Tetracyclines (tetracycline, doxycycline, minocycline, oxtetracycline, ...) are
antibiotics which inhibit the bacterial growth by stopping protein synthesis. They
have been widely used for the past forty years as therapeutic agent in human and
veterinary medicine but also as growth promotor in animal husbandry. The emergence
of bacterial resistances to these antibiotics has nowadays limited their use. Three
different specific mechanisms of tetracycline resistance have been identified
so far: tetracycline efflux, ribosome protection and tetracycline modification.
Tetracycline efflux is achieved by an export protein from the major facilitator superfamily
(MFS). The export protein was shown to function as an electroneutral antiport system
which catalyzes the exchange of tetracycline-divalent-metal-cation complex for a
proton. In Gram-negative bacteria the export protein contains 12 TMS (transmembrane
fragments) whereas in Gram-positive bacteria it displays 14 TMS. Ribosome protection
is mediated by a soluble protein which shares homolgy with the GTPases participating
in protein synthesis, namely EF-Tu and EF-G. The third mechanism involves a cytoplasmic
protein that chemically modifies tetracycline. This reaction takes only place in
the presence of oxygen and NADPH and does not function in the natural host (Bacteroides).
The two first mechanisms are the most widespread and most of their genes are normally
acquired via transferable plasmids and/or transposons. These two mechanisms were
observed both in aerobic and anaerobic Gram-negative or Gram-positive bacteria demonstrating their wide distribution
among the bacterial kingdom. To date, about sixty-one tetracycline resistance genes
have been sequenced and thirty-two classes of genes identified in non-producers and
producers (Streptomyces). Each new class is identified by its inability to
hybridize with any of the known tet genes under stringent conditions (Levy et al. 1989. AAC 33:1373-1374). A new nomenclature for
the resistance determinants has been proposed for the future with the S. B. Levy
group to coordinate the naming of the detreminants (Levy et al.
1999. AAC 43:1523-1524).
DETERMINANT CLASSIFICATION
Non-producers: Tet A - B - C - D - E - F - G - H - I - J - K - L - M - N (withdrawn)
- O - P(A) - P(B) - Q - S - T - U - V - W - X - Y - Z - 30
Producers: otrA - otrB - otrC - tcr3 (trcC) -
tet
Several tetracycline resistance determinants are currently
used in molecular biology. The most encountered are the tetA genes of classes
A (RP1, RP4 or Tn1721 derivatives), B (Tn10 derivatives) and C (pSC101
or pBR322 derivatives) encoding a tetracycline efflux system.
These genes are regulated by a repressor protein (TetR). This feature
has also been exploited to construct tightly regulated, high level mammalian expression
systems by using the regulatory elements of the Tn10 tetracycline operon (Tet-OffTM and Tet-OnTM Expression
Systems & Cell Lines, Clontech).
The tetM gene from Tn916 which can
be expressed both in Gram-positive and Gram-negative bacteria is also frequently
used. Several Bacteroides/Escherichia shuttle vectors contain the tetQ
gene. tetM and tetQ encode a soluble protein protecting the ribosome
from the inhibiting effects of tetracycline. The distribution of these genes is given
in the pages relating to the determinant
classification.
Tetracycline antibiotics - (Copyrights © by Purdue Research
Foundation)
Tetracycline
- (Copyright © 1997 by Mosby Inc. - Mosby's GenRx)
Tetracyclines
- (link to the University of Winconsin Hospital)
Lloyd
H. Conover Born June 13, 1923 - Tetracycline Patent - (Inventure Place)
Paulsen, I. T., M. H. Brown, and R. A. Skurray. 1996. Proton-depenent multidrug efflux systems. Microbiol. Rev. 60:575-608.
Review.
Roberts, M.C. 1994. Epidemiology of tetracycline-resistance determinants. Trends
in Microbiol. 2:353-357.
Roberts, M. C. 1996. Tetracycline resistance determinants: mechanisms of action, regulation
of expression, genetic mobility, and distribution. FEMS Microbiol. Rev.
19:1-24. Review.
Roberts, M. C. 1997. Genetic mobility and distribution of tetracycline resistance determinants.
Ciba Found. Symp. 207:206-218.
Schappinger, D. and W. Hillen. 1996. Tetracyclines: antibiotic action, uptake, and resistance mechanisms.
Arch. Microbiol. 165:359-369. Review.
Speer, B.S., N.B. Shoemaker, and A.A. Salyers. 1992. Bacterial resistance to tetracycline: mechanisms, transfer, and clinical
significance. Clin. Microbiol. Rev. 5:387-399. Review.
Taylor, D.E., and A. Chau . 1996. Tetracycline resistance mediated by ribosomal protection. Antimicrob.
Agents Chemother. 40:1-5. Review. No abstract available.
Yamaguchi, A. 1997. Bacterial resistance mechanisms for tetracyclines [Article in Japanese].
Nippon Rinsho 55:1245-1251. Review.