Antibiotic or Anti-inflammatory Agent? The Double-Edged Sword of Tetracyclines

Abstract

The tetracyclines are broad-spectrum bacteriostatic antibiotics which interfere with the protein synthesis of bacteria at the ribosomal level. More recently the nonantibiotic properties of tetracyclines have attracted increasing interest. Since the initial observations that tetracyclines inhibit collagenases, extensive number of studies have shown that tetracyclines have effects on inflammation, proteolysis, angiogenesis, apoptosis, and bone metabolism. The mechanism of their action is complex and not completely understood. It includes inhibition of free radical formation and cytokine production, interference with protein synthesis, and modulation of matrix metalloproteinase activity. Chemically modified tetracyclines (CMTs) are tetracycline derivates which lack the antibiotic activity of tetracyclines but possess anti-inflammatory properties. The therapeutic effects of tetracyclines and its analogues have been studied in various inflammatory diseases. Encouraging results have been obtained in the treatment of rheumatoid arthritis (RA) and based on those results minocycline is currently used in the treatment of selected RA patients. Doxycycline has been approved for the treatment of adult periodontal diseases and rosacea. The role of tetracyclines has been studied also in cardiovascular diseases and neuroprotection but their true potential in these diseases remains to be determined. In this review the nonantibiotic properties of tetracycline and its analogues will be examined and their potential for clinical applications in inflammatory diseases will be discussed.

Nonantibiotic Properties of Tetracyclines: Structural Basis for Inhibition of Secretory Phospholipase A2

“…CMTs might be useful for the therapy of inflammatory processes, since they have no antimicrobial activity but are inhibitors of both pro-inflammatory sPLA 2 17 and some matrix metalloproteinases. 2 CMTs might have a higher potential to interact with PLA 2 because of reduced charge and polarity due to the protonated O3 and the missing dimethylamino group. An advantage of tetracyclines or CMTs as inhibitors of PLA 2 is their ability to penetrate membrane cell walls easily, which is a problem of some other inhibitors of PLA 2 that have a zwitterionic or highly charged nature.…”

“…They have been found to inhibit neutral matrix metalloproteinases, including collagenases and gelatinases, and other hydrolases such as α-amylases and phospholipase A 2 (PLA 2 ). [2][3][4] Secretory phospholipase A 2 (sPLA 2 ) catalyzes the hydrolysis of fatty acid ester in the sn-2 position of membrane phospholipids. 5 The liberation of arachidonate is the rate-limiting step for the biosynthesis of eicosanoids, 6 which are involved in the pathogenesis of inflammatory diseases.…”