scholarly journals Evernimicin (SCH27899) Inhibits both Translation and 50S Ribosomal Subunit Formation in Staphylococcus aureusCells

2000 ◽  
Vol 44 (6) ◽  
pp. 1413-1417 ◽  
Author(s):  
W. Scott Champney ◽  
Craig L. Tober
Keyword(s):  
Bacterial Infections ◽  
Ribosomal Subunit ◽  
Viable Cell ◽  
Cellular Growth ◽  
Antibiotic Resistant ◽  
Ribosomal Subunits ◽  
Dose Dependent Fashion ◽  
Antibiotic Inhibition ◽  
Reduced Rate ◽  
Dose Dependent

ABSTRACT The effects of the everninomicin antibiotic evernimicin (SCH27899) on growing Staphylococcus aureus cells were investigated. Cellular growth rates and viable cell numbers decreased with increasing antibiotic concentrations. The rate of protein synthesis, measured as35S-amino acid incorporation, declined in parallel with the growth rate. Significantly, the formation of the 50S ribosomal subunit was inhibited in a dose-dependent fashion as well. 30S ribosomal subunit synthesis was not affected over the same concentration range. Evernimicin did not stimulate the breakdown of mature ribosomal subunits. Pulse-chase labeling experiments revealed a reduced rate of 50S subunit formation in drug-treated cells. Two erythromycin-resistant strains of S. aureus that carried the ermC gene were as sensitive as wild-type cells to antibiotic inhibition. In addition, two methicillin-resistant S. aureus organisms, one sensitive to erythromycin and one resistant to the macrolide, showed similar sensitivities to evernimicin. These results suggest a use for this novel antimicrobial agent against antibiotic-resistant bacterial infections.

scholarly journals Monoclonal antibody-defined functional epitopes on the adhesion- promoting glycoprotein complex (CDw18) of human neutrophils

Blood ◽  
1986 ◽  
Vol 67 (4) ◽  
pp. 1007-1013 ◽  
Author(s):  
WJ Wallis ◽  
DD Hickstein ◽  
BR Schwartz ◽  
CH June ◽  
HD Ochs ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Active Site ◽  
Bacterial Infections ◽  
Quaternary Structure ◽  
Alpha Subunit ◽  
Human Neutrophils ◽  
Glycoprotein Complex ◽  
Dose Dependent Fashion ◽  
Alpha Beta ◽  
Dose Dependent

Abstract We have evaluated the functional and immunochemical activities of three monoclonal antibodies (MoAbs) minimally reactive with adherence- defective neutrophils (PMN) from a patient with recurrent bacterial infections. In studies with normal PMN, MoAbs OKM1 and 60.1 both precipitate the same 165kd alpha-subunit (alpha M) within an alpha-beta heterodimer complex (CD11). The CD11 complex is part of a larger complex composed of four glycoproteins (CDw18) precipitated by MoAb 60.3, with properties suggesting that the CDw18 complex is equivalent to the Mac-1, LFA-1, p150, 95 glycoprotein family implicated in adherence-dependent leukocyte functions. PMN adherence to endothelium, spreading on surfaces, aggregation, and phagocytosis of zymosan particles were all inhibited in a dose-dependent fashion by MoAb 60.1 (analogous to previous studies with MoAb 60.3) while MoAb OKM1 had no effect. These findings unify previously disparate observations and suggest that a functionally active site on the adherence promoting glycoprotein complexes CD11 and CDw18 is distant from the alpha M epitope recognized by MoAb OKM1 but closely associated with the alpha M epitope recognized by MoAb 60.1 and the beta-epitope (or epitope created by alpha-beta quaternary structure) recognized by MoAb 60.3.

scholarly journals C5a stimulates secretion of tumor necrosis factor from human mononuclear cells in vitro. Comparison with secretion of interleukin 1 beta and interleukin 1 alpha.

1988 ◽  
Vol 168 (1) ◽  
pp. 443-448 ◽  
Author(s):  
S Okusawa ◽  
K B Yancey ◽  
J W van der Meer ◽  
S Endres ◽  
G Lonnemann ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Human Pbmc ◽  
Human Mononuclear Cells ◽  
Dose Dependent Fashion ◽  
Clinical Conditions ◽  
Dose Dependent

We have demonstrated that purified C5a is a potent stimulus to human PBMC secretion of TNF-alpha, IL-1 beta, and IL-1 alpha, which proceeds in a dose-dependent fashion. At a given concentration of C5a, TNF-alpha and IL-1 beta secretion did not differ significantly; both were secreted in significantly greater quantity than IL-1 alpha. Clinical conditions such as Gram-positive and Gram-negative bacterial infections, trauma, and immune complex diseases activate complement. Through the mediation of TNF and IL-1 secreted in response to C5a, these diverse disorders can share common features of fever, coagulopathy, acute phase protein production, and disordered metabolism.

scholarly journals A Synthetic Antibiotic Scaffold Effective Against Multidrug-Resistant Bacterial Pathogens

2021 ◽  
Author(s):  
Matthew Mitcheltree ◽  
Amarnath Pisipati ◽  
Egor A. Syroegin ◽  
Katherine J. Silvestre ◽  
Dorota Klepacki ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Ribosomal Subunit ◽  
Multidrug Resistant ◽  
Health Concern ◽  
Structural Basis ◽  
Resistant Bacteria ◽  
Global Public Health ◽  
Antibiotic Resistant ◽  
New Antibiotics ◽  
Orally Bioavailable

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern. For more than five decades, the search for new antibiotics has relied heavily upon the chemical modification of natural products (semi-synthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semi-synthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings. Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, here named iboxamycin. Iboxamycin is effective in strains expressing Erm and Cfr rRNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins, and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native 70S bacterial ribosome, as well as the Erm-methylated 70S ribosome, uncover the structural basis for this enhanced activity, including an unforeseen and unprecedented displacement of upon antibiotic binding. In mice, iboxamycin is orally bioavailable, safe, and effective in treating bacterial infections, testifying to the capacity for chemical synthesis to provide new antibiotics in an era of rising resistance.

scholarly journals Monoclonal antibody-defined functional epitopes on the adhesion- promoting glycoprotein complex (CDw18) of human neutrophils

Blood ◽  
1986 ◽  
Vol 67 (4) ◽  
pp. 1007-1013 ◽  
Author(s):  
WJ Wallis ◽  
DD Hickstein ◽  
BR Schwartz ◽  
CH June ◽  
HD Ochs ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Active Site ◽  
Bacterial Infections ◽  
Quaternary Structure ◽  
Alpha Subunit ◽  
Human Neutrophils ◽  
Glycoprotein Complex ◽  
Dose Dependent Fashion ◽  
Alpha Beta ◽  
Dose Dependent

We have evaluated the functional and immunochemical activities of three monoclonal antibodies (MoAbs) minimally reactive with adherence- defective neutrophils (PMN) from a patient with recurrent bacterial infections. In studies with normal PMN, MoAbs OKM1 and 60.1 both precipitate the same 165kd alpha-subunit (alpha M) within an alpha-beta heterodimer complex (CD11). The CD11 complex is part of a larger complex composed of four glycoproteins (CDw18) precipitated by MoAb 60.3, with properties suggesting that the CDw18 complex is equivalent to the Mac-1, LFA-1, p150, 95 glycoprotein family implicated in adherence-dependent leukocyte functions. PMN adherence to endothelium, spreading on surfaces, aggregation, and phagocytosis of zymosan particles were all inhibited in a dose-dependent fashion by MoAb 60.1 (analogous to previous studies with MoAb 60.3) while MoAb OKM1 had no effect. These findings unify previously disparate observations and suggest that a functionally active site on the adherence promoting glycoprotein complexes CD11 and CDw18 is distant from the alpha M epitope recognized by MoAb OKM1 but closely associated with the alpha M epitope recognized by MoAb 60.1 and the beta-epitope (or epitope created by alpha-beta quaternary structure) recognized by MoAb 60.3.

scholarly journals A Synthetic Antibiotic Scaffold Effective Against Multidrug-Resistant Bacterial Pathogens

2021 ◽  
Author(s):  
Matthew Mitcheltree ◽  
Amarnath Pisipati ◽  
Egor A. Syroegin ◽  
Katherine J. Silvestre ◽  
Dorota Klepacki ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Ribosomal Subunit ◽  
Multidrug Resistant ◽  
Health Concern ◽  
Structural Basis ◽  
Resistant Bacteria ◽  
Global Public Health ◽  
Antibiotic Resistant ◽  
New Antibiotics ◽  
Orally Bioavailable

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern. For more than five decades, the search for new antibiotics has relied heavily upon the chemical modification of natural products (semi-synthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semi-synthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings. Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, here named iboxamycin. Iboxamycin is effective in strains expressing Erm and Cfr rRNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins, and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native 70S bacterial ribosome, as well as the Erm-methylated 70S ribosome, uncover the structural basis for this enhanced activity, including an unforeseen and unprecedented displacement of upon antibiotic binding. In mice, iboxamycin is orally bioavailable, safe, and effective in treating bacterial infections, testifying to the capacity for chemical synthesis to provide new antibiotics in an era of rising resistance.

scholarly journals Succinate Promotes Phagocytosis of Monocytes/Macrophages in Teleost Fish

2021 ◽  
Vol 8 ◽  
Author(s):  
Dai-xiao Yang ◽  
Hao Yang ◽  
Yun-chao Cao ◽  
Ming Jiang ◽  
Jun Zheng ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Tca Cycle ◽  
Edwardsiella Tarda ◽  
Resistant Bacteria ◽  
Dependent Manner ◽  
Antibiotic Resistant ◽  
Expression Of Genes ◽  
The Tca Cycle ◽  
Before And After ◽  
Dose Dependent

Development of immunity-based strategy to manage bacterial infection is urgently needed in aquaculture due to the widespread of antibiotic-resistant bacteria. Phagocytosis serves as the first line defense in innate immunity that engulfs bacteria and restricts their proliferations and invasions. However, the mechanism underlying the regulation of phagocytosis is not fully elucidated and the way to boost phagocytosis is not yet explored. In this manuscript, we profiled the metabolomes of monocytes/macrophages isolated from Nile tilapia, prior and after phagocytosis on Vibrio alginolyticus. Monocytes/macrophages showed a metabolic shift following phagocytosis. Interestingly, succinate was accumulated after phagocytosis and was identified as a crucial biomarker to distinguish before and after phagocytosis. Exogenous succinate increased the phagocytotic rate of monocytes/macrophages in a dose-dependent manner. This effect was dependent on the TCA cycle as the inhibitor of malonate that targets succinate dehydrogenase abrogated the effect. Meanwhile, exogenous succinate regulated the expression of genes associated with innate immune and phagocytosis. In addition, succinate-potentiated phagocytosis was applicable to both gram-negative and -positive cells, including V. alginolyticus, Edwardsiella tarda, Streptococcus agalactiae, and Streptococcus iniae. Our study shed light on the understanding of how modulation on host’s metabolism regulates immune response, and this can be a potent therapeutic approach to control bacterial infections in aquaculture.

scholarly journals Analysis of the Effects of Cigarette Smoke on Staphylococcal Virulence Phenotypes

2015 ◽  
Vol 83 (6) ◽  
pp. 2443-2452 ◽  
Author(s):  
Elisa K. McEachern ◽  
John H. Hwang ◽  
Katherine M. Sladewski ◽  
Shari Nicatia ◽  
Carola Dewitz ◽  
...  
Keyword(s):  
Surface Charge ◽  
Cigarette Smoke ◽  
Bacterial Infections ◽  
Content Type ◽  
Immune Resistance ◽  
Dose Dependent Fashion ◽  
Human Immune ◽  
Macrophage Killing ◽  
Dose Dependent

Cigarette smoking is the leading preventable cause of death, disease, and disability worldwide. It is well established that cigarette smoke provokes inflammatory activation and impairs antimicrobial functions of human immune cells. Here we explore whether cigarette smoke likewise affects the virulence properties of an important human pathogen,Staphylococcus aureus, and in particular methicillin-resistantS. aureus(MRSA), one of the leading causes of invasive bacterial infections. MRSA colonizes the nasopharynx and is thus exposed to inhalants, including cigarette smoke. MRSA exposed to cigarette smoke extract (CSE-MRSA) was more resistant to macrophage killing (4-fold higher survival;P< 0.0001). CSE-MRSA demonstrated reduced susceptibility to cell lysis (1.78-fold;P= 0.032) and antimicrobial peptide (AMP) (LL-37) killing (MIC, 8 μM versus 4 μM). CSE modified the surface charge of MRSA in a dose-dependent fashion, impairing the binding of particles with charge similar to that of AMPs by 90% (P< 0.0001). These changes persisted for 24 h postexposure, suggesting heritable modifications. CSE exposure increased hydrophobicity by 55% (P< 0.0001), which complemented findings of increased MRSA adherence and invasion of epithelial cells. CSE induced upregulation ofmprF, consistent with increased MRSA AMP resistance.S. aureuswithoutmprFhad no change in surface charge upon exposure to CSE.In vivo, CSE-MRSA pneumonia induced higher mouse mortality (40% versus 10%) and increased bacterial burden at 8 and 20 h postinfection compared to control MRSA-infected mice (P< 0.01). We conclude that cigarette smoke-induced immune resistance phenotypes in MRSA may be an additional factor contributing to susceptibility to infectious disease in cigarette smokers.

Three-dimensional reconstruction of the 40S ribosomal subunit from rabbit reticulocytes

1987 ◽  
Vol 45 ◽  
pp. 936-937
Author(s):  
Neng-Yu Zhang ◽  
Terence Wagenknecht ◽  
Michael Radermacher ◽  
Tom Obrig ◽  
Joachim Frank
Keyword(s):  
Three Dimensional ◽  
Ribosomal Subunit ◽  
Uranyl Acetate ◽  
Reconstruction Method ◽  
Single Exposure ◽  
Electron Dose ◽  
Ribosomal Subunits ◽  
40S Ribosomal Subunit ◽  
Dimensional Reconstruction ◽  
Rabbit Reticulocytes

We have reconstructed the 40S ribosomal subunit at a resolution of 4 nm using the single-exposure pseudo-conical reconstruction method of Radermacher et al.Small (40S) ribosomal subunits were Isolated from rabbit reticulocytes, applied to grids and negatively stained (0.5% uranyl acetate) in a manner that “sandwiches” the specimen between two layers of carbon. Regions of the grid exhibiting uniform and thick staining were identified and photographed twice (magnification 49,000X). The first micrograph was always taken with the specimen tilted by 50° and the second was of the Identical area untilted (Fig. 1). For each of the micrographs the specimen was subjected to an electron dose of 2000-3000 el/nm2.Three hundred thirty particles appearing in the L view (defined in [4]) were selected from both tilted- and untilted-specimen micrographs. The untilted particles were aligned and their rotational alignment produced the azimuthal angles of the tilted particles in the conical tilt series.

Plasminogen Interactions with Immobilized Fibrinogen

1989 ◽  
Vol 62 (04) ◽  
pp. 1078-1082 ◽  
Author(s):  
Burt Adelman ◽  
Patricia Ouynn
Keyword(s):  
Immunosorbent Assay ◽  
Aminocaproic Acid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Binding Regions ◽  
Dose Dependent Fashion ◽  
Epsilon Aminocaproic Acid ◽  
Dose Dependent

SummaryThis report describes the binding of plasminogen to fibrinogen adsorbed onto polystyrene wells. Binding was determined by enzyme linked immunosorbent assay. Both glu- and lys-plasminogen bound to immobilized fibrinogen in a dose-dependent fashion. However, more lys- than glu-plasminogen bound when equal concentrations of either were added to immobilized fibrinogen. Plasminogen binding was inhibited by epsilon aminocaproic acid indicating that binding was mediated via lysine-binding regions of plasminogen. Soluble fibrinogen added in excess of immobilized fibrinogen did not compete for plasminogen binding but fibrinogen fragments produced by plasmin digestion of fibrinogen did. Treatment of immobilized fibrinogen with thrombin caused a small but significant (p <0.01) increase in plasminogen binding. These studies demonstrate that immobilized fibrinogen binds both glu- and lys-plasminogen and that binding is mediated via lysine-binding regions. These interactions may facilitate plasminogen binding to fibrinogen adsorbed on to surfaces and to cells such as platelets which bind fibrinogen.

Soluble Thrombomodulin Purified from Human Urine Exhibits a Potent Anticoagulant Effect In Vitro and In Vivo

1995 ◽  
Vol 73 (05) ◽  
pp. 805-811 ◽  
Author(s):  
Yasuo Takahashi ◽  
Yoshitaka Hosaka ◽  
Hiromi Niina ◽  
Katsuaki Nagasawa ◽  
Masaaki Naotsuka ◽  
...  
Keyword(s):  
Human Urine ◽  
Specific Activity ◽  
Anticoagulant Activity ◽  
Rabbit Lung ◽  
Soluble Thrombomodulin ◽  
Molecular Weights ◽  
Dose Dependent Fashion ◽  
Dose Dependent

SummaryWe examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity >5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (>1 TMU/ml), APTT (>5 TMU/ml), TT (>5 TMU/ml) and PT (>40 TMU/ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.

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