key: cord-1016826-x58vcoyz authors: Prathapan, Praveen title: A determination of pan-pathogen antimicrobials? date: 2022-01-24 journal: Med Drug Discov DOI: 10.1016/j.medidd.2022.100120 sha: 921fd455c383e35b0d08f1def4d5fa48b0e45e8f doc_id: 1016826 cord_uid: x58vcoyz While antimicrobial drug development has historically mitigated infectious diseases that are known, COVID-19 revealed a dearth of ‘in-advance’ therapeutics suitable for infections by pathogens that have not yet emerged. Such drugs must exhibit a property that is antithetical to the classical paradigm of antimicrobial development: the ability to treat infections by any pathogen. Characterisation of such ‘pan-pathogen’ antimicrobials requires consolidation of drug repositioning studies, a new and growing field of drug discovery. In this review, a previously-established system for evaluating repositioning studies is used to highlight 4 therapeutics which exhibit pan-pathogen properties, namely azithromycin, ivermectin, niclosamide, and nitazoxanide. Recognition of the pan-pathogen nature of these antimicrobials is the cornerstone of a novel paradigm of antimicrobial development that is not only anticipatory of pandemics and bioterrorist attacks, but cognisant of conserved anti-infective mechanisms within the host-pathogen interactome that are only now beginning to emerge. Ultimately, the discovery of pan-pathogen antimicrobials is concomitantly the discovery of a new class of antivirals, and begets significant implications for pandemic preparedness research in a world after COVID-19. At the close of the 19 th 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 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 20 th century as antibiotics, antifungals, antiparasitics, and antivirals: therapeutics which treat infectious disease by targeting the disease-causing pathogen 3 . Nevertheless, over the ensuing decades, several limitations of the germ theory for disease have arisen, chief amongst which is the consideration of the host in determining disease outcome, encapsulated by the growing success of immunomodulatory therapies in treating infectious diseases 4 . Even today, an increasing understanding of the immune system has facilitated the discovery and development of novel drug targets and approaches for immunomodulatory interventions 5 . This has led to more advanced types of immune therapies, such as monoclonal antibodies and cytokines, entering clinical use 6 . During COVID-19 there was a paucity of effective antiviral drugs and the most effective treatments emerged from anti-inflammatory drugs such as dexamethasone and even the antiparasitic agent ivermectin 7, 8 . A further limitation of germ theory is the lack of consideration of mutable pathogen properties, such as antigenic determinants, replicative rates, and tropism, which stimulate immune responses to pathogens and in turn affect pathogenicity. A more inclusive approach to investigating pathogenesis must ultimately consider both the pathogen and host as complex systems that dynamically affect each other 9, 10 . Today, these limitations have now been consolidated by the contemporary 'hostpathogen interactome' model, which recognises the contribution of both the host and pathogen in determining disease outcome 11 . This review highlights the development of host-modulating antimicrobials and the recent discovery of general anti-infective signalling pathways such as STING and MAPK, and contends that deliberation of the host-pathogen interactome model requires that antimicrobials should be defined not merely by their ability to inhibit a pathogen, but by their propensity to treat a disease. This theoretical excogitation, as argued henceforth, gives rise to 'pan-pathogen' antimicrobials, and thus contributes significantly to bioterrorist and pandemic preparedness therapeutic research in the 21 st century. The use of immunomodulatory therapies to treat infectious disease, such as the recent success of dexamethasone to treat COVID-19, is indicative of the need to consider not only the disease-causing pathogen in therapeutic development, but contributions of the host too. Casadevall and Pirofski's seminal damage-response framework was propounded as an alternative to host-based and pathogen-based systems, and stated that microbial pathogenesis, whether bacterial, fungal, parasitic or viral is the outcome of interactions between both the host and a microorganism 12 . Host damage is identified as a common principle with which to define and measure this interaction ( Fig.1) [13] [14] [15] . Recognition of the need to consider both the host and pathogen in pathogenesis has implications both for disease characterisation and antimicrobial development. Currently, classifications of microorganisms are based on phylogenetic groups (bacteria, fungi, parasites, viruses) 16, 17 . Casadevall and Pirofski argue this system is limited by the fact that most members of any group are not pathogenic in a host; of 150,000 fungal species, for example, only around 150 are pathogenic for humans 17 . However, classifications based on the perceived capacity of a microorganism to cause disease are equally inadequate as changes in host immune function, ecology, and/or behaviour can render them obsolete 18 . As discussed later, classifying pathogens based on phylogenetic groups has been mirrored by the antimicrobial lexicon, which currently classifies antimicrobials according to their inhibitory activity against microbial phylogenetic groups (antibiotics, antifungals, antiparasitics, antivirals), encouraging a bias of therapeutic development towards pathogen-killing as opposed to host-pathogen interactome targeting and modulation 19 . The use of host damage as the principle with which to categorise pathogens allows them to be classified according to the common denominator of pathogenic outcomes. Pathogens that cause similar types of diseases can be grouped together despite differences in phylogeny and growth characteristics. According to Casadevall and Pirofski, pathogens grouped in a single 'Class' can share similarities with regard to the shape of the damage-response curve as a function of the host immune response 20, 21 . Ultimately, the host-pathogen interactome model crystallises the contemporary view of disease outcome as being determined both by the contributions of the host as well as the pathogen, a marked departure from the classical pathogencentred view propounded in the early 20 th century, with ramifications for microbial, immunological, and antimicrobial studies. The success of magic bullets and immunomodulatory therapies in the 20 th century and the recent induction of the host-pathogen interactome model have propelled convergent research into antimicrobials with host-modulating 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 . The last few years have seen a number of reviews describing various ways the host response can be modulated to maximise bacterial killing whilst minimising inflammatory tissue damage, reflecting a need for an orthogonal view for treating bacterial infection 24-27 . Host-directed therapies for bacterial infections have also long been argued as a strategy to overcome antimicrobial resistance, even emerging as a promising approach to the treatment of tuberculosis 28-29 . In addition to antibiotics, canonical antiviral drug development has also been challenged, even before COVID-19. Traditional antivirals target virus proteins, incur higher development costs relative to antibiotics, offer limited therapeutic range, and are liable to escape mutant selection 30 . RNA viruses like SARS-CoV-2 are particularly limited in informational size, and have adapted to subvert multitasking host proteins 31 . Such solutions to the viral information economy paradox are conserved, offering the chance to leverage dependency on host proteins with hostdirected antiviral therapies that are more effective, broad-acting, and economical 32 . Moreover, 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 33 . Indeed, such advances have been driven by an increasingly holistic appreciation of host-virus interactions, the cornerstone of the emerging field of neovirology 34 . Particularly in light of the recent pandemic, successful antiviral development paradigm will serve to complement rather than replace vaccine development for emerging viruses 35 ; host-directed antivirals can reduce replication and tissue tropism whilst maintaining viral antigenicity for vaccine development 36, 37 . As viruses are obligate parasites, key similarities exist between antiviral and antiparasitic development 38 . For example, antimicrobials that directly target Leishmania parasites have been limited by the capacity of Leishmania to rapidly evolve towards drug-resistance phenotypes, a property linked to its genome plasticity 39 . 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 40 . Interestingly, several purported antivirals, including ivermectin, niclosamide, and nitazoxanide, have been discovered as host-modulating antiparasitic agents. 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 41 . 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 42 . 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) 43 . Utilisation of immunomodulatory properties of available antifungals has been suggested as a strategy to treat IFI 44 . Overall, Casadevall and Pirofski envisioned that a consequence of the host-pathogen interactome model would be the unification of a lexicon which emphasised differences between microbes and specific microbial attributes instead of highlighting commonalities. Without this unification, the disciplines of bacteriology, mycology, parasitology, and virology become increasingly insular, despite asking similar questions about the nature of infection. Yet, what is evident today is the movement of these disparate disciplines towards host-modulation, not unification. This is because the current lexicon for antimicrobial development has cemented the disciplines of antibiotic, antifungal, antiparasitic, and antiviral development by classifying antimicrobials according to the associated inhibited pathogen. Promisingly, however, recent discoveries of conserved targetable moieties of the host-pathogen interactome across pathogen classes may reignite unification of the microbial disciplines. Recent biotechnological advancements have made possible the characterisation of signalling pathways that are conserved across infection types 45, 46 . For example, profiling global gene expression and aligning sequences to reference genomes has enabled isolation of differentially expressed genes pre-and post-infection 47, 48 . Selected genes are assessed against repositories and online databases to probe enrichment of functional biological pathways, and subnetworks are constructed by comparing and connecting identified genes to curated protein-protein interaction databases 49 . Traditional monolayer cell cultures have also been supplanted by human in vitro 3D models which probe functional multicellular interactions of epithelial and immune cells (dendritic cells, neutrophils) 50 . A consequence of such highly detailed mapping techniques is the discovery of general anti-infective signalling pathways that may be therapeutically targeted, particularly STING and MAPK. To protect against infectious agents, the first line of defence by the host requires activation of innate immune signalling pathways. Such pathways are multifactorial, primarily serving to recognise pathogen-associated molecular patterns (PAMPs) 51, 52 . For example, detection of viral RNA particles, such as those associated with COVID-19, is achieved by RIG-I-like receptors (RLRs) 53 . Host defence countermeasures, including production of type I interferons (IFNs), are similarly triggered by microbial DNA from bacteria, viruses, and perhaps parasites, and are regulated by the cytosolic sensor, stimulator of interferon genes (STING) 54, 55 . Recent discovery of STING signalling has provided considerable insight into microbial pathogenesis, mechanisms of host defence, and causes of inflammatory disease and even cancer 56 . Regulation of the STING pathway has therefore been suggested as a pan-pathogen antimicrobial strategy 57 . Given the importance of STING as a modulator of both antiviral and proinflammatory 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 58 . STING also exhibits tissue-specific localisation of expression in the lung, thus potentially contributing to protection against both bacterial and viral respiratory tract infection 59 . Considering the ability of azithromycin, a pan-pathogen antimicrobial, to upregulate virus-induced type I interferon responses, its use as an therapeutic 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, with exciting implications for the development of future pan-pathogen antimicrobials with identified host targets 60, 61 . The MAP kinases (MAPKs), which include ERK, JNK, and p38 families, comprise an integral part of the host intracellular signalling network, essential for signal transduction from receptors and stimuli to biological reaction [62] [63] [64] [65] . 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 66, 67 . Macrolides, including azithromycin, are a class of diverse compounds which span 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 hyperinflammatory diseases such as diffuse panbronchiolitis (DPB) has served to extend their use to a number of chronic inflammatory diseases 68 . Macrolides have been shown to modulate intracellular MAPK, especially ERK1/2, and the NF-kB pathway downstream of ERK 69 . Due to the fact that these pathways exert plethoric cellular functions, including inflammatory 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 70, 71 . Intriguingly, however, specific proteins and receptors targeted by macrolides that affect MAPK/NF-kB signalling have not yet been identified, offering an avenue for experimental verification. 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 72 . 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 73 . Tizoxanide, the main active metabolite of nitazoxanide, exerts anti-inflammatory effects by inhibiting the production of proinflammatory cytokines and suppressing activation of the NF-kB and the MAPK signalling pathways in LPS-treated macrophage cells 74 . 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 75 . Moreover, ivermectin, a potential treatment for COVID-19, reverses drug resistance in cancer cells via the EGFR/ERK/Akt/NF-kB pathway 76 . During pathogenesis, signalling pathways governing apoptosis, mitogenesis, cell proliferation, metabolism, and cytoskeletal reorganisation, which are regulated by ERK/MAPK signalling, are co-opted for biologic needs of the virus 77 . 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 78, 79 . As a corollary, it is of no surprise that host-directed anti-cancer therapies exhibit promising anti-infective properties with pan-pathogen potential; these include heat shock protein 90 (Hsp90) inhibitors, tamoxifen, and tyrosine kinase inhibitors such as diarylureas [80] [81] [82] . Autophagy signalling has also emerged as a host pharmacological target with broad- With such efficacy against a range of infectious diseases, to define azithromycin as an antibiotic or nitazoxanide as an antiparasitic agent oversimplifies their antimicrobial efficacy, precluding discovery of general infection mechanisms, rapid consideration for pandemics, and constructive unification of antimicrobial studies. Indeed, in the present pandemic, several studies addressed this by compiling pan-pathogen repositioning histories of therapeutic candidates 99 . In order to more accurately describe a candidate's properties as well as hasten their consideration for pandemics, we previously propounded a system used to define antimicrobials based on both their ability to inhibit a pathogen in vitro and treat the corresponding disease in the clinical setting 100 . This system is based on Oprea and Overington's Drug Repositioning Evidence Level (DREL) classification 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) (Table 2) [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] . We have made two corrections to our system. Pan-pathogen antimicrobials can therefore simply be defined as antimicrobials that are DREL 4 for two antimicrobial classes. Previously we propounded the term 'broad-spectrum therapeutic' to denote this; 'panpathogen antimicrobial' and 'broad-spectrum anti-infective' are preferred alternatives 118 . However, we affirm the term 'broad-spectrum therapeutic' may be used to describe a drug with pan-pathogen pharmacological properties that has not been fully tested in a clinical setting. Thus, a broad-spectrum therapeutic such as niclosamide may but not be a pan-pathogen antimicrobial until DREL 4 repositioning studies are conducted. Our system, hereby termed 'BFPV classification' (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 the magic bullet-oriented lexicon by defining 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 physiological context. As the Casadevall-Pirofski model for disease considers contributions from both the pathogen and host, so the BFPV classification considers the ability of a given antimicrobial to treat the disease, not merely its facility to inhibit a pathogen. This classification would also consider the effectiveness of nonantimicrobial therapeutics in treating infections, such as dexamethasone for COVID- 19 . 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 classifies drugs according to the degree to which they reduce damage resulting from the hostpathogen 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 classifications and predictions are subject to 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. 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, due to their range, such drugs are preparatory to pandemics and bioterrorism, and so their health and economic value is of significance for both governments and enterprise. Bioterrorism is a unique topic in the literature, appearing at the confluence of research publications and government mitigation strategy reports. The term 'bioterrorism' is distinct from 'biowarfare' with regard to the origin of the threat being from terrorist groups rather than nation states. In contrast to conventional warfare, where the mode of warfare is known, terrorism is more difficult to predict. 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 definition. Indeed, terrorists can deploy a range of agents including classical chemical warfare agents (as in WWII). However, for the scope of this review and in consideration of the recent COVID-19 pandemic, the definition is herein limited to biologically viable particles i.e. bacteria, fungi, parasites, and viruses. In 2004, the British Association for Lung Research organised a symposium entitled 'Bioterrorism: The Lung Under Attack' in which the lung was identified as a physiological target for gaseous and aerosol-based compounds 119 . Understanding the effects of these substances on the lung was identified as a key consideration in the mitigation of bioterrorist threats 120 . COVID-19 emerged as a respiratory viral pandemic, leading to the use of steroid treatments to curb acute respiratory distress and lung hyperinflammation in affected patients. Even prior to the pandemic the use of potential pan-pathogen antimicrobials to treat inflammation of the lung was increasing. For example, in vivo studies showed that ivermectin is an effective suppressor of inflammation, rationalising its use as a treatment for non-infectious respiratory inflammatory diseases such as allergic asthma, similar to azithromycin 121 . By inhibiting mucus and cytokine release, as well as inducing bronchorelaxation, niclosamide, another potential pan-pathogen antimicrobial, has also emerged as a potentially suitable drug for the treatment of inflammatory airway diseases including cystic fibrosis, COPD, and asthma 122 . A novel mechanism of bronchodilating airways has emerged through the discovery of antagonists of the Ca 2+ -activated Clchannel, TMEM16A, offering a new mechanism to block multiple contractiles operating in severe disease 123 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 emerging infectious diseases. The success of host-modulating therapies alone represents a century-spanning, Kuhnian paradigm shift from the magic bullet. It must be stated, however, that this is not a rejection of Paul Ehrlich's paradigm. Rather, as Einstein explicated: 'the larger view encompasses rather than rejects the more restricted view'; azithromycin is still a magic bullet antibiotic, yet its host-modulating properties offer undetermined repositioning potential. In viral infections such as COVID-19, targeting host cell factors and pathways that are required by a given virus for productive replication and proliferation offers the opportunity for broad-acting treatments against both viral annexation of host cellular processes as well as ensuing pathophysiology. Indeed, all four antimicrobials highlighted herein exhibit host-directed broad-spectrum antiviral properties, the desideratum of post-COVID-19 antiviral development 9 . In the future, 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 20 th century became more specific for the bacterium and virus, it is conceivable that pan-pathogen antimicrobials of the 21 st 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 This review represents the first time 'pan-pathogen' has been recognised as a pharmacological property. Azithromycin, ivermectin, niclosamide, and nitazoxanide assert an advantage over traditional antibiotics and antivirals in their ability to treat a wider range of infectious diseases by regulating the host-pathogen interactome, as evidenced by their extensive repositioning history and recent spotlighting during the pandemic. Like with all 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. The growing practice of drug repositioning for infectious diseases can alternatively be considered the sole method of pan-pathogen antimicrobial discovery, such that current antimicrobial repositioning programmes have profound contributions to 21 st century antiviral development. Indeed, pan-pathogen antimicrobials can be considered a novel antiviral class, one that has been previously hypothesised in pandemic preparedness research. Damage can occur throughout the host response, which is represented by a continuum from 'weak' to 'strong'. 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As repositioning studies ensue, DREL numbers for any given therapeutic are subject to change.