Tetracycline compounds with non-antimicrobial organ protective properties: possible mechanisms of action

Abstract

Tetracyclines were developed as a result of the screening of soil samples for antibiotics. The first(t) of these compounds, chlortetracycline, was introduced in 1947. Tetracyclines were found to be highly effective against various pathogens including rickettsiae, as well as both gram-positive and gram-negative bacteria, thus becoming the first class of broad-spectrum antibiotics. Many other interesting properties, unrelated to their antibiotic activity, have been identified for tetracyclines which have led to widely divergent experimental and clinical uses. For example, tetracyclines are also an effective anti-malarial drug. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Another tetracycline, doxycycline is known to exert anti-protease activities. Doxycycline can inhibit matrix metalloproteinases which contribute to tissue destruction activities in diseases such as periodontitis. A large body of literature has provided additional evidence for the "beneficial" actions of tetracyclines, including their ability to act as reactive oxygen species scavengers and anti-inflammatory agents. This review provides a summary of tetracycline's multiple mechanisms of action as a means to understand their beneficial effects.

Graphical abstract

Fig. 1

Proposed means by which tetracyclines loose their protein synthesis inhibitory capacity in pathogens. This may occur secondary to the enhanced extrusion of the drug, decreased entry, displacement from ribosomes or enzymatic inactivation.

Fig. 2

Chemical structure of tetracyclines.

Fig. 3

Proposed means by which doxycycline acting through zinc and calcium chelation may act to inhibit matrix metalloproteinases.

Fig. 4

Possible sites of action of minocycline on suppressing apoptotic signals in cells.