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.