scholarly journals In vitro and In vivo characterization of NOSO-502, a novel inhibitor of bacterial translation

2018 ◽  
Author(s):  
Emilie Racine ◽  
Patrice Nordmann ◽  
Lucile Pantel ◽  
Matthieu Sarciaux ◽  
Marine Serri ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Acquired Resistance ◽  
Systemic Infection ◽  
Resistance Mechanisms ◽  
E Coli ◽  
Spectrum Activity ◽  
In Vivo Characterization ◽  
Bacterial Translation

ABSTRACTAntibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the Odilorhabdins, a novel antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a novel mechanism of action on ribosomes. A lead-optimization program identified NOSO-502 as a promising candidate. NOSO-502 has MIC values ranging from 0.5 to 4 μg/ml against standard Enterobacteriaceae strains and carbapenem-resistant Enterobacteriaceae (CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-β-lactamases. In addition, this compound overcomes multiple chromosome-encoded or plasmid-mediated resistance mechanisms of acquired resistance to colistin. It is effective in mouse systemic infection models against E. coli EN122 (ESBL) or E. coli ATCC BAA-2469 (NDM-1), achieving an ED50 of 3.5 mg/kg and 1-, 2- and 3-log reductions in blood burden at 2.6, 3.8, and 5.9 mg/kg, respectively, in the first model and 100% survival in the second, starting with a dose as low as 4 mg/kg. In a UTI model of E. coli UTI89, urine, bladder and kidney burdens were reduced by 2.39, 1.96, and 1.36 log10 CFU/ml, respectively, after injecting 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or HRPT cells, no inhibition of hERG-CHO or Nav 1.5 -HEK current, and no increase of micronuclei at 512 μM. NOSO-502, a compound with a novel mechanism of action, is active against Enterobacteriaceae, including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorable in vitro safety profile.

scholarly journals In VitroandIn VivoCharacterization of NOSO-502, a Novel Inhibitor of Bacterial Translation

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Emilie Racine ◽  
Patrice Nordmann ◽  
Lucile Pantel ◽  
Matthieu Sarciaux ◽  
Marine Serri ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Acquired Resistance ◽  
Systemic Infection ◽  
Resistance Mechanisms ◽  
Content Type ◽  
E Coli ◽  
Proximal Tubular Epithelial Cells ◽  
Renal Proximal Tubular ◽  
Bacterial Translation

ABSTRACTAntibacterial activity screening of a collection ofXenorhabdusstrains led to the discovery of the odilorhabdins, a new antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a new mechanism of action on ribosomes. A lead optimization program identified NOSO-502 as a promising candidate. NOSO-502 has MIC values ranging from 0.5 to 4 μg/ml against standardEnterobacteriaceaestrains and carbapenem-resistantEnterobacteriaceae(CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-β-lactamases. In addition, this compound overcomes multiple chromosome-encoded or plasmid-mediated resistance mechanisms of acquired resistance to colistin. It is effective in mouse systemic infection models againstEscherichia coliEN122 (extended-spectrum β-lactamase [ESBL]) orE. coliATCC BAA-2469 (NDM-1), achieving a 50% effective dose (ED50) of 3.5 mg/kg of body weight and 1-, 2-, and 3-log reductions in blood burden at 2.6, 3.8, and 5.9 mg/kg, respectively, in the first model and 100% survival in the second, starting with a dose as low as 4 mg/kg. In a urinary tract infection (UTI) model withE. coliUTI89, urine, bladder, and kidney burdens were reduced by 2.39, 1.96, and 1.36 log10CFU/ml, respectively, after injection of 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or human renal proximal tubular epithelial cells (HRPTEpiC), no inhibition of hERG-CHO or Nav 1.5-HEK current, and no increase of micronuclei at 512 μM. NOSO-502, a compound with a new mechanism of action, is active againstEnterobacteriaceae, including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorablein vitrosafety profile.

scholarly journals DDRE-07. DIPG HARBOUR ALTERATIONS TARGETABLE BY MEK INHIBITORS, WITH ACQUIRED RESISTANCE MECHANISMS OVERCOME BY COMBINATORIAL INHIBITION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii62-ii62
Author(s):  
Elisa Izquierdo ◽  
Diana Carvalho ◽  
Alan Mackay ◽  
Sara Temelso ◽  
Jessica K R Boult ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Mapk Pathway ◽  
Synergistic Effects ◽  
Acquired Resistance ◽  
Mek Inhibitor ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Mesenchymal Transition

Abstract The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly emerge, playing an important role in treatment failure. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling (methylation BeadArray, exome, RNAseq, phospho-proteomics) linked to drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib (GI50 16-50nM) in samples, which harboured genetic alterations targeting the MAPK pathway, including the non-canonical BRAF_G469V mutation, and those affecting PIK3R1 and NF1. However, treatment of PDX models and of a patient with trametinib at relapse failed to elicit a significant response. We generated trametinib-resistant clones (62-188-fold, GI50 2.4–5.2µM) in the BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 (MEK1_K57N, MEK1_I141S and MEK2_I115N) with sustained pathway up-regulation. These cells showed the hallmarks of mesenchymal transition, and expression signatures overlapping with inherently trametinib-insensitive primary patient-derived cells that predicted an observed sensitivity to dasatinib. Combinations of trametinib with dasatinib and the downstream ERK inhibitor ulixertinib showed highly synergistic effects in vitro. These data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatments likely to be required for meaningful clinical translation.

Lactoferrin protects neonatal rats from gut-related systemic infection

2001 ◽  
Vol 281 (5) ◽  
pp. G1140-G1150 ◽  
Author(s):  
Lynn Edde ◽  
Ronaldo B. Hipolito ◽  
Freda F. Y. Hwang ◽  
Denis R. Headon ◽  
Robert A. Shalwitz ◽  
...  
Keyword(s):  
Systemic Infection ◽  
In Vitro Studies ◽  
Peptide Antibiotics ◽  
Neonatal Rats ◽  
Vitro Assay ◽  
E Coli ◽  
Severity Scores ◽  
Factor Α

Lactoferrin is a milk protein that reportedly protects infants from gut-related, systemic infection. Proof for this concept is limited and was addressed during in vivo and in vitro studies. Neonatal rats pretreated orally with recombinant human lactoferrin (rh-LF) had less bacteremia and lower disease severity scores ( P < 0.001) after intestinal infection with Escherichia coli. Control animals had 1,000-fold more colony-forming units of E. coli per milliliter of blood than treated animals ( P < 0.001). Liver cultures from control animals had a twofold increase in bacterial counts compared with cultures from rh-LF-treated pups ( P < 0.02). Oral therapy with rh-LF + FeSO4did not alter the protective effect. In vitro studies confirmed that rh-LF interacted with the infecting bacterium and rat macrophages. An in vitro assay showed that rh-LF did not kill E. coli, but a combination of rh-LF + lysozyme was microbicidal. In vitro studies showed that rat macrophages released escalating amounts of nitric oxide and tumor necrosis factor-α when stimulated with increasing concentrations of rh-LF. The in vitro studies suggest that rh-LF may act with other “natural peptide antibiotics” or may prime macrophages to kill E. coli in vivo.

Synergistic growth inhibition of RCC and NSCLC cell lines by sorafenib plus vorinostat and induction of angiogenic genes by ER stress

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16114-e16114
Author(s):  
H. A. Drabkin ◽  
G. Sharma ◽  
L. J. Costa ◽  
C. Korch ◽  
R. M. Gemmill
Keyword(s):  
Growth Inhibition ◽  
Er Stress ◽  
Cell Lines ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Angiogenic Factors ◽  
Nsclc Cell ◽  
Angiogenic Genes

e16114 Sorafenib, vorinostat and the combination were examined in 34 RCC and NSCLC cell lines. In growth assays, sorafenib at 8 μM resulted in synergy with multiple vorinostat doses, whereas no synergy was seen with lower doses. Changes in phospho-ERK and AKT were not predictive of growth inhibition, whereas frequent inhibition of cyclin D1 and upregulation of p21Waf1 was observed. To anticipate resistance mechanisms to the anti-angiogenic effects of sorafenib, we studied the expression of 13 angiogenic factors in 10 selected lines. At baseline, bFGF, VEGF and IL-8 were highly expressed in RCCs, whereas Gro-α, VEGF, and IL-8 predominated in NSCLCs. Multiple angiogenic factors were upregulated by sorafenib and vorinostat, especially VEGF, IL-6, CTGF, EDN1, PDGFβ, and IL-8. Importantly, sorafenib at 8 μM, but not lower doses, induced ER stress in these cell lines and thapsigargin or tunicamycin treatment recapitulated many, but not all, of the observed angiogenic gene responses to sorafenib. In fact, CHOP induction by sorafenib plus vorinostat was the only parameter, other than growth inhibition, that changed in a synergistic manner. In summary, sorafenib plus vorinostat potently inhibits the in vitro growth of RCC and NSCLC cell lines. Upregulation of multiple angiogenic genes, in part by an ER-stress mechanism, may contribute to acquired resistance in vivo. No significant financial relationships to disclose.

scholarly journals Systemic Infection by Pseudomonas aeruginosa in a Dog

2016 ◽  
Vol 44 (1) ◽  
pp. 5
Author(s):  
Layze Cilmara Alves Da Silva ◽  
Danielle Aluska Do Nascimento Pessoa ◽  
Lisanka Ângelo Maia ◽  
Rodrigo Antonio Torres Matos ◽  
Meire Maia da Silva Macêdo
Keyword(s):  
Internal Medicine ◽  
Pseudomonas Aeruginosa ◽  
Veterinary Medicine ◽  
Acquired Resistance ◽  
Systemic Infection ◽  
Care Needs ◽  
Cutaneous Lesions ◽  
Disk Diffusion Test

Background: Pseudomonas aeruginosa is an important pathogen frequently associated with nosocomial infections affecting mainly immunosuppressed patients. In Veterinary Medicine, infections caused by P. aeruginosa are becoming increasingly frequent; infections are related to intrinsic or acquired resistance mechanisms, which limit the choice of effective agents.Case: This study describes the case of a four-month-old male Pitt Bull dog treated at the Small Animal Internal Medicine service of the Veterinary Hospital at the Health and Rural Technology Center of Federal University of Campina Grande, Patos/Paraíba. The patient presented with apathy, inappetence, moderate dehydration, tachypnea, tachycardia, hyperther­mia, pale mucosae, small lesions in the pelvic limbs, with edema and subsequent widespread petechiae. Treatment with intravenous fluid therapy using 0.9% NaCl with B-complex vitamins, and 20 mg/kg cephalexin every 12 h was established. The patient did not respond well to treatment, and died two days later. Necropsy was performed at the Veterinary Pathology sector of the Hospital and histopathological findings revealed focally extensive areas of necrosis associated to myriads of bacteria and mild mononuclear inflammatory infiltrates in the liver, heart and kidneys. Secretions and organ fragments were submitted to the Microbiology Laboratory of the same institution, which identified a systemic bacterial infection caused by P. aeruginosa. In vitro bacterial susceptibility to 15 different antimicrobials was assessed using the Bauer-Kirby disk diffusion test in Mueller Hinton agar. The agent exhibited multiple resistance to enrofloxacin, cephalexin, ceftiofur, gentamicin, imipenem, kanamycin, cephalothin, norfloxacin, amoxicillin, polymyxin B, ampicillin, tetracycline, and penicillin. It was sensitive to amikacin and neomycin only. Phenotypic detection was performed via disk approximation test (D-test) established by the Clinical and Laboratory Standard Institute (CLSI), which showed metallo-beta-lactamase (MBLs)-producing bacteria.Discussion: Clinical-pathological and microbiological aspects confirmed a systemic infection by P. aeruginosa characterized by yellowish nodular lesions and occasional hemorrhage, associated with myriads of bacteria in the lumen of the vessels in multiple organs. The agent was probably disseminated hematogenously, and it is likely that the cutaneous lesions in the pelvic limbs were the entry point. Treatment using cephalexin proved to be inefficient for the animal of the present study, which may have been be due to the patient’s immunosuppression and the agent’s natural or acquired resistance to this drug; therefore, special care needs to be taken when using these antibiotics as a preventive measure against the dissemination of gram-negative (MBL)-producing P. aeruginosa. We can conclude that P. aeruginosa may cause systemic infection in dogs. Amikacin and neomycin are the most efficient antimicrobials for the in vitro elimination of the bacteria; however, other studies on the use of these drugs in vivo are needed. Considering the occurrence of resistance to multiple antimicrobials and the production of MBLs observed in this study, it is important to monitor P. aeruginosa through phenotypical and antimicrobial susceptibility tests to verify its level of resistance in diseases in Veterinary Medicine.Keywords: microbiological, internal medicine, infections, Veterinary Medicine.

scholarly journals Cranberry-Derived Proanthocyanidins Potentiate β-Lactam Antibiotics Against Resistant Bacteria

2021 ◽  
Author(s):  
Mathias Gallique ◽  
Kuan Wei ◽  
Vimal B. Maisuria ◽  
Mira Okshevsky ◽  
Geoffrey McKay ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Antimicrobial Agents ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
E Coli ◽  
New Generation ◽  
Future Work ◽  
Emergence Of Resistance

The emergence and spread of extended-spectrum β-lactamases (ESBLs), metallo-β-lactamases (MBLs) or variant low affinity penicillin-binding proteins (PBPs) pose a major threat to our ability to treat bacterial infection using β-lactam antibiotics. Although combinations of β-lactamase inhibitors with β-lactam agents have been clinically successful, there are no MBL inhibitors in current therapeutic use. Furthermore, recent clinical use of new generation cephalosporins targeting PBP2a, an altered PBP, has led to the emergence of resistance to these antimicrobial agents. Previous work shows that natural polyphenols such as cranberry-extracted proanthocyanidins (cPAC) can potentiate non-β-lactam antibiotics against Gram-negative bacteria. This study extends beyond previous work by investigating the in vitro effect of cPAC in overcoming ESBL-, MBL- and PBP2a-mediated β-lactam resistance. The results show that cPAC exhibit variable potentiation of different β-lactams against β-lactam resistant Enterobacteriaceae clinical isolates as well as ESBL- and MBL-producing E. coli. We also discovered that cPAC have broad-spectrum inhibitory properties in vitro on the activity of different classes of β-lactamases, including CTX-M3 ESBL and IMP-1 MBL. Furthermore, we observe that cPAC selectively potentiate oxacillin and carbenicillin against methicillin-resistant but not methicillin-sensitive Staphylococci, suggesting that cPAC also interfere with PBP2a-mediated resistance. This study motivates the need for future work to identify the most bioactive compounds in cPAC and to evaluate their antibiotic potentiating efficacy in vivo. IMPORTANCE Emergence of β-lactam resistant Enterobacteriaceae and Staphylococci compromised the efficiency of β-lactams-based therapy. By acquisition of ESBLs, MBLs or PBPs, it is highly likely that bacteria become completely resistant to the most efficient β-lactam agents in the near future. In this study, we described a natural extract rich in proanthocyanidins which exerts adjuvant properties by interfering with two different resistance mechanisms. By their broad-spectrum inhibitory ability, cranberry-extracted proanthocyanidins could have the potential to enhance effectiveness of existing β-lactam agents.

scholarly journals Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Jacopo Gavini ◽  
Noëlle Dommann ◽  
Manuel O. Jakob ◽  
Adrian Keogh ◽  
Laure C. Bouchez ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Antitumor Effect ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Resistance Mechanisms ◽  
Chemotherapeutic Agents ◽  
Anti Cancer

Abstract Lysosomal sequestration of anti-cancer compounds reduces drug availability at intracellular target sites, thereby limiting drug-sensitivity and inducing chemoresistance. For hepatocellular carcinoma (HCC), sorafenib (SF) is the first line systemic treatment, as well as a simultaneous activator of autophagy-induced drug resistance. The purpose of this study is to elucidate how combination therapy with the FDA-approved photosensitizer verteporfin (VP) can potentiate the antitumor effect of SF, overcoming its acquired resistance mechanisms. HCC cell lines and patient-derived in vitro and in vivo preclinical models were used to identify the molecular mechanism of action of VP alone and in combination with SF. We demonstrate that SF is lysosomotropic and increases the total number of lysosomes in HCC cells and patient-derived xenograft model. Contrary to the effect on lysosomal stability by SF, VP is not only sequestered in lysosomes, but induces lysosomal pH alkalinization, lysosomal membrane permeabilization (LMP) and tumor-selective proteotoxicity. In combination, VP-induced LMP potentiates the antitumor effect of SF, further decreasing tumor proliferation and progression in HCC cell lines and patient-derived samples in vitro and in vivo. Our data suggest that combination of lysosome-targeting compounds, such as VP, in combination with already approved chemotherapeutic agents could open a new avenue to overcome chemo-insensitivity caused by passive lysosomal sequestration of anti-cancer drugs in the context of HCC.

scholarly journals Novel R41Q- and R46Q-PAR1-Modified Mice Enable Proof-of-Concept Studies for In Vivo Protective Mechanisms of Action for Activated Protein C (APC) in Sepsis and Stroke

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 13-13
Author(s):  
Ranjeet Kumar Sinha ◽  
Yaoming Wang ◽  
Zhen Zhao ◽  
Jose A. Fernandez ◽  
Naveen Gupta ◽  
...  
Keyword(s):  
Cell Signaling ◽  
Brain Damage ◽  
Mechanism Of Action ◽  
Protein C ◽  
Activated Protein C ◽  
Proof Of Concept ◽  
E Coli ◽  
Apc Mutations

Abstract Introduction: Although much is known about in vitro mechanisms for Activated Protein C (APC)'s beneficial actions on endothelial, neuronal, and epithelial cells, much less is known about its in vivo mechanism(s) of action. EPCR-bound APC can cleave protease activated receptor (PAR) 1 at Arg41 or Arg46 to initiate cell signaling. Notably, cleavage at Arg46 can initiate arrestin-dependent biased signaling whereas thrombin's canonical cleavage occurs at Arg41. Which PAR1 cleavage may mediate APC's in vivo benefits? Inferences often come from using PAR1 knockout mice. But knocking out PAR1 disrupts PAR1 interactomes, thereby potentially disrupting many protein-protein interactions, e.g., PAR heterodimers, etc. To elucidate PAR1-dependent aspects of APC's in vivo mechanism of action, we generated C57BL/6 strains carrying either Arg41Gln (R41Q) or Arg46Gln (R46Q) PAR1 point mutations. Using these strains, we determined whether or not recombinant murine signaling-selective APC mutants would reduce septic death or provide neuroprotection against stroke when mice carried PAR1 mutations that prevent PAR1 cleavages at either Arg41 or Arg46. Methods: Standard homologous recombination methods and C57BL/6-ES cells were used to make C57BL/6 strains carrying PAR1 mutations. Brain microvascular endothelial cells (BECs) were isolated from mice by published protocols. Bioassays using BECs and APC, thrombin, or a thrombin receptor activating peptide (TRAP) included: (1) endothelial barrier stabilization or disruption that was monitored using Trans-Endothelial Resistance (TER) (iCelligence, Acea, San Diego) and (2) induction of cell signaling that was quantified using in-cell Western blotting. The ability of 5A-APC (mutations: KKK191-193AAA+RR229-230AA) (0.2 mg/kg, i.v. at 0h and 6 h) to reduce death due to live E. coli-induced pneumonia was determined using standard protocols. The ability of 3K3A-APC (mutations: KKK191-193AAA) (0.04 mg/kg, i.v. at 4 h) to reduce brain damage caused by transient distal middle cerebral artery occlusion (tdMCAO) (1 h) was determined at 24 h, as described. Results : R46Q mice were normal in breeding whereas R41Q mice, like PAR1 KO, gave less than half the expected QQ or null homozygotes. PAR1 knockout-derived BECs showed no TER decrease for either TRAP or thrombin, proving PAR1 was needed. TER assays showed that TRAP disrupted endothelial barriers of BECs from QQ41-PAR1 and QQ46-PAR1 mice similar to BECs from WT-mice, proving the expression of normally functional PAR1 in each PAR1-mutated strain. As expected, thrombin decreased TER for BECs from WT mice and QQ46-PAR1 mice but not for BECs from QQ41-PAR1 mice. APC inhibited thrombin-induced TER decreases for BECs from WT mice but not for BECs from QQ46-PAR1 mice, showing R46 is required for APC's barrier stabilization. The QQ46-PAR1 BECs showed significantly reduced APC-induced phosphorylation of Akt whereas thrombin-induced phosphorylation of ERK was not significantly affected. Thus, in vitro studies showed the predicted retention or loss of responses to TRAP, thrombin or APC for each PAR1 mutation. In sepsis studies, 5A-APC reduced mortality from 50 % to 10 % in E. coli-induced pneumonia for WT-PAR1 and 41QQ-PAR1 mice (p < 0.01) but had no benefit for 46QQ-PAR1 mice. In tdMCAO stroke studies, 3K3A-APC significantly reduced infarct size, edema and neuronal apoptosis for WT mice and QQ41-PAR1 mice but had no detectable benefits for mice carrying QQ46-PAR1. In functional studies of forelimb asymmetry and foot fault tests at 24 h after tdMCAO, 3K3A-APC was beneficial for mice with QQ41-PAR1 but not for QQ46-PAR1. Conclusions : Genetically altered mice carrying 41QQ-PAR1 and 46QQ-PAR1 provide unique, powerful tools to explore in vivo requirements for Arg41 or Arg46 cleavages by APC or other proteases that initiate PAR1-dependent signaling. The failures of 5A-APC to reduce death following intratracheal E. coli in 46QQ-PAR1 mice and of 3K3A-APC to reduce brain damage following ischemia in 46QQ-PAR1 mice provide very clear in vivo proof-of-concept data for the hypothesis that APC's cleavage of PAR1 at Arg46 is central to its in vivo mechanism of action in these two very different pathologies. These results strongly support the concept that APC's biased PAR1-dependent signaling following Arg46 cleavage is central to APC's in vivo benefits. Figure. Figure. Disclosures Mosnier: The Scripps Research Institute: Patents & Royalties; Hematherix LLC: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Speakers Bureau; Baxalta: Honoraria, Speakers Bureau.

scholarly journals Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions.

1997 ◽  
Vol 41 (10) ◽  
pp. 2132-2136 ◽  
Author(s):  
D L Shinabarger ◽  
K R Marotti ◽  
R W Murray ◽  
A H Lin ◽  
E P Melchior ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Pathogenic Bacteria ◽  
Coli Strain ◽  
In Vitro Translation ◽  
E Coli ◽  
Initiation Phase ◽  
New Class ◽  
Bacterial Translation

The oxazolidinones are a new class of synthetic antibiotics with good activity against gram-positive pathogenic bacteria. Experiments with a susceptible Escherichia coli strain, UC6782, demonstrated that in vivo protein synthesis was inhibited by both eperezolid (formerly U-100592) and linezolid (formerly U-100766). Both linezolid and eperezolid were potent inhibitors of cell-free transcription-translation in E. coli, exhibiting 50% inhibitory concentrations (IC50s) of 1.8 and 2.5 microM, respectively. The ability to demonstrate inhibition of in vitro translation directed by phage MS2 RNA was greatly dependent upon the amount of RNA added to the assay. For eperezolid, 128 microg of RNA per ml produced an IC50 of 50 microM whereas a concentration of 32 microg/ml yielded an IC50 of 20 microM. Investigating lower RNA template concentrations in linezolid inhibition experiments revealed that 32 and 8 microg of MS2 phage RNA per ml produced IC50s of 24 and 15 microM, respectively. This phenomenon was shared by the translation initiation inhibitor kasugamycin but not by streptomycin. Neither oxazolidinone inhibited the formation of N-formylmethionyl-tRNA, elongation, or termination reactions of bacterial translation. The oxazolidinones appear to inhibit bacterial translation at the initiation phase of protein synthesis.

GOLD COMPLEXES - ANTITUMOR PROPERTIES, TARGETS AND MECHANISM OF ACTION

2018 ◽  
Vol 64 (6) ◽  
pp. 697-707 ◽  
Author(s):  
David Korman ◽  
Larisa Ostrovskaya ◽  
Vladimir Kuzmin
Keyword(s):  
Tumor Cells ◽  
Mechanism Of Action ◽  
Wide Spectrum ◽  
Acquired Resistance ◽  
Thioredoxin Reductase ◽  
Human Tumor ◽  
Gold Complexes ◽  
Antitumor Properties

Gold complexes (GC) reveal antitumor activity against xenografts of human tumors as well as against transplantable animal tumors in vivo and demonstrate cytotoxic effect against the wide spectrum of human tumor cells in vitro. GC had been effective against tumors with the acquired resistance to the platinum compounds. It is revealed the strong difference between mechanism of action of GC and platinum derivatives. Proteins, mainly thioredoxin reductase and proteasoma 26S, are the principal targets for the GC action but not for the platinum derivatives impact. Thioredoxin reductase and proteasoma 26S activity inhibition by GC leads to the development of the apoptosis mainly by the mitochondrial way in tumor cells.

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