resistance23.
Even before COVID-19, canonical antiviral drug development was being
challenged. Traditional antivirals target virus proteins, incur higher
development costs relative to antibiotics, offer limited therapeutic
range, and are liable to escape mutant selection24.
RNA viruses like SARS-CoV-2 are particularly limited in informational
size, and have adapted to subvert multitasking host
proteins25. Such solutions to the viral information
economy paradox are conserved, offering the chance to leverage
dependency on host proteins for host-directed antiviral therapies that
are more effective, broad-acting, and economical26.
Furthermore, host-directed therapies can synergise with increased
availability of bioactive compounds (such as the development of
nitazoxanide), and recent advances in precision medicine, such as genome
editing, targeted delivery methods, and RNAi27.
Indeed, such advances have been driven by an increasingly holistic
appreciation of host-virus interactions, the cornerstone of the emerging
field of neo-virology28. A successful antiviral
development paradigm will serve to complement rather than replace
vaccine development for emerging viruses29. Indeed,
host-directed antivirals can reduce replication and tissue tropism
whilst maintaining viral antigenicity for vaccine
development30,31.
As viruses are obligate parasites, key similarities exist between
antiviral and antiparasitic development32. For
example, antimicrobials that directly target Leishmania parasites
has been limited by the capacity of Leishmania to rapidly evolve
towards drug-resistance phenotypes, a property linked to its genome
plasticity33. New strategies that are more refractory
to the emergence of drug resistance target Leishmania viability
indirectly via mechanisms of host-parasite interaction, including
parasite-released ectokinases and host epigenetic regulation, which
modulate host cell signalling and transcriptional regulation
respectively34.
The past 15 years have seen an acceleration in antifungal drug
development, culminating in an armamentarium of systemic antifungal
agents including 5 classes of drugs including amphotericin B (AmB), the
azoles, and the echinocandins35. Although theirin vitro inhibitory and direct fungicidal effects are well
characterised, antifungals also have indirect, immune system-mediated
effects on fungi, which are only now coming to
light36. Considering the substantial role of the
host’s immune response in regulating fungal infection, a better
understanding of these immunopharmacological properties have been argued
to be potentially instrumental in designing rational drug therapy for
invasive fungal infection (IFI)37. Utilisation of
immunomodulatory properties of available antifungals has been suggested
as a strategy to treat IFI38.
Overall, Casadevall and Pirofski envisioned that a consequence of the
host-pathogen interactome model would be the unification of a lexicon
which emphasised the difference between microbes and specific microbial
attributes instead of highlighting common attributes. Without this
unification, the disciplines of bacteriology, mycology, parasitology,
and virology become increasingly insular, despite asking similar
questions about the nature of infection. However, what is evident today
is the movement of these disparate disciplines towards host-modulation,
not unification. This is because the magic bullet model for
antimicrobial development has cemented the fragmentary disposition of
the disciplines of antibiotic, antifungal, antiparasitic, and antiviral
development by classifying antimicrobials according to the associated
inhibited pathogen. However, discoveries of conserved targetable
moieties of the host-pathogen interactome across pathogen classes is
representative of a movement towards unification of the microbial
disciplines.