The tetracycline resistome

Abstract

Resistance to tetracycline emerged soon after its discovery six decades ago. Extensive clinical and non-clinical uses of this class of antibiotic over the years have combined to select for a large number of resistant determinants, collectively termed the tetracycline resistome. In order to impart resistance, microbes use different molecular mechanisms including target protection, active efflux, and enzymatic degradation. A deeper understanding of the structure, mechanism, and regulation of the genes and proteins associated with tetracycline resistance will contribute to the development of tetracycline derivatives that overcome resistance. Newer generations of tetracyclines derived from engineering of biosynthetic genetic programs, semi-synthesis, and in particular recent developments in their chemical synthesis, together with a growing understanding of resistance, will serve to retain this class of antibiotic to combat pathogens.

Fig. 1

Chemical structures of various tetracycline antibiotics. a Structure of tetracycline, b advances in new generation tetracycline development over a period of time

Fig. 2

Three-dimensional architecture of tetracycline and chelocardin. Tetracycline binding to the ribosome is achieved by its unique three-dimensional architecture including the kink between rings A and B. In contrast, chelocardin is a more planar molecule than tetracycline and consequently inhibits bacterial growth by not binding to the ribosome but most likely due to interference with the cell membrane. Tetracycline structure taken from Hinrichs et al. [69] (PDB file *2trt). Chelocardin generated using Chem3D Pro 7.0 and MOPAC minimization [70]

Fig. 3

Newly developed tetracycline analogs. a Promising anticancer drug candidate COL-3, a chemically modified tetracycline. b Recently developed new tetracycline derivatives using the Myers total synthesis approach, which are inaccessible using conventional semi-synthetic approach [71]

Fig. 4

Diversity and abundance of tetracycline resistance determinants found in nature: the tetracycline resistome. Asterisk indicates activity not confirmed with pure protein

Fig. 5

Model of the TetA(B) efflux pump. a Orientation of 12 transmembrane helices to form water-filled channel for export of tetracycline. b Amino acids D66, R101, G247, and D285 implicated to be vital for efflux activity are shown

Fig. 6

Schematic diagram illustrating interactions of magnesium bound tetracycline with a the TetR homodimer [69] and b primary binding site in 16S rRNA of the small ribosomal subunit [8]. While TetR interactions surround the tetracycline scaffold from all directions, the ribosome binding sites are confined to the bottom portion alone, providing possible sites for modifications within the top portion (dotted ellipse) of the molecule. These modifications may be exploited to create interference in TetR tetracycline docking, and thereby overcome TetR mediated efflux resistance without compromising its ribosome binding antibiotic property

Fig. 7

Ribosomal protection protein-mediated tetracycline resistance. a Tetracycline binds the ribosome at the apex of the A-site which in turn sterically blocks the aminoacyl-tRNA binding site and inhibits protein synthesis. b When bound by tetracycline, RPPs along with bound GTP will associate with the ribosome which results in tetracycline release from the A-site. c Upon tetracycline release, GTP is hydrolyzed and the RPP subsequently dissociates from the ribosome which restores protein synthesis

Fig. 8

TetX mediated tigecycline inactivation. The enzymatic inactivation of tigecycline is mediated by TetX, a flavin-dependent monooxygenase. In the presence of oxygen, TetX catalyze the regiospecific hydroxylation of tigecycline at position 11a producing 11a-hydroxytigecycline

Fig. 9

Venn diagram showing prevalence of resistance against first, second, and third generation tetracyclines from soil actinomycetes. Data are derived from [67]