Pleiotropic Effects of Tetracyclines in the Management of COVID-19: Emerging Perspectives

Abstract

Coronavirus disease 2019 (COVID-19) is a global infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Approximately 15% of severe cases require an intensive care unit (ICU) admission and mechanical ventilation due to development of acute respiratory distress syndrome (ARDS). Tetracyclines (TCs) are a group of bacteriostatic antibiotics, like tetracycline, minocycline, and doxycycline, effective against aerobic and anaerobic bacteria as well as Gram-positive and Gram-negative bacteria. Based on available evidences, TCs may be effective against coronaviruses and thus useful to treat COVID-19. Thus, this review aims to provide a brief overview on the uses of TCs for COVID-19 management. SARS-CoV-2 and other coronaviruses depend mainly on the matrix metalloproteinases (MMPs) for their proliferation, cell adhesion, and infiltration. The anti-inflammatory mechanisms of TCs are linked to different pathways. Briefly, TCs inhibit mitochondrial cytochrome c and caspase pathway with improvement of lymphopenia in early COVID-19. Specifically, minocycline is effective in reducing COVID-19-related complications, through attenuation of cytokine storm as apparent by reduction of interleukin (IL)-6, IL-1, and tumor necrosis factor (TNF)-α. Different clinical trials recommend the replacement of azithromycin by minocycline in the management of COVID-19 patients at high risk due to two main reasons: 1) minocycline does not prolong the QT interval and even inhibits ischemia-induced arrhythmia; 2) minocycline displays synergistic effect with chloroquine against SARS-CoV-2. Taken together, the data presented here show that TCs, mainly doxycycline or minocycline, may be potential partners in COVID-19 management, derived pneumonia, and related complications, such as acute lung injury (ALI) and ARDS.

Keywords: COVID-19; SARS-CoV-2; acute respiratory distress syndrome; coronavirus disease 2019; tetracyclines.

FIGURE 1

Pleiotropic effects of tetracycline in SARS-CoV-2 infection. Tetracycline has antiviral and anti-inflammatory effects. Antiviral effects of tetracycline are through inhibition of RNA-polymerase and serine protease dependent viral replications, and inhibition of the expression of CD26 and CD147, which are regarded as entry-point for SARS-CoV-2 with subsequent reduction in viral load. Anti-inflammatory effects of tetracycline are through inhibition of matrix metalloproteinases (MMPs), nuclear factor kappa B (NF-κB), Nod-like receptor pyrin 3 (NLRP3) inflammasome, and release of pro-inflammatory cytokines with subsequent attenuation of cytokine storm development. Taken together, both anti-inflammatory and antiviral effects of tetracycline inhibit development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in COVID-19.