Structural basis for potent inhibitory activity of the antibiotic tigecycline during protein synthesis

Jenner, L.; Starosta, Agata L.; Terry, Daniel S.; Mikolajka, Aleksandra; Filonava, Liudmila; Yusupov, Marat; Blanchard, Scott C.; Wilson, Daniel N.; Yusupova, G.

doi:10.1073/pnas.1216691110

Cited by 166 publications

(256 citation statements)

References 31 publications

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“…This complex then binds reversibly to the A site on the head of the 30S subunit (Figure 18). 96, 97 This binding site has a slight overlap with the anticodon stem‐loop, which correlates well with previous observations that tetracycline prevents binding of the aforementioned aa‐tRNA ⋅ EF‐Tu ⋅ GTP ternary complex to the A site 98…”

Section: Protein Synthesis Inhibitorssupporting

confidence: 88%

“…The superimposition was generated by means of the cryo‐electron microscopy density map EMD‐2183 of the TetM‐70S complex from E. coli according to Jenner et al. and Dönhöfer et al 96, 99…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 92%

“…The tert‐ butylglycylamido moiety of tigecycline engages in stacking interactions with C1054 of the 16S rRNA, which leads to increased potency of tigecycline compared to tetracycline (Figure 18). 96 …”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

“…As shown in Figure 19, tigecycline and TetM overlap in the ribosome owing to the bulky tert‐ butylglycylamido substitution of the drug molecule 96…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

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Targeting Antibiotic Resistance

2016

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Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens.

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Section: Protein Synthesis Inhibitorssupporting

confidence: 88%

Section: Protein Synthesis Inhibitorsmentioning

confidence: 92%

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

“…As shown in Figure 19, tigecycline and TetM overlap in the ribosome owing to the bulky tert‐ butylglycylamido substitution of the drug molecule 96…”

Section: Protein Synthesis Inhibitorsmentioning

confidence: 99%

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Targeting Antibiotic Resistance

2016

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“…To provide a pharmacologic correlate to these findings, we tested the effect of tigecycline (also known as Tygacil), an FDA-approved glycylcycline antibiotic known to inhibit the prokaryotic ribosome [31][32][33] and to interfere with mitochondrial translation in eukaryotes without affecting the translation of mitochondrial proteins encoded by nuclear genes (Supplementary Figure 2a). 34 The effect of tigecycline on viability of DLBCL subsets was examined at a dose range of 1-5 μM over a 24-72 h time course (Figures 3a-c; Supplementary Figure 2b).…”

Section: Resultsmentioning

confidence: 99%

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

et al. 2016

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Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components. To gain insights into molecular determinants of the selective increase in ETC activity and dependence on mitochondrial energy metabolism in OxPhos-DLBCLs, we examined the mitochondrial translation pathway in charge of the synthesis of mitochondrial DNA encoded ETC subunits. Quantitative mass spectrometry identified increased expression of mitochondrial translation factors in OxPhos-DLBCL as compared with the BCR subtype. Biochemical and functional assays indicate that the mitochondrial translation pathway is required for increased ETC activity and mitochondrial energy reserves in OxPhos-DLBCL. Importantly, molecular depletion of several mitochondrial translation proteins using RNA interference or pharmacological perturbation of the mitochondrial translation pathway with the FDA-approved inhibitor tigecycline (Tigecyl) is selectively toxic to OxPhos-DLBCL cell lines and primary tumors. These findings provide additional molecular insights into the metabolic characteristics of OxPhosDLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors. Cells adapt their metabolism to satisfy changing biosynthetic and bioenergetic needs.1,2 Investigation of metabolic reprogramming in cancer has provided insights into the metabolic control of proliferation and survival.3-5 Although the initial focus of this field has been aerobic glycolysis (the Warburg effect), 6 increasing evidence points to a complex landscape of tumor metabolic circuitries beyond aerobic glycolysis, including varied contribution of mitochondria to tumor metabolism as well as heterogeneity in fuel utilization pathways. 7-12Diffuse large B-cell lymphomas (DLBCLs) are a genetically heterogeneous group of tumors that can be classified into distinct molecular subtypes based on gene expression profiles. The cell-of-origin (COO) classification defined DLBCL subsets that shared certain components of their RNA profiles with normal germinal center B cells (GCBs) or in vitroactivated B cells (ABCs), and a third undefined subset designated 'type 3'. 13 Using an independent approach, the consensus cluster classification (CCC) framework compared the transcriptional profiles of DLBCL groups with each other without referencing normal B cells. 14 CCC identified tumorintrinsic distinctions in three highly reproducible clusters; the B-cell receptor/proliferation cluster (BCR-DLBCL) showing increased expression of BCR signa...

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Tetracycline Antibiotics

Anderson

Groundwater

Todd

et al. 2012

Antibacterial Agents

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Tetracyclines belong to the first broad-spectrum, well-tolerated, and easy-to-administer antibiotics, which are effective against plague, cholera, typhoid, syphilis, Legionnaire's disease, and anthrax. Some can also be used to treat malaria, Lyme disease, tuberculosis, Rocky Mountain spotted fever, and leprosy. Humans first encountered these chemical species involuntarily in ancient times, as evidenced from the analysis of bone samples dating back more than 1500 years. Shortly after World War II, they were "rediscovered" at Lederle Laboratories and Pfizer as a result of an intense search for new antibiotics. Their bacteriostatic action is based on the inhibition of protein biosynthesis. Since the structure elucidation by Robert Woodward, Lloyd Hillyard Conover, and others in the 1950s, tetracyclines have become preferred targets for natural product synthesis. However, on industrial scale, they became readily available by fermentation and partial synthesis. Their casual and thoughtless use in the initial decades after launch not only in humans but for veterinary purposes and as growth-enhancement agents in meat production rapidly led to the emergence of resistance. In an arms race for new antibiotics, more and more new drugs have been developed to deal with the threat. In this ongoing endeavor, a remarkable milestone was set by Andrew Myers in 2005 with the convergent total synthesis of (−)-doxycycline, as well as numerous azatetracyclines and pentacyclines, which has inspired chemists in the pharmaceutical industry to discover novel and highly active tetracyclines in recent years.

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Structural basis for potent inhibitory activity of the antibiotic tigecycline during protein synthesis

Cited by 166 publications

References 31 publications

Targeting Antibiotic Resistance

Targeting Antibiotic Resistance

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

Tetracycline Antibiotics

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