Fluorocyclines. 2. Optimization of the C-9 Side-Chain for Antibacterial Activity and Oral Efficacy

Clark, Roger B.; Hunt, Diana K.; He, Minsheng; Achorn, Catherine; Chen, Chi-Li; Deng, Yuqi; Fyfe, Corey; Grossman, Trudy H.; Hogan, Philip C.; O’Brien, William J.; Plamondon, Louis; Rönn, Magnus; Sutcliffe, Joyce A.; Zhu, Zengtai; Xiao, Xiao-Yi

doi:10.1021/jm201467r

Cited by 68 publications

(40 citation statements)

References 39 publications

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“…Linezolid (catalog number 70412) was from AK Scientific, Union City, CA; tigecycline was from Wyeth Laboratories (Pfizer), Pearl River, NY. TP-434 was synthesized at Tetraphase Pharmaceuticals (8,44). …”

Section: Methodsmentioning

confidence: 99%

“…The parenteral glycylcycline tigecycline, another semisynthetic derivative, was developed to have improved activity against both tetracycline-specific efflux and RPP mechanisms (26) and is a more potent inhibitor of protein synthesis. More recently, TP-434, a novel fluorocycline antibiotic, was made by total synthesis using methodology first described by Charest et al (7) and further developed at Tetraphase Pharmaceuticals (8,18,44). TP-434 contains the tetracyclic core scaffold common to other tetracycline antibiotics, with two unique modifications: a fluorine atom at position C-7 and a pyrrolidinoacetamido group at C-9 on the tetracyclic D ring (Fig.…”

mentioning

confidence: 99%

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Target- and Resistance-Based Mechanistic Studies with TP-434, a Novel Fluorocycline Antibiotic

Grossman

Starosta²,

Fyfe

et al. 2012

Antimicrob Agents Chemother

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141

123

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c TP-434 is a novel, broad-spectrum fluorocycline antibiotic with activity against bacteria expressing major antibiotic resistance mechanisms, including tetracycline-specific efflux and ribosomal protection. The mechanism of action of TP-434 was assessed using both cell-based and in vitro assays. In Escherichia coli cells expressing recombinant tetracycline resistance genes, the MIC of TP-434 (0.063 g/ml) was unaffected by tet(M), tet(K), and tet(B) and increased to 0.25 and 4 g/ml in the presence of tet(A) and tet(X), respectively. Tetracycline, in contrast, was significantly less potent (MIC > 128 g/ml) against E. coli cells when any of these resistance mechanisms were present. TP-434 showed potent inhibition in E. coli in vitro transcription/translation (50% inhibitory concentration [IC 50 ] ‫؍‬ 0.29 ؎ 0.09 g/ml) and [ 3 H]tetracycline ribosome-binding competition (IC 50 ‫؍‬ 0.22 ؎ 0.07 M) assays. The antibacterial potencies of TP-434 and all other tetracycline class antibiotics tested were reduced by 4-to 16-fold, compared to that of the wild-type control strain, against Propionibacterium acnes strains carrying a 16S rRNA mutation, G1058C, a modification that changes the conformation of the primary binding site of tetracycline in the ribosome. Taken together, the findings support the idea that TP-434, like other tetracyclines, binds the ribosome and inhibits protein synthesis and that this activity is largely unaffected by the common tetracycline resistance mechanisms.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Target- and Resistance-Based Mechanistic Studies with TP-434, a Novel Fluorocycline Antibiotic

Grossman

Starosta²,

Fyfe

et al. 2012

Antimicrob Agents Chemother

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141

123

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“…It has modifications at both the C-7 (fluorine) and C-9 [2-(pyrrolidin-1-yl)ethanamido] positions on the tetracyclic core that were made possible by using a totally synthetic route ( Fig. 1) (15,18,19). In this work, we show that eravacycline has broad-spectrum antimicrobial activity, with MIC 90 values of Յ2 g/ml against panels of all major bacterial species except for Pseudomonas aeruginosa and Burkholderia cenocepacia.…”

mentioning

confidence: 69%

Antibacterial Activity of Eravacycline (TP-434), a Novel Fluorocycline, against Hospital and Community Pathogens

Sutcliffe

O’Brien

Fyfe

et al. 2013

Antimicrob Agents Chemother

201

190

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Eravacycline (TP-434 or 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline) is a novel fluorocycline that was evaluated for antimicrobial activity against panels of recently isolated aerobic and anaerobic Gram-negative and Gram-positive bacteria. Eravacycline showed potent broad-spectrum activity against 90% of the isolates (MIC 90 ) in each panel at concentrations ranging from <0.008 to 2 g/ml for all species panels except those of Pseudomonas aeruginosa and Burkholderia cenocepacia (MIC 90 values of 32 g/ml for both organisms). The antibacterial activity of eravacycline was minimally affected by expression of tetracycline-specific efflux and ribosomal protection mechanisms in clinical isolates. Furthermore, eravacycline was active against multidrug-resistant bacteria, including those expressing extended-spectrum ␤-lactamases and mechanisms conferring resistance to other classes of antibiotics, including carbapenem resistance. Eravacycline has the potential to be a promising new intravenous (i.v.)/oral antibiotic for the empirical treatment of complicated hospital/health care infections and moderate-to-severe community-acquired infections.

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“…This pathway for tetracycline synthesis has been employed by Tetraphase Pharmaceuticals (Watertown, MA, USA), leading to the generation of a 7-fl uorotetracycline derivative coded TP-434 (eravacycline, Fig. 2), containing 7-fl uoro and 9-pyrrolidinoacetoamido modifications of D ring (16). Eravacycline was shown to have a much higher affi nity for the ribosome than tetra cycline; it consistently inhibits in vitro translation more effi ciently than tetracycline.…”

Section: Tetracyclines In the Pipelinementioning

confidence: 99%

“…Eravacycline was shown to have a much higher affi nity for the ribosome than tetra cycline; it consistently inhibits in vitro translation more effi ciently than tetracycline. Eravacycline displays similar ribosome binding affi nity to tigecycline (2,6,(16)(17)(18) …”

Section: Tetracyclines In the Pipelinementioning

confidence: 99%

Biosynthesis of Oxytetracycline by Streptomyces rimosus: Past, Present and Future Directions in the Development of Tetracycline Antibiotics

Petković

Lukežič²,

Šušković

2017

Food Technol. Biotechnol.

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SummaryNatural tetracycline (TC) antibiotics were the fi rst major class of therapeutics to earn the distinction of 'broad-spectrum antibiotics' and they have been used since the 1940s against a wide range of both Gram-positive and Gram-negative pathogens, mycoplasmas, intracellular chlamydiae, rickett siae and protozoan parasites. The second generation of semisynthetic tetracyclines, such as minocycline and doxycycline, with improved antimicrobial potency, were introduced during the 1960s. Despite emerging resistance to TCs erupting during the 1980s, it was not until 2006, more than four decades later, that a third--generation TC, named tigecycline, was launched. In addition, two TC analogues, omadacycline and eravacycline, developed via (semi)synthetic and fully synthetic routes, respectively, are at present under clinical evaluation. Interestingly, despite very productive early work on the isolation of a Streptomyces aureofaciens mutant strain that produced 6-demethyl-7-chlortetracycline, the key intermediate in the production of second-and third-generation TCs, biosynthetic approaches in TC development have not been productive for more than 50 years. Relatively slow and tedious molecular biology approaches for the genetic manipulation of TC-producing actinobacteria, as well as an insuffi cient understanding of the enzymatic mechanisms involved in TC biosynthesis have signifi cantly contributed to the low success of such biosynthetic engineering eff orts. However, new opportunities in TC drug development have arisen thanks to a signifi cant progress in the development of aff ordable and versatile biosynthetic engineering and synthetic biology approaches, and, importantly, to a much deeper understanding of TC biosynthesis, mostly gained over the last two decades.

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Fluorocyclines. 2. Optimization of the C-9 Side-Chain for Antibacterial Activity and Oral Efficacy

Cited by 68 publications

References 39 publications

Target- and Resistance-Based Mechanistic Studies with TP-434, a Novel Fluorocycline Antibiotic

Target- and Resistance-Based Mechanistic Studies with TP-434, a Novel Fluorocycline Antibiotic

Antibacterial Activity of Eravacycline (TP-434), a Novel Fluorocycline, against Hospital and Community Pathogens

Biosynthesis of Oxytetracycline by Streptomyces rimosus: Past, Present and Future Directions in the Development of Tetracycline Antibiotics

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