7. 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 significant both for 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’ 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 identified as a physiological target for all compounds that can be dispersed as gases or aerosols123. Understanding the effects of these substances on the lung was identified as a key consideration in the mitigation of bioterrorist threats124. 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 from 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.
COVID-19 emerged as a respiratory viral pandemic, leading to the use of steroid treatments to curb hyperinflammatory symptoms in affected patients. Prior to the pandemic, however, the use of pan-pathogen antimicrobial agents to treat inflammatory 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 of non-infectious airway inflammatory diseases such as allergic asthma125. 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 inflammatory airway diseases such as cystic fibrosis, asthma, and COPD126. Antagonists of the Ca2+-activated Cl- channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease127. Screening a library of 580,000 compounds identified niclosamide and nitazoxanide as potent TMEM16A antagonists blocking airway smooth muscle depolarisation and contraction128. 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.
The idea for ‘general’ drugs for pandemics is not new. In 2007, the Strategic Plan for Biodefense Research by the U.S. Department of Health and Human Services (HHS) and the National Institute of Allergy and Infectious Diseases (NIAID) stated that ‘anti-infectives with broad-spectrum activity directed at common, invariable, and essential components of different classes of microbes could potentially be effective against both traditional and non-traditional threats’129. However, developing broad-spectrum drugs has proven difficult because pharmaceutical companies and regulators are more accustomed to developing and evaluating drugs that target a specific disease: the ‘one bug-one drug’ paradigm. Similarly, the Transformational Medical Technologies (TMT) initiative, established in the U.S. Department of Defense in 2006, was conceived as a five-year, US$1.5-billion project that would accelerate the development of countermeasures such as ‘broad-spectrum’ therapies that would work against multiple bacterial and viral pathogens, especially haemorrhagic fever viruses such as Ebola and Marburg130. Indeed, the Oxford dictionary definition for the term ‘general’ is: ‘affecting or concerning all things; broad, comprehensive, and widespread’. There are no pan-pathogen inhibitors that target conserved properties across pathogen classes. However, by targeting the host-pathogen interactome, host-modulating antimicrobials overcome this limitation, being able to treat diseases across pathogen classes. This property is what makes host-modulating antimicrobials the first antimicrobial class to display ‘pan-pathogen’ properties. Pan-pathogen antimicrobials, due to their clinical safety profile for a myriad of diseases and anti-infective efficacy against a range of pathogens, may therefore satisfy the requirements for a new ‘general’ class of antimicrobials for pandemics, even as stipulated by the current director of NIAID and chief medical advisor to the current U.S. President (Fig. 2)131.