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.