Eravacycline, a newly approved fluorocycline

Lee, Young Ran; Burton, Caitlin E.

doi:10.1007/s10096-019-03590-3

Cited by 59 publications

(52 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Eravacycline, developed at Tetraphase Pharmaceuticals, Inc., varies from the other clinical available 3rd generation tetracycline analogues with its fluorine atom at the C7 position and a pyrrolidinoacetamido group on the C9 of ring D (Figure 7) [139,140]. It displays activity against both Gram-positives and Gram-negatives and has been approved by the US FDA for treatment of infections caused by multidrug-resistant microorganisms, including carbapenem-resistant Enterobacteriaceae, MRSA, VREs, and extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae [141]. Following the same logic as for tigecycline and omadacycline, the altered functional groups on this fully synthetic tetracycline derivative was designed to evade tetracycline resistance determinants, which is evident from the retained activity of eravacycline against TetM-protected E. coli cells tested in an in vitro transcription/translation assay [140].…”

Section: Tetracyclinesmentioning

confidence: 99%

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Robertsen

Musiol-Kroll

2019

Antibiotics

View full text Add to dashboard Cite

Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes (biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant proportion of the identified BGCs in actinomycetes encode pathways for the biosynthesis of polyketide compounds, nonribosomal peptides, or hybrid products resulting from the combination of both polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The potency of these molecules, in terms of bioactivity, was recognized in the 1940s, and started the “Golden Age” of antimicrobial drug discovery. Since then, several valuable polyketide drugs, such as erythromycin A, tylosin, monensin A, rifamycin, tetracyclines, amphotericin B, and many others were isolated from actinomycetes. This review covers the most relevant actinomycetes-derived polyketide drugs with antimicrobial activity, including anti-fungal agents. We provide an overview of the source of the compounds, structure of the molecules, the biosynthetic principle, bioactivity and mechanisms of action, and the current stage of development. This review emphasizes the importance of actinomycetes-derived antimicrobial polyketides and should serve as a “lexicon”, not only to scientists from the Natural Products field, but also to clinicians and others interested in this topic.

show abstract

Section: Tetracyclinesmentioning

confidence: 99%

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Robertsen

Musiol-Kroll

2019

Antibiotics

View full text Add to dashboard Cite

show abstract

“…Erava has robust antimicrobial activity against a broad range of microorganisms, including Gram-positive, Gram-negative, anaerobic, and atypical bacteria (Sutcliffe et al, 2013;Livermore et al, 2016;Monogue et al, 2016;Zhanel et al, 2016). Intravenous Erava is newly approved in several countries for the treatment of adult patients with complicated intra-abdominal infections (cIAIs) caused by enteric microorganisms, including multidrug resistant, difficultto-treat enterococci infection (Lee and Burton, 2019;Scott, 2019;Alosaimy et al, 2020). Against E. faecalis clinical isolates collected globally (Hackel et al, 2013;Sutcliffe et al, 2013;Olesky et al, 2017), in Canada (CANWARD surveillance study; 2014-2015; Zhanel et al, 2018), and the USA -2016Bouchillon et al, 2018), Erava exhibited potent in vitro activity, including against vancomycin-resistant E. faecalis isolates.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Eravacycline Resistance in Clinical Enterococcus faecalis Isolates From China

Wen

Shang

et al. 2020

Front. Microbiol.

View full text Add to dashboard Cite

Opportunistic infections caused by multidrug-resistant Enterococcus faecalis strains are a significant clinical challenge. Eravacycline (Erava) is a synthetic fluorocycline structurally similar to tigecycline (Tige) that exhibits robust antimicrobial activity against Gram-positive bacteria. This study investigated the in vitro antimicrobial activity and heteroresistance risk of Eravacycline (Erava) in clinical E. faecalis isolates from China along with the mechanism of Erava resistance. A total of 276 non-duplicate E. faecalis isolates were retrospectively collected from a tertiary care hospital in China. Heteroresistance to Erava and the influence of tetracycline (Tet) resistance genes on Erava susceptibility were examined. To clarify the molecular basis for Erava resistance, E. faecalis variants exhibiting Erava-induced resistance were selected under Erava pressure. The relative transcript levels of six candidate genes linked to Erava susceptibility were determined by quantitative reverse-transcription PCR, and their role in Erava resistance and heteroresistance was evaluated by in vitro overexpression experiments. We found that Erava minimum inhibitory concentrations (MICs) against clinical E. faecalis isolates ranged from ≤0.015 to 0.25 mg/l even in strains harboring Tet resistance genes. The detection frequency of Erava heteroresistance in isolates with MICs ≤ 0.06, 0.125, and 0.25 mg/l were 0.43% (1/231), 7.5% (3/40), and 0 (0/5), respectively. No mutations were detected in the 30S ribosomal subunit gene in Erava heteroresistance-derived clones, although mutations in this subunit conferred cross resistance to Tige in Erava-induced resistant E. faecalis. Overexpressing RS00630 (encoding a bone morphogenetic protein family ATP-binding cassette transporter substrate-binding protein) in E. faecalis increased the frequency of Erava and Tige heteroresistance, whereas RS12140, RS06145, and RS06880 overexpression conferred heteroresistance to Tige only. These results indicate that Erava has potent in vitro antimicrobial activity against clinical E. faecalis isolates from China and that Erava heteroresistance can be induced by RS00630 overexpression.

show abstract

“…Compared with other tetracyclines, compound 85 incorporates some important modificationst ot he core tetracycline unit, especially on the aromatic ring, and thus, provides improved antibacterial activity.E ravacycline( 85)c ontains ap yrrolidine moiety on the C9 side chain and a fluorine substituent at the C7 position, whichh as been shown to be very important for its broad-spectrum antibacterial activity.E ravacycline (85)w as approvedf or the treatment of complicated intra-abdominali nfections by the FDA in August 2018 and is marketed as Xerava TM . [40][41][42] Te traphase Pharmaceuticals developed as ynthetic method for the preparation of 85 (Scheme 9). [42][43][44] Scheme5.Synthesis of intermediate 52.…”

Section: Ghsr1a Antagonistsmentioning

confidence: 99%

“…Eravacycline ( 85 ) contains a pyrrolidine moiety on the C9 side chain and a fluorine substituent at the C7 position, which has been shown to be very important for its broad‐spectrum antibacterial activity. Eravacycline ( 85 ) was approved for the treatment of complicated intra‐abdominal infections by the FDA in August 2018 and is marketed as Xerava TM …”

Section: Aliphatic Aasmentioning

confidence: 99%

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Mei

Han

White

et al. 2020

Chemistry A European J

View full text Add to dashboard Cite

Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor‐made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man‐made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

show abstract

Eravacycline, a newly approved fluorocycline

Cited by 59 publications

References 18 publications

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Mechanism of Eravacycline Resistance in Clinical Enterococcus faecalis Isolates From China

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Contact Info

Product

Resources

About