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).