Tetracyclines: antibiotic action, uptake, and resistance mechanisms
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© Springer-Verlag 1996
MINI-REVIEW
Dirk Schnappinger · Wolfgang Hillen
Tetracyclines: antibiotic action, uptake, and resistance mechanisms
Received: 19 January 1996 / Accepted: 1 March 1996
Abstract Tetracyclines probably penetrate bacterial cells by passive diffusion and inhibit bacterial growth by interfering with protein synthesis or by destroying the membrane. A growing number of various bacterial species acquire resistance to the bacteriostatic activity of tetracycline. The two widespread mechanisms of bacterial resistance do not destroy tetracycline: one is mediated by efflux pumps, the other involves an EF-G-like protein that confers ribosome protection. Oxidative destruction of tetracycline has been found in a few species. Several efflux transporters, including multidrug-resistance pumps and tetracycline-specific exporters, confer bacterial resistance against tetracycline. Single amino acids of these carrier proteins important for tetracycline transport and substrate specificity have been identified, allowing the mechanism of tetracycline transport to begin to emerge. Key words Antibiotic resistance · Tetracycline resistance · Ribosomal protection · Efflux pumps · Multidrug resistance · Tetracycline-proton antiporters Abbreviations M2+ Divalent metal ions · [M-tc]+ Metal tetracycline chelate complex · TcR Tetracycline resistance Several properties make tetracyclines (Fig. 1) nearly perfect therapeutic agents: (1) they are active against most common pathogens, (2) they show good oral absorption, (3) they exhibit low toxicity, (4) they cause only few allergic reactions, and (5) they are relatively inexpensive (Moellering 1990; Standiford 1990). This has led to an intensive use of tetracyclines in therapy and prophylactic control of bacterial infections in humans and animals over the last 48 years. Subtherapeutic levels of oxytetracycline
D. Schnappinger · W. Hillen (Y) Institut für Mikrobiologie, Biochemie und Genetik der Friedrich-Alexander Universität Erlangen-Nürnberg, Staudtstrasse. 5, D-91058 Erlangen, Germany Tel. +49-9131-858081; Fax +49-9131-858082 e-mail [email protected]
Fig. 1 Structure of tetracycline
are also used as food additives for growth promotion in animal husbandry. As a result of this extensive application, tetracyclines have been produced on the largest scale of all antibiotics (Johnson and Adams 1992; Levy 1992). The emergence of bacterial resistance against tetracyclines – and the emergence of bacterial resistance against antimicrobial agents in general – has caused severe drawbacks in their use (Service 1995). Therefore, the development of strategies for circumvention of bacterial resistance is one of the most important future goals in the treatment of infectious diseases. An understanding of the antibiotic action and resistance mechanisms would certainly facilitate such developments. After a short description of the antibiotic action and the uptake of tetracycline, this review focuses on the molecular details known about the two most widely distributed modes of t
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