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.