Third-Generation Tetracyclines: Current Knowledge and Therapeutic Potential

Abstract

Tetracyclines constitute a unique class of antibiotic agents, widely prescribed for both community and hospital infections due to their broad spectrum of activity. Acting by disrupting protein synthesis through tight binding to the 30S ribosomal subunit, their interference is typically reversible, rendering them bacteriostatic in action. Resistance to tetracyclines has primarily been associated with changes in pump efflux or ribosomal protection mechanisms. To address this challenge, tetracycline molecules have been chemically modified, resulting in the development of third-generation tetracyclines. These novel tetracyclines offer significant advantages in treating infections, whether used alone or in combination therapies, especially in hospital settings. Beyond their conventional antimicrobial properties, research has highlighted their potential non-antibiotic properties, including their impact on immunomodulation and malignancy. This review will focus on third-generation tetracyclines, namely tigecycline, eravacycline, and omadacycline. We will delve into their mechanisms of action and resistance, while also evaluating their pros and cons over time. Additionally, we will explore their therapeutic potential, analyzing their primary indications of prescription, potential future uses, and non-antibiotic features. This review aims to provide valuable insights into the clinical applications of third-generation tetracyclines, thereby enhancing understanding and guiding optimal clinical use.

Keywords: eravacycline; immunomodulation; malignancy; mechanism of action; non-antibiotic properties; omadacycline; resistance; tetracyclines; tigecycline.

Figure 1

The chemical structure of tetracyclines (A), including their third-generation analogs, namely tigecycline (B), eravacycline (C), and omadacycline (D) [12,13,14,15,16,17]. Created with BioRender.com (accessed on 26 June 2024).

Figure 1

The chemical structure of tetracyclines (A), including their third-generation analogs, namely tigecycline (B), eravacycline (C), and omadacycline (D) [12,13,14,15,16,17]. Created with BioRender.com (accessed on 26 June 2024).

Figure 2

Main mechanisms of resistance to tetracyclines and third-generation analogs. (A) MFS and non-MFS (ABC, MATE, RND, and SMR) efflux pumps facilitate the removal of traditional and novel tetracyclines from bacterial cells to the external environment. (B) The plasmid-mediated Tet(X) family encodes enzymes that prevent third-generation tetracyclines from binding to ribosomes, resulting in resistance. (C) Mutations in the rpsJ gene, which encodes residues 53–60 in the S10 protein, result in the reduced binding affinity of third-generation analogs to their binding site on the 30S ribosome subunit. (D) Mutations in genes responsible for the structure of OMPs have been implicated in tetracycline resistance. (E) Activation of RecA and RecBCD results in an impaired DNA damage response in bacteria, particularly in Acinetobacter baumannii isolates [55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77]. Abbreviations: ABC, ATP binding cassette; ERV, eravacycline; MATE, multi antimicrobial extrusion; MFS, major facilitator superfamily; OMC, omadacycline; OMP, outer membrane proteins; RND, resistance nodulation cell division family; SMR, small multidrug resistance; TIG, tigecycline. Created with BioRender.com (accessed on 26 June 2024).

Figure 3

Schematic illustration of the potential mechanisms by which tetracyclines and tigecycline may interfere with the inflammatory response via NLRP3 inflammasome. Acute pulmonary infection triggers the release of PAMPs, which stimulate TLRs and subsequently activate NF-κB. The phosphorylation of NF-κB induces the transcription of genes encoding pro-IL-18 and pro-IL-1β cytokines, leading to the polymerization and activation of the NLRP3 receptor. Tigecycline reduces NF-κB phosphorylation, thereby mitigating the inflammatory response. Hence, tigecycline may attenuate the inflammatory process by intervening at an earlier stage before the formation of NLRP3. In contrast, tetracyclines act at a different point in this pathway by inhibiting caspase-1 to alleviate inflammation. Despite these differences, both tetracyclines and tigecycline weaken the inflammatory response and are considered anti-inflammatory agents [129,130,131]. Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD domain; ΙκΒ, IκB kinase; IL-1β, interleukin-1β; IL-18, interleukin-18; NF-κΒ, nuclear factor-kappa-light-chain-enhancer of activated B cells; NLRP3, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome; PAMPs, pathogen-associated molecular patterns; Pro-IL-1β, pro-interleukin-1β; Pro-IL-18, pro-interleukin-18; TET, tetracyclines; TIG, tigecycline; TLR, toll-like receptor. Created with BioRender.com (accessed on 26 June 2024).

Figure 4

Schematic presentation of the effects of third-generation tetracyclines, particularly tigecycline in tumor cells. Tigecycline affects programmed cell death pathways, including autophagy and apoptosis. It promotes autophagy by activating the AMPK pathway, which inactivates mTOR, and by downregulating the PI3K-AKT-mTOR pathway. Tigecycline facilitates apoptosis through the activation of BCL-2 and the release of cytochrome c, and by enhancing the cleavage of caspase-3, caspase-7, and caspase-9. In mitochondria, tigecycline induces oxidative injury, suppresses oxidative phosphorylation, and inhibits mitochondrial biogenesis. Additionally, it promotes cell cycle arrest, affecting the proliferation of cancer cells through alterations in cyclins and cyclin-dependent kinase levels. Lastly, tigecycline exhibits anti-angiogenic properties [135,136,137,138,139,140,141]. Abbreviations: Akt, serine/threonine kinase 1; AMPK, adenosine monophosphate-activated protein kinase; BCL-2, B-cell lymphoma 2; CDK, cyclin-dependent kinase; mTOR, mammalian target of rapamycin; OxPhos, oxidative phosphorylation; PI3K, phosphatidylinositol-3 kinase; ROS, reactive oxygen species. Created with Biorender.com (accessed on 26 June 2024).