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Target- and Resistance-Based Mechanistic Studies with TP-434, a Novel Fluorocycline Antibiotic
Open accessAbstract
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 μg/ml) was unaffected by tet (M), tet (K), and tet (B) and increased to 0.25 and 4 μg/ml in the presence of tet (A) and tet (X), respectively. Tetracycline, in contrast, was significantly less potent (MIC ≥ 128 μg/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 μg/ml) and [ 3 H]tetracycline ribosome-binding competition (IC 50 = 0.22 ± 0.07 μM) 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.
Overview
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Written from the paper’s full text.
TL;DR
TP-434 is a novel fluorocycline that inhibits E. coli translation and binds the ribosome, with activity largely unaffected by common tetracycline resistance mechanisms. However, TP-434 MIC still rises with tet(A), tet(X), and a 16S rRNA G1058C mutation.
Key findings
- In an E. coli-coupled in vitro transcription/translation assay, TP-434 had an IC50 of 0.29 ± 0.09 μg/ml, while tetracycline had an IC50 of 1.26 ± 0.48 μg/ml. Addition of purified Tet(M) did not affect TP-434 (0.27 ± 0.09 μg/ml) but increased tetracycline’s IC50 5-fold to 6.50 ± 3.3 μg/ml.
- TP-434 competed with [3H]tetracycline for 70S ribosome binding with an IC50 of 0.22 ± 0.07 μM; tigecycline had a similar IC50 (0.22 ± 0.08 μM), and tetracycline was ~14-fold less potent (IC50 = 3.00 ± 1.15 μM). Erythromycin up to 100 μM did not compete.
- Against isogenic E. coli DH10B expressing resistance genes, TP-434 MIC was 0.063 μg/ml for lacZ, tet(M), and tet(B); 0.031 μg/ml for tet(K); 0.25 μg/ml for tet(A); and 4 μg/ml for tet(X). Tetracycline MIC was ≥128 μg/ml with each resistance mechanism.
- In P. acnes, strains SW101T and P:413 carrying the 16S rRNA G1058C mutation had TP-434 MICs of 1 μg/ml versus 0.063 μg/ml for wild-type ATCC 6919; all tetracycline-class antibiotics tested showed 4- to 16-fold reduced potency against the mutant strains.
Methods
- Mechanistic assays: E. coli-coupled in vitro transcription/translation with a firefly luciferase readout, with and without purified Tet(M) at 2.75 μM; [3H]tetracycline ribosome-binding competition using 0.4 μM E. coli 70S ribosomes and 8 μM [3H]tetracycline.
- Susceptibility testing: MIC assays against E. coli DH10B expressing recombinant tet(A), tet(B), tet(K), tet(M), tet(X), or lacZ control, performed by CLSI methods with ampicillin and arabinose induction; P. acnes strains ATCC 6919, SW101 CDA, SW101T, and P:413 tested anaerobically in Wilkins-Chalgren broth.
- Analysis: IC50s were averaged from at least two independent experiments; MIC assays were performed at least twice, with representative results reported.
Limitations
- Not stated in the paper (no explicit limitations section).
- Evident from the text: mechanistic assays use E. coli in vitro translation and purified ribosomes, and resistance testing uses recombinant isogenic E. coli plus a small set of P. acnes strains, so clinical generalizability is limited.
- Evident from the text: TP-434 activity is still reduced by tet(A) (4-fold MIC increase to 0.25 μg/ml), tet(X) (MIC 4 μg/ml), and the G1058C mutation (MIC 1 μg/ml), so resistance is not fully overcome.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Susceptibility to tigecycline (MIC = 0.063 μg/ml) was unaffected by tet(M), tet(K), and tet(B)”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The MIC of ceftriaxone, a nontetracycline control, remained unaffected by the overexpression of any of the tetracycline resistance mechanisms.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“The tet(A) gene expressed in the present study had the same variations as the Tn1721-associated tet(A) gene, where the amino acids are Ala-201, Ser-202, and Phe-203 rather than those of the tet(A) sequence from E. coli plasmid RP1, Ser-201, Phe-202, and Val-203”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“increased to 0.25 and 4 μg/ml in the presence of tet(A) and tet(X), respectively.”
- Also stated in: § RESULTS AND DISCUSSION · plain
“a 4-fold increase in TP-434 MIC (0.25 μg/ml) was observed in the presence of tet(A) expression”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § RESULTS AND DISCUSSION · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tetracycline, in contrast, was significantly less potent (MIC ≥ 128 μg/ml) against E. coli cells when any of these resistance mechanisms were present.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a 16-fold increase (MIC = 1 μg/ml) was observed in the presence of tet(A) for tigecycline”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a ≥64-fold increase in MIC value, relative to the lacZ control strain, was associated with overexpression of each of the resistance genes.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“all strains were similarly susceptible to penicillin (MIC ≤ 0.016 μg/ml; Table 2).”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tigecycline had a similar IC50 (0.22 ± 0.08 μM)”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“tetracycline was ∼14-fold less potent (IC50 = 3.00 ± 1.15 μM)”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 11
- Probably not a substantial claim. 7
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“[3H]tetracycline ribosome-binding competition (IC50 = 0.22 ± 0.07 μM) assays.”
- Also stated in: § RESULTS AND DISCUSSION · plain
“TP-434 competed with [3H]tetracycline for ribosome binding (Fig. 3), with an IC50 of 0.22 ± 0.07 μM.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § RESULTS AND DISCUSSION · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When purified Tet(M) was added to the transcription/translation reaction, the IC50s of both TP-434 and tigecycline were unaffected (0.27 ± 0.09 μg/ml and 0.09 ± 0.04 μg/ml, respectively), whereas the IC50 for tetracycline increased 5-fold (6.50 ± 3.3 μg/ml).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“mutations within helices h31 and h34 of 16S rRNA have been reported to confer tetracycline resistance in Helicobacter pylori and Propionibacterium acnes (31, 40).”
What the sources say
- Not checked yetcites [31] 31. Ross JI, Eady EA, Cove JH, Cunliffe WJ. 1998. 16S rRNA mutation associated with tetracycline resistance in a Gram-positive bacterium. Antimicrob. Agents Chemother. 42:1702–1705 [DOI] [PMC free article] [PubMed] [Google Scholar] source
- Not checked yetcites [40] 40. Trieber CA, Taylor DE. 2002. Mutations in the 16S rRNA genes of Helicobacter pylori mediate resistance to tetracycline. J. Bacteriol. 184:2131–2140 [DOI] [PMC free article] [PubMed] [Google Scholar] source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further, TP-434 has improved activity against major tetracycline resistance mechanisms and is 4-fold more potent than tigecycline in E. coli expressing a widespread tetracycline efflux pump, Tn1721-associated tet(A).”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Results were reported as averages from at least two independent experiments.”
- Also stated in: § MATERIALS AND METHODS · plain
“Results presented are averages from at least two independent experiments.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § MATERIALS AND METHODS · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The IC50 for linezolid, a nontetracycline control, was unaffected by the addition of Tet(M), substantiating that the RPP mechanism was specific to tetracycline.”
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Optimal preinduction conditions producing tetracycline MIC values of ≥128 μg/ml were identified for each strain in preliminary experiments, in which temperatures and l-arabinose concentrations were varied.”
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Assays were performed at least twice, and results from a representative experiment are reported in Table 3.”
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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. 1).”
What the sources say
- Not checked yetcites [8] 8. Clark RB, et al. 2012. Fluorocyclines. 2. Optimization of the C-9 side-chain for antibacterial activity and oral efficacy. J. Med. Chem. 55:606–622 [DOI] [PubMed] [Google Scholar]
- Not checked yetcites [18] 18. Hunt D, et al. 2010. TP-434 is a novel broad-spectrum Fluorocycline, abstr F1-2157. Abstr. 50th Intersci. Conf. Antimicrob. Agents Chemother American Society for Microbiology, Washington, DC [Google Scholar]
- Not checked yetcites [44] 44. Xiao XY, et al. 2012. Fluorocyclines. 1. 7-Fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent. J. Med. Chem. 55:597–605 [DOI] [PubMed] [Google Scholar]
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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.”
What the sources say
- Not checked yetcites [26] 26. Peterson LR. 2008. A review of tigecycline—the first glycylcycline. Int. J. Antimicrob. Agents 32(S4):S215–S222 [DOI] [PubMed] [Google Scholar]
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To verify that the constant presence of ampicillin and l-arabinose had no effect on assay results, all antibiotics used in this study were tested against DH10B cells containing the lacZ plasmid (in the presence of 50 μg/ml ampicillin plus 1% l-arabinose) versus DH10B cells (without ampicillin and l-arabinose); MIC values obtained under both conditions were within 2-fold for all antibiotics tested,”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, the findings support the idea that TP-434, like other tetracyclines, binds the ribosome and inhibits protein synthesis”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Semisynthetic tetracycline derivatives, such as doxycycline and minocycline (Fig. 1), show improved activity versus tetracycline against tetracycline-specific efflux but remain susceptible to resistance by RPPs (39).”
What the sources say
- Not checked yetcites [39] 39. Thaker M, Spanogiannopoulos P, Wright GD. 2010. The tetracycline resistome. Cell. Mol. Life Sci. 67:419–431 [DOI] [PMC free article] [PubMed] [Google Scholar]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Tetracycline antibiotics bind to the bacterial 30S ribosomal subunit and prevent chain elongation by blocking aminoacyl-tRNA binding to the A site (3, 21, 27).”
What the sources say
- Not checked yetcites [3] 3. Brodersen DE, et al. 2000. The structural basis for the action of the antibiotics tetracycline, pactamycin and hygromycin B on the 30S ribosomal subunit. Cell 103:1143–1154 [DOI] [PubMed] [Google Scholar] source
- Not checked yetcites [21] 21. Maxwell IH. 1967. Partial removal of bound transfer RNA from polysomes engaged in protein synthesis in vitro after addition of tetracycline. Biochim. Biophys. Acta 138:337–346 [DOI] [PubMed] [Google Scholar]
- Not checked yetcites [27] 27. Pioletti M, et al. 2001. Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3. EMBO J. 20:1829–1839 [DOI] [PMC free article] [PubMed] [Google Scholar] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Cloned inserts were verified by sequencing and comparing with reported sequences in GenBank”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper relies on this without support.
The E. coli in vitro transcription/translation and ribosome-binding assays reflect TP-434's mechanism of action in other bacterial species.
“The mechanism of action of TP-434 was assessed using both cell-based and in vitro assays.”
“TP-434 inhibits translation and is unaffected by Tet(M).”
The paper relies on this without support.
The recombinant resistance genes expressed in E. coli DH10B reproduce the effects of the same resistance mechanisms in clinical pathogens.
“To determine the impact of specific tetracycline resistance genes in isogenic E. coli strains”
“These properties impart to TP-434 a broad spectrum of activity against multidrug-resistant Gram-positive and Gram-negative pathogens”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The third generation of tetracycline derivatives, such as tigecycline (Tgc), display enhanced antimicrobial activity, overcoming efflux and ribosome protection mechanisms (6)(7)(8).”
From Structural basis for TetM-mediated tetracycline resistance (2012) · cites this paper as [8]
In the citing paper
“In contrast, the attached C9-glycyl side chain of Tgc would prevent access of the residues of loop III of TetM (Fig. 3 E and F), leading us to suggest that this steric hindrance contributes, together with the increased affinity of Tgc (7,8,27), to explaining how Tgc overcomes TetM-mediated resistance whereas tetracycline cannot (8).”
From Structural basis for TetM-mediated tetracycline resistance (2012) · cites this paper as [8]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
TP-434 IC50 standard deviation differs between text and Table 1
MinorFor the TP-434 IC50 of 0.27 μg/ml, the results text reports a standard deviation of 0.09 μg/ml, while Table 1 reports 0.16 μg/ml.
“the IC50s of both TP-434 and tigecycline were unaffected (0.27 ± 0.09 μg/ml and 0.09 ± 0.04 μg/ml, respectively)”
“TP-434 0.29 ± 0.09 0.27 ± 0.16”
Table 1 reverses the Tet(M) condition labels
MinorTable 1 labels the 1.26 μg/ml tetracycline IC50 as measured with Tet(M) and the 6.50 μg/ml value as measured without it. The results text says the opposite: adding Tet(M) increased the IC50 to 6.50 μg/ml. The condition labels appear to be reversed for the table.
“Antibiotic IC 50 (μg/ml) ±SD With Tet(M) Without Tet(M) TP-434 0.29 ± 0.09 0.27 ± 0.16 Tigecycline 0.08 ± 0.01 0.09 ± 0.04 Tetracycline 1.26 ± 0.48 6.50 ± 3.30 Linezolid 1.30 ± 0.28 1.08 ± 0.74”
“When purified Tet(M) was added to the transcription/translation reaction, the IC50s of both TP-434 and tigecycline were unaffected (0.27 ± 0.09 μg/ml and 0.09 ± 0.04 μg/ml, respectively), whereas the IC50 for tetracycline increased 5-fold (6.50 ± 3.3 μg/ml).”
Reported MICs exceed the stated assay concentration range
MinorThe methods state that MIC assay drug concentrations went only up to 32 μg/ml, but Table 3 reports MICs of 64 and 128 μg/ml and values greater than 128 μg/ml. Those values cannot be determined from the stated range.
“MIC assays with drug concentrations ranging from 0.016 to 32 μg/ml were incubated at 35°C for 18 to 20 h, and results were read visually.”
“Doxycycline 2 64 4 32 32 16 Minocycline 0.5 64 1 8 16 4 Tetracycline 2 128 128 >128 >128 128”
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Research works printed but not linked: 4
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Metadata
- Authors
- Grossman, T. H., Starosta, A. L., Fyfe, C., O'Brien, W., Rothstein, D. M., Mikolajka, A., Wilson, D. N., & Sutcliffe, J. A.
- Affiliations
- Tetraphase Pharmaceuticals (United States) (US)
- Ludwig-Maximilians-Universität München (DE)
- Center for Integrated Protein Science Munich (DE)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2012-05
- Volume
- 56
- Issue
- 5
- Pages
- 2559-2564
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC3346605
- OpenAlex
- W2163177484
- Semantic Scholar
- b655674a6d32982275d3dbbd3f3ff85d545567c6
- Cited by
- 162
- References
- 44
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 13 · 2023: 9 · 2022: 5 · 2021: 14 · 2020: 14 · 2019: 19 · 2018: 13 · 2017: 5 · 2016: 16 · 2015: 6 · 2014: 8 · 2013: 18 · 2012: 5
- FWCI
- 5.46
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-08-14)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Health Sciences › Medicine › Pharmacology (medical) › Antibiotics Pharmacokinetics and Efficacy
- Keywords
- tetracycline resistance, tetracycline resistance genes, tetM, tetK, tetB, tetA, tetX, Escherichia coli, Propionibacterium acnes, ribosome binding, protein synthesis inhibition, mechanism of action, antibiotic resistance
- MeSH terms
- Anti-Bacterial Agents, Bacterial Proteins, Binding, Competitive, Escherichia coli, Microbial Sensitivity Tests, Mutation, Propionibacterium acnes, Ribosomes, RNA, Ribosomal, 16S, Tetracycline, Tetracycline Resistance, Tetracyclines, Transformation, Bacterial, Protein Biosynthesis, Gene Expression
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