Impact of metal coordination on the antibiotic and non-antibiotic activities of tetracycline-based drugs

The tetracycline family of antibiotics possesses, in addition to the advantages of a broad-spectrum of action, low toxicity, and the fact that they can be administered orally, a very interesting chemical structure with several metal coordinating sites. This ability to chelate metal ions dictates their pharmacological profile. The species that inhibits bacterial growth is a complex with magnesium ion, which acts by impairing protein synthesis through binding to the 30S ribosomal subunits. The appearance of bacterial resistance to tetracycline and derivatives has compromised their use in the treatment of bacterial infections. The most commonly found mechanism of bacterial resistance to tetracyclines also involves metal chelation: a membrane-associated protein in the resistant bacteria acts as an antiporter by coupling the efflux of a monocationic metal complex with tetracycline out of the bacterial cell to the influx of one proton. Interestingly, this mechanism can be overcome by administering the drug as metal complexes with some divalent metal ions, such as Pt2+ or Pd2+ ions. The discovery of non-antibiotic activities of doxycycline, minocycline and chemically modified tetracyclines, such as the inhibition of matrix metalo-proteinases or the induction of cellular apoptosis, restored the interest in this long-standing family of pleiotropic drugs. The inhibition of matrix metalo-proteinases seems to result from the binding to a Zn2+ ion present in the structural metal center of the protein. Furthermore, transition metal complexes with tetracyclines exhibit antitumor activity and act as nucleases. In this review, we discuss the importance of metal chelation to the antibiotic and non-antibiotic activities of tetracyclines, either by coordinating to biological metal ions in vivo or by being administered as metal complexes. (C) 2016 Elsevier B.V. All rights reserved.