Tetracyclines, a timely resurgence or doomed to fail again?

Tetracyclines are bacteriostatic antimicrobials used in the treatment of both bacterial and protozoan pathogens. They abolish protein synthesis by binding to the 16S rRNA, blocking aminoacyl-tRNA access and preventing polypeptide elongation. Tetracyclines are polyketide antimicrobials, with members of this drug family (doxycycline, minocycline and tigecycline) on the World Health Organization (WHO) list of essential medicines. Bacterial resistance to this antimicrobial family is widespread and arises via multiple mechanisms. The most common of these resistance mechanisms are tetracycline efflux, ribosomal protection proteins and the newly emerging tetracycline destructases (TDases). The rise of resistance has limited the clinical use of first- and second-generation tetracyclines; however, third-generation tetracyclines are now reserved as antimicrobials of last resort for complicated bacterial infections. However, genetically mobile TDases have now been identified in opportunistic pathogens, with this mechanism of resistance capable of inactivating third-generation tetracyclines. This presents the question, are third-generation tetracyclines doomed to fail in the same manner as first-generation tetracyclines?