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.