Tetracycline Antibiotics and Resistance

Abstract

Tetracyclines possess many properties considered ideal for antibiotic drugs, including activity against Gram-positive and -negative pathogens, proven clinical safety, acceptable tolerability, and the availability of intravenous (IV) and oral formulations for most members of the class. As with all antibiotic classes, the antimicrobial activities of tetracyclines are subject to both class-specific and intrinsic antibiotic-resistance mechanisms. Since the discovery of the first tetracyclines more than 60 years ago, ongoing optimization of the core scaffold has produced tetracyclines in clinical use and development that are capable of thwarting many of these resistance mechanisms. New chemistry approaches have enabled the creation of synthetic derivatives with improved in vitro potency and in vivo efficacy, ensuring that the full potential of the class can be explored for use against current and emerging multidrug-resistant (MDR) pathogens, including carbapenem-resistant Enterobacteriaceae, MDR Acinetobacter species, and Pseudomonas aeruginosa.

Figure 1.

Chemical structures of clinically used tetracyclines and development candidates. Tetracycline structures are labeled with generic names; trade names and year of discovery are indicated within parentheses. The core structure rings (A–D) and carbons (1–12) are labeled in the chemical structure of tetracycline using the convention for tetracycline carbon numbering and ring letter assignments.

Figure 2.

Alternative binding modes of tigecycline at the primary ribosomal-binding site. Alternative tigecycline-binding modes in the 30S (green) and 70S (red) structures are shown, superimposed within the primary tetracycline-binding site. Key nucleotides (G530, A965, G966, C1054, U1196) and helices (h18, h31, h34) are shown in both structures. (From Schedlbauer et al. 2015; reprinted, with permission, from the American Society for Microbiology © 2015.)

Figure 3.

Regulation of expression of Gram-negative intrinsic multidrug-resistance mechanisms affecting tetracyclines. A summary of known regulatory mechanisms affecting tetracycline susceptibility are shown. Green arrows indicate interactions in which tetracycline resistance is “increased,” and red arrows indicate interactions in which tetracycline resistance is “reduced.” See the text for details. TCS, Two-component signal transduction system.