MANUSCRIPT
The COVID-19 pandemic has positioned vaccines at the top of the
therapeutic arsenal. “Born” to help us fight infections, their
effectiveness has been demonstrated in the context of a multitude of
infectious diseases, and there is no doubt of their key role in our
current fight against COVID-19. However, even more remarkable is their
adaptation and development to face new therapeutic challenges, such as
fighting cancer. This is a strikingly similar story to that of another
versatile therapeutic family, the tetracyclines. Following the discovery
of their non-antibiotic properties, such as inhibition of matrix
metalloproteinases (MMPs) and different immunomodulatory effects, they
have been tested in many non-infectious conditions with promising
results. However, their categorization as “antibiotic drugs” is
holding back their clinical application to other pathological
conditions, despite their proven potential and the development of a
novel class of chemically modified tetracyclines (CMTs) devoided of
antibiotic properties. Whilst CMTs could have a chance in a
patent-dominated market, the pharmaceutical industry is not likely to
get on board with drug repurposing strategies involving old tetracycline
antibiotics, such as minocycline and doxycycline. Yet, the
exceptional circumstances that
characterise the current pandemic, particularly challenging for
developing countries, demand cost-effective therapies that can be
readily applied worldwide. Therefore, based on their well-described
benefit in acute respiratory distress syndrome (ARDS) in general, and
given recent reports of their activity against SARS-CoV2 infection, we
would like to draw attention to and encourage the repurposing of
tetracyclines to fight COVID-19.
As of end of July 2021, COVID-19 incidence worldwide remains very high.
Despite the success of vaccination programs in developed countries,
infections are rising again with the spread of new variants, whose
impact on developing countries is far more devastating. The cumulative
number of cases now exceeds 190 million and the number of global
reported deaths exceeds 4 million. Severe COVID-19 cases require
hospital care due to viral pneumonia progressing into ARDS, causing
difficulty in breathing and low blood oxygen levels (Figure 1). However,
in addition to direct respiratory failure (accounting for 70% of fatal
COVID-19 cases), some may succumb to secondary bacterial and fungal
infections. Furthermore, an aggressive inflammatory response (the
‘cytokine storm’) is strongly implicated in airway and multi-organ
damage, leading to permanent sequelae or death by septic shock and
circulatory failure.
Why do we believe that immunomodulatory tetracyclines could help facing
this pathological setting? Many of their pharmacological activities have
already proven useful in ARDS and viral infections. Starting with their
antibiotic properties, tetracyclines are effective and particularly
useful in pneumonias and infections caused by hospital-adquired
multi-resistant bacteria. Hence, rather than a limitation, their
antibiotic activity would play an important role against secondary
bacterial pneumonia in COVID-19 patients (Figure 1 A).