1. Introduction
At the close of the 19th century, the work of Louis
Pasteur and Robert Koch led to the ‘germ theory’ of disease, which
stated that pathogens, too small to see without magnification, can cause
disease1. This was reciprocated by Paul Ehrlich’s
‘magic bullet’, which described the need for chemical drugs that target
the pathogen without harming the host2. The magic
bullet hypothesis was successfully realised in the
20th century as antibiotics, antifungals,
antiparasitics, and antivirals: therapeutics which treat infectious
disease by targeting the disease-causing pathogen3.
The success of immunomodulatory therapies in treating infectious
diseases highlighted a limitation of the germ theory of disease, which
did not consider the contribution of the host in determining disease
outcome4. Even today, a growing understanding of the
immune system has enabled the discovery and development of novel drug
targets and approaches for immunomodulatory
interventions5. More advanced types of immune
therapies, such as monoclonal antibodies and cytokines, have already
entered clinical use and their application is being increasingly
expanded6. Moreover, during infection, pathogen
properties that are mutable, such as antigenic determinants, replicative
rates, and tropism, stimulate immune responses to pathogens, which in
turn affects the lifecycle of the pathogen. A more inclusive approach to
investigating pathogenesis therefore considers the pathogen and host as
complex systems that dynamically affect each other7,8.
When COVID-19 emerged, there were no suitable antiviral drugs
available9. Over a year later, the most effective
treatments for this viral disease have emerged from unanticipated
places: anti-inflammatory drugs such as dexamethasone and even the
antiparasitic agent ivermectin10.
This therapeutic outcome is congruent with the now-accepted model for
infectious disease, the ‘host-pathogen interactome’ model, which
recognises the contribution of both the host and pathogen in determining
disease outcome; an advancement from germ theory11.
This review examines how antimicrobial development has concomitantly
evolved from pathogen-killing magic bullets to host-modulating magic
blankets; explores how the discovery of general anti-infective
signalling pathways such as STING and MAPK provides a pharmacological
targetome for such antimicrobials; and formally identifies two
clinically-approved pan-pathogen antimicrobials which underscore a novel
paradigm of drug development cognisant of antimicrobial resistance,
pandemics such as COVID-19, the threat of bioterrorist attacks, and the
host-pathogen interactome model of disease.