Emergence of Third Generation Tetracyclines: New Magic Bullets to Tackle Antibiotic Resistance in the Post-antibiotic Era

Tetracyclines are broad-spectrum antibiotics effective against a wide variety of microorganisms including bacteria, both Gram-positive and Gram-negative, mycoplasmas, rickettsiae, chlamydiae, and protozoan parasites. Owing to their broad-spectrum antimicrobial activities and inexpensiveness, tetracyclines have been used extensively in both human and animal infections and in animal feed as growth promoters. Owing to this, the global prevalence of antibiotic resistance, particularly of tetracyclines, for Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae and Gram-negative extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella species is high. Indeed, the acquisition of tetracycline-specific resistance genes, mutations within the ribosomal binding site, and/or chromosomal mutations lead to both class-specific and intrinsic antimicrobial resistance (AMR) mechanisms. As drug resistance increases globally, rendering diseases difficult to manage and eventually to mortality, antibiotics are becoming progressively less effective. Therefore, the discovery and development of novel antibiotics with appropriate indications is of the utmost importance. Among all antibiotics, the tetracyclines have acquired much attention due to the optimization of their chemical structures that paved the way to develop and introduce modern tetracyclines, referred to as third generation, namely tigecycline in the recent past, followed by omadacycline, eravacycline, and sarecycline very recently. Intriguingly, these novel tetracyclines are unique in two ways, first, these are highly effective against pathogens that acquired tetracycline-class resistance, and second, these agents exhibit either narrow or broad spectrum of in vitro activity against Gram-positive, Gram-negative, anaerobic, and atypical pathogens, including many drug-resistant strains lead to approval for limited use and unique indications. These beneficial effects represent a new era in the rational use of newer tetracyclines, the new magic bullets to tackle AMR in the post-antibiotic era. The present review focuses on third-generation tetracyclines emphasizing their safety, efficacy, and therapeutic choices in various clinical conditions of in-patient and out-patient settings.