scholarly journals The third-generation tetracycline, KBP-7072, exploits and reveals a new potential of the primary tetracycline binding pocket

2018 ◽  
Author(s):  
Tatsuya Kaminishi ◽  
Andreas Schedlbauer ◽  
Borja Ochoa-Lizarralde ◽  
Elisa de Astigarraga ◽  
Retina Çapuni ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Ribosomal Subunit ◽  
Binding Pocket ◽  
Protein Synthesis Inhibitor ◽  
Third Generation ◽  
Bacterial Strains ◽  
Synthesis Inhibitor ◽  
The Third ◽  
Spectrum Activity ◽  
A Site

Antibiotic resistance is a growing threat to human health requiring the discovery or development of new anti-infectives. As such, KBP-7072 is a novel tetracycline derivative that exhibits broad-spectrum activity against Gram-positive and -negative bacterial strains. To determine the mechanism of action of KBP-7072 and understand how its unique C9 extension can be used to combat the growing problem of antibiotic resistance we determined the structure of KBP-7072 bound to the bacterial 30S ribosomal subunit, the inhibitory target of typical tetracyclines. We show that KBP-7072 binds to the primary tetracycline binding site on the 30S ribosomal subunit consistent with it acting as a protein synthesis inhibitor that blocks A-site occupation. Moreover, the unique chemical nature of KBP-7072s C9 extension leads to a distinctive interaction pattern with the 30S subunit that distinguishes KBP-7072 from the third-generation tetracycline, Tigecycline, and thus expands the interaction potential of the primary tetracycline binding pocket.

Structure of the translating Neurospora ribosome arrested by cycloheximide

2021 ◽  
Vol 118 (48) ◽  
pp. e2111862118
Author(s):  
Lunda Shen ◽  
Zhaoming Su ◽  
Kailu Yang ◽  
Cheng Wu ◽  
Thomas Becker ◽  
...  
Keyword(s):  
Binding Site ◽  
Messenger Rna ◽  
Large Subunit ◽  
Structural Data ◽  
Binding Pocket ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Translation Elongation ◽  
Elongation Step ◽  
A Site

Ribosomes translate RNA into proteins. The protein synthesis inhibitor cycloheximide (CHX) is widely used to inhibit eukaryotic ribosomes engaged in translation elongation. However, the lack of structural data for actively translating polyribosomes stalled by CHX leaves unanswered the question of which elongation step is inhibited. We elucidated CHX’s mechanism of action based on the cryo-electron microscopy structure of actively translating Neurospora crassa ribosomes bound with CHX at 2.7-Å resolution. The ribosome structure from this filamentous fungus contains clearly resolved ribosomal protein eL28, like higher eukaryotes but unlike budding yeast, which lacks eL28. Despite some differences in overall structures, the ribosomes from Neurospora, yeast, and humans all contain a highly conserved CHX binding site. We also sequenced classic Neurospora CHX-resistant alleles. These mutations, including one at a residue not previously observed to affect CHX resistance in eukaryotes, were in the large subunit proteins uL15 and eL42 that are part of the CHX-binding pocket. In addition to A-site transfer RNA (tRNA), P-site tRNA, messenger RNA, and CHX that are associated with the translating N. crassa ribosome, spermidine is present near the CHX binding site close to the E site on the large subunit. The tRNAs in the peptidyl transferase center are in the A/A site and the P/P site. The nascent peptide is attached to the A-site tRNA and not to the P-site tRNA. The structural and functional data obtained show that CHX arrests the ribosome in the classical PRE translocation state and does not interfere with A-site reactivity.

scholarly journals Analysis of Antibiotics Susceptibility of Old and Fresh ATCC Strain of Staphylococcus aureus by Standard Agar Diffusion Technique

1970 ◽  
Vol 24 (2) ◽  
pp. 137-142
Author(s):  
Marufa Zerin Akhter ◽  
Ibrahim Khalil ◽  
Priyanath Roy ◽  
Mir Mohammad Ibna Masud
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Antibiotic Sensitivity ◽  
Acid Synthesis ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Agar Diffusion ◽  
Diffusion Technique ◽  
Atcc Strain ◽  
Sensitivity Pattern

A comparative study of an old and fresh ATCC strain of Staphylococcus aureus was carried out to determine the mechanism of antibiotic resistance of the old one, which had been preserved in lyophilized condition. Five different antibiotics having five different modes of action were used. They included amoxicillin, azithromycin, neomycin, ciprofloxacin and polymixin B. Agar diffusion technique was followed to determine the antibiotic sensitivity. It was observed that the old strain showed the highest resistance against amoxicillin, whereas no remarkable changes in the sensitivity pattern were observed against polymixin B and neomycin. In case of azithromycin and ciprofloxacin, the old strain showed resistance up to some extent. From these results it was clearly evident that in the controlled preserved conditions, cell wall-mediated resistance was predominating, while the cell membrane- and 30S ribosome-mediated resistance were the least likely ones. The nucleic acid synthesis inhibitors and the 50S ribosomal protein synthesis inhibitor lied in between these two extremes showing variations up to some extent in the sensitivity pattern between the old and fresh ATCC strain of S. aureus. Keywords: Staphylococcus aureus, Antibiotic resistance mechanismDOI: http://dx.doi.org/10.3329/bjm.v24i2.1259 Bangladesh J Microbiol, Volume 24, Number 2, December 2007, pp 137-142

scholarly journals Antibiotic Resistance Bacteria Associated in Waters Discharges of a Hospital in Patna

2017 ◽  
Vol 7 (1) ◽  
pp. 9
Author(s):  
Vyomesh Vibhaw ◽  
Kumar Pranay ◽  
Krishnadutt Pratihast ◽  
Bipin Bihari Mishra ◽  
S. R. Padmadeo
Keyword(s):  
Antibiotic Resistance ◽  
Group Iv ◽  
Bacterial Isolates ◽  
Bacterial Strains ◽  
Antibiotic Resistant ◽  
Group Iii ◽  
E Coli ◽  
Group I ◽  
Three Samples ◽  
A Site

The isolation and screening of antibiotic resistance strains from three samples sites present in and around hospital of Patna resulted in isolation of 300 bacterial isolates. Out of which maximum number of isolates were obtained from site B while site A gave least number of isolates. 89 bacterial strains showed antibiotic resistance. Among these 89 isolates Site B had maximum number of antibiotic resistant isolates (51) followed by site C with 33 isolates. Among the four groups of antibiotic selected for investigation, the isolates showed highest antibiotic resistance against fluoroquinolones with 1, 20 and 14 isolates from site A, site B and site C respectively showing antibiotic resistance. Site B isolates showed significant resistance against group III (aminoglycosides) antibiotic. Site C isolates also showed maximum resistance against Group IV antibiotics followed by Group II, III and Group I. Site A sample showed resistance against Ciprofloxacin, however it showed sensitivity against all other antibiotics. Study showed that there was a dynamic flux in the response of E. coli strains against antibiotic. Antibiotic resistant E. coli was present in wastewater. Key words: bacterial isolates, antibiotic resistance, E. coli.

scholarly journals Functional, Biophysical, and Structural Bases for Antibacterial Activity of Tigecycline

2006 ◽  
Vol 50 (6) ◽  
pp. 2156-2166 ◽  
Author(s):  
Matthew W. Olson ◽  
Alexey Ruzin ◽  
Eric Feyfant ◽  
Thomas S. Rush ◽  
John O'Connell ◽  
...  
Keyword(s):  
Molecular Model ◽  
Thermus Thermophilus ◽  
Ribosomal Subunit ◽  
Tetracycline Resistance ◽  
X Ray Diffraction ◽  
Spectrum Activity ◽  
Modeling Data ◽  
A Site ◽  
Bacterial Protein Synthesis ◽  
Broad Spectrum Activity

ABSTRACT Tigecycline is a novel glycylcycline antibiotic that possesses broad-spectrum activity against many clinically relevant species of bacterial pathogens. The mechanism of action of tigecycline was delineated using functional, biophysical, and molecular modeling experiments in this study. Functional assays showed that tigecycline specifically inhibits bacterial protein synthesis with potency 3- and 20-fold greater than that of minocycline and tetracycline, respectively. Biophysical analyses demonstrated that isolated ribosomes bind tigecycline, minocycline, and tetracycline with dissociation constant values of 10−8, 10−7, and >10−6 M, respectively. A molecular model of tigecycline bound to the ribosome was generated with the aid of a 3.40-angstrom resolution X-ray diffraction structure of the 30S ribosomal subunit from Thermus thermophilus. This model places tigecycline in the A site of the 30S subunit and involves substantial interactions with residues of H34 of the ribosomal subunit. These interactions were not observed in a model of tetracycline binding. Modeling data were consistent with the biochemical and biophysical data generated in this and other recent studies and suggested that tigecycline binds to bacterial ribosomes in a novel way that allows it to overcome tetracycline resistance due to ribosomal protection.

scholarly journals Distribution of Bacterial Strains and their Antibiotic Sensityvity Profile in an Urban Referral Hospital

2018 ◽  
Vol 25 ◽  
pp. 72-76
Author(s):  
M Bulbul Hasan ◽  
S Gul Nahar ◽  
M Nawshad Ali ◽  
Mst Rokeya Khatun ◽  
Chinmoy Kanti Das
Keyword(s):  
Referral Hospital ◽  
Third Generation ◽  
Bacterial Strains ◽  
Klebsiella Species ◽  
Acinetobacter Species ◽  
The Third ◽  
Pseudomonas Species ◽  
Judicious Choice ◽  
Almost All ◽  
Third Generation Cephalosporins

Then Present study was done to assess the distribution of bacterial pathogens with their pattern of antibiotic susceptibility in an urban referral hospital in RMCH. A total of 393 bacteria strains were isolated from various specimens over a 10-months period. The majority of the organisms were Escherichia coli (33.33%) followed by Klebsiella species (27.48%), staphylococcus aureus (17.05%), Acinetobcter species (8.14%), Pseudomonas species (7.12%), and others. The third-generation Cephalosporins like Ceftriaxone, Ceftazidime and Cefotaxime were sensitive to Ciprofloxacin of various Enterobacteriaceae was only between 33-40% compared to 52.8-37.9% against Gentamicin. Majority of the Enterobacteriaceae were resistant to Ampicillin, whereas almost all of the Enterobacteriaceae (94-100%) were sensitive to Imipenem. About 97.0% Acinetobacter species were susceptible to Imipenem. Sensitivity of the organism (Acinetobacter) to third-generation Cephalosporins ranged between 50-56%, whereas 40.6% were found sensitive to Ciprofloxacin. The sensitivity to Chloramphenicol, Co-trimixazole, Cephalexin and Ampicillin ranged between 9.3% to 34.3%. About 93.0% of Pseudomonas species were sensitive to Imipenem. The rate of susceptibility to Gentamicin and Netilmicin was higher than those of the Ciprofloxacin and Ceftriaxone (37.8% and 53.5% vc. 39.2%). About 70% of isolated S. aureus were resistane of Oxacillin but all were sensitive to Vancomycin. The result of this study would help the physicians to make a judicious choice of antibiotics for therapeutic purposes.TAJ 2012; 25: 72-76

scholarly journals The rate of salmonella spp. from healthy people in Ho Chi Minh city in 2018

2019 ◽  
Vol 2 (2) ◽  
pp. 17-22
Author(s):  
Hoang Ngan Nguyen Ly ◽  
Phuc Nguyen Do ◽  
Kim Phan Huynh Thi ◽  
Anh Dao Nguyen Thi ◽  
◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Nalidixic Acid ◽  
Healthy People ◽  
Ho Chi Minh City ◽  
Third Generation ◽  
Salmonella Spp ◽  
Fecal Samples ◽  
The Third ◽  
Survey Results ◽  
Stool Samples

Survey results of 226 stool samples from healthy people collected from four districts in Ho Minh city in 2018 (districts no. 1, 5, 8 and 9) showed that the number of people carrying Salmonella spp. was 12/226 (5.3%). Twelve fecal samples were positive for Salmonella spp. with 15 Salmonella spp. strains isolated. Three of them are S. Indiana (20.0%); S. Typhimurium, S. Rissen and S. Give. Each has two strains (13.3%): 1 strain has serotypes O: 1 and one strains has 9: 1.5 (6.7%). These Salmonella strains belong to the non-typhoid group (the group that causes diarrhea). The Salmonella spp. strains isolated have highest antibiotic resistance to ampicillin, tetracycline, chloramphenicol (80.0%); followed by sulfamethoxazole/trimethoprim (66.7%); nalidixic acid (40.0%); gentamicin, ciprofloxacin, kanamycin (26.7%). Strains resistant to the third generation cephalosporins were found (cefotaxime and ceftazidime). Three of these are resistant to both types of antibiotics (20.0%). No strains resistance to cefoxitin and cosfomycin were detected.

Modulation of Arachidonic Acid Metabolism in Human Endothelial Cells by Glucocorticoids

1986 ◽  
Vol 55 (03) ◽  
pp. 369-374 ◽  
Author(s):  
Raffaele De Caterina ◽  
Babette B Weksler
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Arachidonic Acid Metabolism ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Prolonged Incubation ◽  
Dependent Inhibition ◽  
Human Thrombin ◽  
Umbilical Vein Endothelial Cells

SummaryTo learn whether glucocorticoids inhibit prostaglandin (PG) production in vascular endothelial cells, we investigated the effects of glucocorticoids on PG synthesis by cultured human umbilical vein endothelial cells (EC). Pretreatment of EC with dexamethasone (DX, 10-9 to 5 x 10-5 M) caused a dose-dependent inhibition of PGI2 production when PG synthesis from endogenous arachidonate was stimulated by human thrombin (0.25-2 U/ml) or ionophore A 23187 (1-5 μM). The inhibition was detectable at 10-7 M DX and maximal at 10-5 M (4.0 ± 0.7 vs. control: 7.7 ± 1.9 ng/ml, mean ± S.D., P <0.01). The production of PGE2 and the release of radiolabelled arachidonate (AA) from prelabelled cells were similarly inhibited. Prolonged incubation of EC with glucocorticoids was required to inhibit PG production or arachidonate release: ranging from 8% inhibition at 5 h to 44% at 38 h. In contrast, prostaglandin formation from exogenous AA was not altered by DX treatment. When thrombin or ionophore-stimulated EC were restimulated with exogenous AA (25 μM), DX-treated cells released more PGI2 than control cells (5.7 ± 0.5 vs. 4.1 ± 0.6 ng/ml, P <0.01). Both the decrease in PGI2 production after thrombin/ionophore and the increase after re-stimulation with AA were blunted in the presence of the protein synthesis inhibitor cycloheximide (0.1-0.2 μg/ml). Thus, incubation of EC with glucocorticoids inhibits PG production at the step of phospholipase activation. The time requirement for these steroid effects and their blunting by cycloheximide are consistent with the induction of regulatory proteins, possibly lipocortins, in endothelial cells.

The Third Generation of Guerrilla Warfare

Asian Survey ◽  
1968 ◽  
Vol 8 (6) ◽  
pp. 435-447 ◽  
Author(s):  
Chalmers Johnson
Keyword(s):  
Guerrilla Warfare ◽  
Third Generation ◽  
The Third
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