A New Determination of Pan-Pathogen Antimicrobials

Drug repositioning studies in recent decades have revealed a growing number of antimicrobials effective at treating infection types tangential to their original antimicrobial classication. Such ‘pan-pathogen antimicrobials’ (or ‘broad-spectrum anti-infectives’) have not yet been formally characterised. This review examines historical limitations of the canonical antimicrobial lexicon in light of the contemporary model for infectious disease and propounds a taxonomy that denes antimicrobials according to the host-pathogen interactome, not the pathogen. By doing so, antimicrobials that are effective at treating multiple infection types are highlighted, namely azithromycin, ivermectin, niclosamide, and nitazoxanide. Recognition of the pan-pathogen nature of these antimicrobials can stimulate a more unied approach to antimicrobial development cognisant of generalised anti-infective mechanisms within the host-pathogen interactome and anticipatory of future pandemics and bioterrorist attacks.


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 magni cation, can cause disease 1 . This was reciprocated by Paul Ehrlich's 'magic bullet', which described the need for chemical drugs that target the pathogen without harming the host 2 . 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 pathogen 3 .
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 outcome 4 . Even today, a growing understanding of the immune system has enabled the discovery and development of novel drug targets and approaches for immunomodulatory interventions 5 . More advanced types of immune therapies, such as monoclonal antibodies and cytokines, have already entered clinical use and their application is being increasingly expanded 6 . 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 other 7,8 . When COVID-19 emerged, there were no suitable antiviral drugs available 9 . Over a year later, the most effective treatments for this viral disease have emerged from unanticipated places: anti-in ammatory drugs such as dexamethasone and even the antiparasitic agent ivermectin 10 .
This therapeutic outcome is congruent with the now-accepted model for infectious disease, the 'hostpathogen interactome' model, which recognises the contribution of both the host and pathogen in determining disease outcome; an advancement from germ theory 11 . This review examines how antimicrobial development has concomitantly evolved from pathogen-killing magic bullets to host-

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 hostmodulating properties over the last few decades 22 . 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 resistance 23 .
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 selection 24 . RNA viruses like SARS-CoV-2 are particularly limited in informational size, and have adapted to subvert multitasking host proteins 25 . 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 economical 26 . 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 RNAi 27 . Indeed, such advances have been driven by an increasingly holistic appreciation of host-virus interactions, the cornerstone of the emerging eld of neovirology 28 . A successful antiviral development paradigm will serve to complement rather than replace vaccine development for emerging viruses 29 . Indeed, host-directed antivirals can reduce replication and tissue tropism whilst maintaining viral antigenicity for vaccine development 30,31 .
As viruses are obligate parasites, key similarities exist between antiviral and antiparasitic development 32 . 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 plasticity 33 . 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 respectively 34 .
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 echinocandins 35 . Although their in 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 light 36 . 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 IFI 38 .
Overall, Casadevall and Pirofski envisioned that a consequence of the host-pathogen interactome model would be the uni cation of a lexicon which emphasised the difference between microbes and speci c microbial attributes instead of highlighting common attributes. Without this uni cation, 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 uni cation. 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 hostpathogen interactome across pathogen classes is representative of a movement towards uni cation of the microbial disciplines.

Host Anti-infective Responses
Several biotechnological advancements have made possible the characterisation of signalling pathways that are conserved across infection types 39,40 . Pro ling global gene expression and sequence alignment to reference genomes enable isolation of differentially expressed genes pre-and post-infection 41,42 . Selected genes are assessed against repositories and online databases to probe enrichment of functional biological pathways, and subnetworks are constructed by comparing and connecting identi ed genes to curated protein-protein interaction databases 43 . Traditional monolayer cell cultures are also being supplanted by human in vitro 3D models which probe functional multicellular interactions of epithelial and immune cells (dendritic cells, neutrophils) 44 . Detailed mapping of host anti-infective responses in this way has led to the emergence of key signalling pathways that may be targeted by both existing and future pan-pathogen antimicrobials, such as STING and MAPK.
The rst line of host defence against infectious agents involves activation of innate immune signalling pathways that recognise speci c pathogen-associated molecular patterns (PAMPs) 45,46 . For example, RIG-I-like receptors (RLRs) have evolved to detect viral RNA species and to activate the production of host defence molecules and cytokines that stimulate adaptive immune responses; their regulation by hostderived ncRNAs is of particular interest 47 . In addition, host defence countermeasures, including the production of type I interferons (IFNs), can also be triggered by microbial DNA from bacteria, viruses and perhaps parasites and are regulated by the cytosolic sensor, stimulator of interferon genes (STING) 48, 49 .
The discovery of the STING signalling pathway has provided considerable insight into microbial pathogenesis, mechanisms of host defence, and causes of in ammatory disease and even cancer 50 . Regulation of the STING pathway has therefore been suggested as a pan-pathogen antimicrobial strategy 51 . Given the importance of STING as a mediator of both antiviral and pro-in ammatory responses to viral infection, it is interesting to consider last year it was shown to have a crucial role in replication of RV-A and RV-C rhinoviruses 52 . STING is relatively highly expressed in lung tissue and thus may contribute to protection against both bacterial and viral respiratory tract infection 53 . Considering azithromycin's ability to upregulate virus-induced type I interferon responses, its use as an antibiotic for pulmonary bacterial infections, and the fact that it has been described as a 'holy grail' to prevent exacerbations in chronic respiratory disease, a molecular mechanism of azithromycin and other macrolides via STING is possible 54,55 .
The MAP kinases (MAPKs), which include ERK, JNK, and p38 families, constitute an integral part of the host intracellular signalling network, essential for signal transduction from receptors and stimuli to biological reaction 56-59 . Appropriate functioning of MAPK signalling is thus critical to mount effective immune responses, and presents a broad-spectrum therapeutic target across pathogen classes, which drugs such as macrolides may exploit 60,61 . Macrolides are a class of diverse compounds which include antibiotics, antifungals, prokinetics, and immunosuppressants. The non-antimicrobial properties of macrolides have been suspected as far back as the 1960s and their successful treating of hyperin ammatory diseases such as diffuse panbronchiolitis (DPB) has served to extend their use to a number of chronic in ammatory diseases 62 . Macrolides have been shown to modulate intracellular MAPK, especially ERK1/2, and the NF-kB pathway downstream of ERK 63 . Due to the fact that these pathways exert plethoric cellular functions, including in ammatory cytokine production, cell proliferation, and mucin secretion, modulation of ERK1/2 and NF-kB can explain the majority of the reported immunomodulatory effects of macrolides 64,65 . Intriguingly, however, speci c proteins and receptors targeted by macrolides that affect MAPK/NF-kB signalling have not yet been identi ed, offering an avenue for experimental veri cation. Indeed, putative binding molecule(s) may have multiple mechanisms of action. Overall, macrolide treatment of DPB, asthma, bronchiectasis, rhinosinusitis, and CF is made possible by polymodal modulation exerted at different levels of cellular signalling, yet among these, modulation of ERK1/2 and transcription factors is prominent, consistent, and clearly unrelated to antimicrobial properties 66 .
Due to its broad-spectrum anti-infective effect against bacteria, parasites, and viruses, several studies have sought to delineate the underlying molecular mechanism of nitazoxanide, a thiazolide drug 67 . Tizoxanide, the main active metabolite of nitazoxanide, exerts anti-in ammatory effects by inhibiting the production of pro-in ammatory cytokines and suppressing activation of the NF-kB and the MAPK signalling pathways in LPS-treated macrophage cells 68 . Similarly, niclosamide, a potential pan-pathogen antimicrobial, was found to inhibit MAPK/ERK in human glioblastoma studies, indicative of crosstalk between anti-infectives and anti-cancer therapeutics 69 . Moreover, ivermectin, a potential treatment for COVID-19, reverses drug resistance in cancer cells via the EGFR/ERK/Akt/NF-kB pathway 70 . During viral infection, signalling pathways that govern essential physiological roles, such as apoptosis, mitogenesis, cell proliferation, metabolism, and cytoskeletal reorganisation, can be usurped to the bene t of the virus. Considering the vital role played by the ERK/MAPK pathway in controlling diverse host physiological processes, it is not surprising that many viruses co-opt the pathway for their own biologic needs 71 .
Development of new antiviral therapeutics based on clinical trials of ERK/MAPK inhibitors has been suggested for both DNA and RNA viruses, including SARS-CoV-2 recently 72,73 .
Autophagy signalling has also emerged as a host pharmacological target with broad-spectrum antiinfective potential. Recently, the Centers of Excellence for Translational Research (CETR) Program were founded to develop host-directed broad-spectrum anti-infective agents against pathogens with pandemic potential. According to their grant proposal, later funded by the National Institute of Allergy and Infectious Diseases (NIAID), 'broad-spectrum host-directed therapeutics, once approved for clinical use, can be deployed for emerging pathogens, new outbreaks, and pathogens engineered with ill-intent' 74 . The goal of this proposal is to generate autophagy pathway-directed compounds that are active against a range of taxonomically-unrelated pathogens. To accomplish this, several strategies are being employed including targeting Beclin 1 complexes, genes and pathways for autophagy-dependent inhibition of bacterial infection, and Atg gene-dependent immunity 75,76 .
Virulence factors secreted by pathogens have co-evolved to manipulate host signalling pathways via a range of mechanisms, including constitutive pathway activation and subversion of critical signalling molecules. A major challenge is to determine enzymatic activities and host substrates for pathogen virulence factors that show no clear homology to eukaryotic proteins. Following from this, an even more complex challenge is to glean an understanding of the orchestra of factors within the host-pathogen interactome involved in successful infection. Both temporal and spatial considerations are essential for regulating host cells during infection, justifying the employment of model organisms to understand system-level effects of therapeutic intervention within a physiological context. Ultimately, the discovery of conserved anti-infective pathways is a landmark discovery, not only to incite uni cation of microbiological disciplines rst envisioned by Casadevall and Pirofski, but also to mechanistically con rm the therapeutic success of existing antimicrobials which treat diseases pertaining to multiple pathogen classes.

Anti-cancer Drugs As Broad-spectrum Anti-infectives
Repositioning studies of anti-cancer drugs has led to the discovery that targeting certain host proteins yields broad-spectrum anti-infective activity, a further contribution away from the magic bullet paradigm 77 . Heat shock protein 90 (Hsp90) inhibitors and oestrogen receptor antagonists have unearthed therapeutic targets whose modulation may successfully treat malignancies as well as infection.
It has long been understood that microbes have exploited stress proteins as virulence factors for pathogenesis in their hosts 78 . Owing to its ability to sense and respond to the stress conditions, the molecular chaperone Hsp90 is one of the key stress proteins utilised by parasitic microbes 79 . There is growing evidence for the critical role played by Hsp90 in the growth of pathogenic organisms like Candida, Giardia, Plasmodium, Trypanosoma, among others 80 . The attractiveness of Hsp90 as an anticancer drug target has driven much research at laboratory, preclinical and clinical levels for several Hsp90 inhibitors as potential anti-cancer drugs 81 . Similarly, data pertaining to toxicity studies, pharmacokinetics and pharmacodynamics studies, dosage regime, drug related toxicities, dose limiting toxicities, and adverse drug reactions (ADRs) are available for Hsp90 inhibitors, making them attractive repositioning candidates 82 .
The triphenylethylene class of selective oestrogen receptor modulators related to tamoxifen (TAM) has also shown activity against a range of pathogens including bacteria, fungi, parasites, and viruses 83-85 . It has been suggested that the broad spectrum of activity of TAM may be related to its amphipathic chemical properties: a hydrophobic aromatic core linked to a basic amine function 86-89 . Indeed, a TAM analogue lacking the amine function is rendered completely inactive as an antifungal 90 . In consideration of TAM's relatively low safety pro le, medicinal chemistry-based optimisation of this pharmacologically attractive biologically-privileged scaffold may yield analogues with a balance of activity and toxicity useful within the anti-infective space.
While novel host-modulating properties of antimicrobials such as azithromycin and nitazoxanide are still being elucidated, host-directed anti-cancer drugs are emerging as antimicrobial treatments in their own right. The shared novelty of these therapeutics is the increased range of infection types able to be treated relative to pathogen-targeting antimicrobials, which are limited by the lack of conserved targetable moieties across pathogen types. Repositioning studies, both of anticancer drugs and antimicrobials, are the sole source of discovering clinically-viable pan-pathogen antimicrobials, and can therefore be used as a metric for formally characterising such drugs.

Challenging The Antimicrobial Lexicon
The term antibiotic -literally 'opposing life', derives from the Greek ντι anti, "against" and βίος bios, "life". This terminology has been extended to antifungal, antiparasitic, and antiviral drugs, re ecting a lexicon based on Ehrlich's magic bullet. Though this lexicon does not accurately re ect the array of interactions of modern antimicrobials with the host-pathogen interactome, it has not been problematic. Macrolide antibiotics, for example, have been used to treat bacterial infections with the knowledge that their host-modulating properties play a crucial role in pathogen clearance and disease management. The lexicon is challenged, however, when 1) antimicrobials of one class exhibit inhibitory or host-modulating properties characteristic of another class or 2) antimicrobials are used clinically to treat diseases pertaining to another pathogen class. The 'antibiotic' azithromycin and the 'antiparasitic agent' nitazoxanide are examples of antimicrobials that have done both [91][92][93][94] ; azithromycin is clinically used against malarial parasites and nitazoxanide treats bacterial infections such as H. pylori 95,96 .
Both azithromycin and nitazoxanide are immunomodulatory agents. Nitazoxanide treatment results in an increase in IFNγ-and IL-2-secreting CD4 + cells, TLR8-expressing monocytes, IFNα-and IFNβ-mRNA expression, mRNA speci c for type I IFN inducible genes, and mRNA speci c for gene involved in MHC class I presentation 97,98 . The antiviral effects of nitzoxanide and its metabolite derivative tizoxanide result from the immunomodulatory activity stimulating a strong antiviral immune response mediated by both native and acquired mechanisms. In over 10 years of clinical use there has been no reported drug resistance by nitazoxanide treatment and attempts to produce drug resistance under laboratory conditions have generally not met with much success 99 . The immunomodulatory effects of azithromycin are more well-established, having been proven bene cial in treating a variety of chronic illnesses 100,101 . Azithromycin treatment results in decreased production of pro-in ammatory cytokines in the acute phase and promotes resolution of chronic in ammation in the later phases 102 . Speci cally, azithromycin has direct activity on airway epithelial cells to maintain their function and reduce mucus secretion. These characteristics have resulted in the use of azithromycin in the management of a variety of chronic lung diseases including chronic obstructive pulmonary disease, cystic brosis (CF), non-CF bronchiectasis, bronchiolitis obliterans syndrome, diffuse panbronchiolitis, and asthma 103 . It is conceivable that the immunomodulatory properties of azithromycin and nitazoxanide facilitate their treatment of a range of infection types.
With such e cacy against a range of infectious diseases, to de ne azithromycin as an antibiotic or nitazoxanide as an antiparasitic agent oversimpli es their antimicrobial e cacy, precluding discovery of general infection mechanisms, rapid consideration for pandemics, and constructive uni cation of antimicrobial studies. Indeed, in the present pandemic, several studies addressed this by compiling panpathogen repositioning histories of therapeutic candidates 104 . In order to more accurately describe an antimicrobial candidate's properties as well as well to hasten their consideration for pandemics, we highlighted a system used to de ne antimicrobials based on both their ability to inhibit a pathogen in vitro and treat the corresponding disease in the clinical setting 105 . This system is based on Oprea and Overington's Drug Repositioning Evidence Level (DREL) classi cation scheme, which assigns a numerical value to the quality of evidence, which increases as evidence increases from in vitro investigations to animal models and human clinical trials (Table 1) 106 . From this scheme we determined four antimicrobial types (antibiotics, antifungals, antiparasitics, and antivirals) can correspond to four DREL numbers for a given antimicrobial. An antimicrobial that is used clinically as an antimalarial and an antiviral but has no evidence of e cacy against bacteria or fungi is a 0:0:4:4 antimicrobial. The order of the DREL numbers here are: antibiotic = 0, antifungal = 0, antiparasitic = 4, antiviral = 4. If no investigations have been conducted for an antimicrobial class for a given therapeutic, an 'X' may be used to denote this. With an increasing number of repositioning studies being conducted worldwide, particularly in the midst of the current pandemic, a concomitant taxonomic structure can not only classify potential general antimicrobials, but direct future repositioning studies, facilitate comparative therapeutic investigations, and inform treatment application in global health emergencies 107 . From our classi cation system based on DREL we determined azithromycin is a 4:0:4:3 antimicrobial (Table 2). Pan-pathogen antimicrobials can therefore simply be de ned as antimicrobials that are DREL = 4 for two antimicrobial classes.
Previously the term 'broad-spectrum therapeutic' has been propounded to denote this; 'pan-pathogen antimicrobial' and 'broad-spectrum anti-infective' are preferred alternatives 108 . The system, hereby termed the BFPV classi cation scheme (for antiBiotic, antiFungal, antiParasitic, antiViral; alternatively: Bacterial infection, Fungal infection, Parasitic infection, Viral infection) scores the effectiveness of an antimicrobial for a particular pathogen type using three major parameters: in vitro activity, in vivo activity, and clinical effectiveness. This represents a departure from a magic bulletoriented lexicon by de ning an antimicrobial not solely by its ability to inhibit a pathogen but by its ability to shift the damage-response curve towards mitigating damage within the more holistic, physiological context. As pan-pathogen antimicrobial development matures as a discipline in its own right, the DREL system can be replaced by a more accurate framework that classi es drugs according to the degree to which they reduce damage resulting from the host-pathogen interaction as a function of the host immune response, perhaps based on Casadevall and Pirofski's 'Class' scheme for host-pathogen interactomes 20 .
As with the damage-response framework, associated classi cations and predictions are subject to further experimental studies to validate or refute the framework's ability to account for the perturbation of therapeutic intervention on the damage-response curve during microbial pathogenesis.

Bioterrorism And Pandemics
Upon characterising pan-pathogen antimicrobials, the pertinent question arises: so what? The key advantage of pan-pathogen antimicrobials over single-target antimicrobials is the ability to account for diseases that have not yet emerged either by natural means or by human engineering. In other words, such drugs are preparatory to pandemics and bioterrorism, and so their health and economic value is signi cant both for governments and enterprise.
Bioterrorism is a unique topic in the literature, appearing at the con uence of research publications and government mitigation strategy reports. The term 'bioterrorism' differs from 'biowarfare' in the sense that the threat originates from terrorist groups rather than nation states. Unlike conventional warfare, where the enemy and likely mode of warfare are known and understood, terrorism is less easy to predict. At a Winter Meeting of the British Thoracic Society in 2004, the British Association for Lung Research organised a symposium entitled 'Bioterrorism: The Lung Under Attack' in which the lung was identi ed as a physiological target for all compounds that can be dispersed as gases or aerosols 109 . Understanding the effects of these substances on the lung was identi ed as a key consideration in the mitigation of bioterrorist threats 110 . While bioterrorism is often taken to mean acts that involve the use of biological materials such as bacteria, bacterial spores, and viruses, this is a limited de nition. Indeed, terrorists can deploy a range of agents including classical chemical warfare agents from WWII. However, for the scope of this review and in consideration of the recent COVID-19 pandemic, the de nition is herein limited to biologically viable particles i.e. bacteria, fungi, parasites, and viruses.
COVID-19 emerged as a respiratory viral pandemic, leading to the use of steroid treatments to curb hyperin ammatory symptoms in affected patients. Prior to the pandemic, however, the use of panpathogen antimicrobial agents to treat in ammatory of the lung was increasing. For example, in vivo studies showed that ivermectin is an effective suppressor of in ammation, rationalising its use as a treatment of non-infectious airway in ammatory diseases such as allergic asthma 111 . Inhibition of mucus and cytokine release, bronchorelaxation, and reported antibacterial effects have also made niclosamide, another potential pan-pathogen antimicrobial, a potentially suitable drug for the treatment of in ammatory airway diseases such as cystic brosis, asthma, and COPD 112 . Antagonists of the Ca 2+activated Clchannel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease 113 . Screening a library of 580,000 compounds identi ed niclosamide and nitazoxanide as potent TMEM16A antagonists blocking airway smooth muscle depolarisation and contraction 114 . While isoproterenol, a canonical β-agonist, only showed partial bronchodilation of airways, niclosamide and nitazoxanide showed full effects, representing an important treatment for patients with severe asthma and COPD. That current pan-pathogen antimicrobials are repositioned for a multitude of respiratory diseases is a further reason to consider them for future outbreaks and emphasises the need for further research to unearth underlying mechanisms in relation to physiological context.

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 in ammation 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 identi ed in this review. Consequently, as antibiotics and antivirals of the 20th century became more speci c for the bacterium and virus, panpathogen antimicrobials of the 21st century will be increasingly speci c for the host (Table 3). Table 3 Comparison of two antimicrobial paradigms. Classical antimicrobials contending with a single target exploit phenotypic differences between the host and pathogen. Host-modulating antimicrobials target pathogen properties as developed through co-evolution with the host. Consequently, while broad-spectrum antivirals like remdesivir are magic bullets exclusively targeting viruses, azithromycin and nitazoxanide's immunomodulatory properties have rationalised their use against bacterial, parasitic, and even viral infections. Pan-pathogen antimicrobials, therefore, have emerged from magic blanket, not magic bullet, development.

Magic bullet Magic blanket
Drug class Antimicrobial Host-modulating antimicrobial Target Pathogen Host-pathogen interactome Drugs Antibiotics, antifungals, antiparasitics, antivirals BFPV antimicrobials 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 re ect 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 in ammation, and permit patient strati cation for selected immunomodulatory therapies. As biomarkers become increasingly accurate at re ecting 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 identi cation 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 eld for further research.

Conclusion And Future Directions
This review represents the rst time pan-pathogen antimicrobials have been formally identi ed and characterised, and the rst time such drugs have been associated with 'magic blanket' antimicrobial development. Azithromycin, ivermectin, niclosamide, and nitazoxanide assert a unique advantage over traditional antibiotics and antivirals in their ability to treat a wider range of infectious diseases by regulating the host-pathogen interactome. Like with immunomodulatory drugs, however, the use of biomarkers will inform the appropriate application and dosage stipulations of these drugs across infection types. Tempered by their contribution to antimicrobial resistance, such broad-acting drugs may constitute an 'emergency treatment class' for global health emergencies such as COVID-19, future respiratory pandemics, and potential bioterrorist attacks; a property reinforced by their extensive repositioning for pulmonary disorders and substantial affordability and international availability relative to antibody, vaccine, and plasma-based strategies. Ultimately, formal recognition of pan-pathogen antimicrobials can facilitate discovery of conserved infective and anti-infective mechanisms and pharmacophores, enabling the long-campaigned uni cation of the disparate elds of bacteriology, fungology, parasitology, and virology, while heralding a paradigm of antimicrobial development conceptually distinct from the antibiotic era of the 20th century.

Declarations
Acknowledgements Many thanks to our colleagues at the Department of Biochemistry and Trinity College, University of Oxford.
Availability of data and material Not applicable.
Authors' contributions PP conceived, wrote, and edited the manuscript.
Code availability Not applicable.

Con ict of interest
The author declares no con ict of interest.  is represented by a continuum from 'weak' to 'strong'. Therapeutic intervention can shift the curve towards bene ting the host, as denoted by the arrow.