8. Discussion
For over a century, drug development has been tailored towards known
diseases and pathogens. In order to prepare for a novel pathogen, a
generalised drug development strategy is required, cognisant of a range
infection types. In theory, both magic bullet and magic blanket
paradigms can yield pan-pathogen antimicrobials. In reality, only one
has. Host-directed therapies that interfere with host cell mechanisms,
enhance immune responses, and reduce exacerbated inflammation or balance
host reactions at the site of pathology hold promise for the selective
and symptomatic treatment of infectious diseases. In viral infections
such as COVID-19, targeting host cell factors and pathways that are
required by a given virus for productive replication and spread offers
the opportunity for broad-acting treatments. Knowledge of host cell
factors and pathways commonly used by different pathogens can be greatly
enhanced by probing host targets of the pan-pathogen antimicrobials
identified in this review. Consequently, as antibiotics and antivirals
of the 20th century became more specific for the
bacterium and virus, pan-pathogen antimicrobials of the
21st century will be increasingly specific for the
host (Table 3).
Development of antimicrobials which target the host-pathogen interactome
has more opportunity for growth relative to pathogen-targeting
antimicrobials due to the number of factors yet to be discovered. Great
therapeutic potential also derives from the fact that pharmacological
modulation of infectious diseases is considered within an acute, not
chronic, pathological context, allowing for clinical application of more
powerful modulators. A caveat, however, is the dynamic nature of the
host-pathogen interactome across disease pathogenesis. Indeed, a crucial
difference between targeting the host-pathogen interactome and targeting
the pathogen is temporality, and great emphasis has been placed on the
need to develop biomarkers that accurately reflect the host
immunological signature in order to effectively inform application of
host modulators. Biomarkers indicate the stage of infection, allow the
monitoring of treatment success or failure, provide information on organ
involvement and type of inflammation, and permit patient stratification
for selected immunomodulatory therapies. As biomarkers become
increasingly accurate at reflecting immune status, so the effects of
host-modulating antimicrobials can be better predicted. That being said,
most immunomodulatory strategies have been developed without
understanding the full complexity of their interaction with the host and
hence the fact that we do not yet fully understand the complexity of the
host-drug interaction of host-modulating antimicrobials need not
preclude development and application of host-modulating therapies;
rather identification of successful magic blankets can inspire further
investigations into the nature and context of their pharmacological
targets. As was the case for magic bullets a century ago, current
understanding of host-modulating antimicrobials is still in its infancy,
and is an attractive field for further research.