A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

Abstract The fungicide tolprocarb (TPC) is a melanin biosynthesis inhibitor, but it may also have another mode of action. Here in tests of TPC for inducing plant systemic acquired resistance (SAR), TPC induced promoter activity of the tobacco pathogenesis-related gene PR-1a in Arabidopsis thaliana and genes for PBZ1, β-1,3-glucanase, and chitinase 1 in the defense-related salicylic acid (SA) signaling pathway in rice, but not genes for the jasmonate signaling pathway. Probenazole (PBZ), a commercially used plant defense activator, induced genes in both signaling pathways. The antibacterial activity of TPC was equivalent to that of PBZ. Irrigation with 200 μM TPC prevented growth by Pseudomonas syringae pv. maculicola in A. thaliana, and 30 μM TPC inhibited Xanthomonas oryzae pv. oryzae growth in rice. The results of this study suggest that TPC functions not only as a melanin biosynthesis inhibitor but also as an SAR inducer and is applicable as a novel bacterial control agent that induces SAR activity in both A. thaliana and rice.

Download Full-text

Insect Neuronal Cultures as Models in Insecticide Studies

Outlook on Agriculture ◽

10.1177/003072708801700205 ◽

1988 ◽

Vol 17 (2) ◽

pp. 65-70 ◽

Cited By ~ 1

Author(s):

David J. Beadle

Keyword(s):

Nervous System ◽

Mode Of Action ◽

Acquired Resistance ◽

Neuronal Cultures ◽

Controlled Conditions ◽

Fundamental Understanding ◽

Uptake Mechanisms

The constant need to develop new types of insecticide particularly to overcome the perennial problem of acquired resistance, demands a fundamental understanding of the mode of action of these substances and their precise point of attack on their usual target, the insect's nervous system. For this purpose it is now in many instances unnecessary to investigate the intact nervous system. Cockroach neurones grown in culture possess neuro-transmitter receptor and uptake mechanisms that show responses essentially similar to those in the live insect. They thus provide a means of investigating the mode of action of insecticides under strictly controlled conditions.

Download Full-text

An Amphipathic Undecapeptide with All d-Amino Acids Shows Promising Activity against Colistin-Resistant Strains of Acinetobacter baumannii and a Dual Mode of Action

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01966-15 ◽

2015 ◽

Vol 60 (1) ◽

pp. 592-599 ◽

Cited By ~ 18

Author(s):

Alberto Oddo ◽

Thomas T. Thomsen ◽

Susanne Kjelstrup ◽

Ciara Gorey ◽

Henrik Franzyk ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Mode Of Action ◽

Acquired Resistance ◽

Antibacterial Activities ◽

The Novel ◽

Human Pathogens ◽

Content Type ◽

Resistant Strains ◽

Multiple Strains

ABSTRACTMultiple strains ofAcinetobacter baumanniihave developed multidrug resistance (MDR), leaving colistin as the only effective treatment. The cecropin-α–melittin hybrid BP100 (KKLFKKILKYL-NH2) and its analogs have previously shown activity against a wide array of plant and human pathogens. In this study, we investigated thein vitroantibacterial activities of 18 BP100 analogs (four known and 14 new) against the MDRA. baumanniistrain ATCC BAA-1605, as well as against a number of other clinically relevant human pathogens. Selected peptides were further evaluated against strains ofA. baumanniithat acquired resistance to colistin due to mutations of thelpxC,lpxD,pmrA, andpmrBgenes. The novel analogue BP214 showed antimicrobial activity at 1 to 2 μM and a hemolytic 50% effective concentration (EC50) of >150 μM. The lower activity of its enantiomer suggests a dual, specific and nonspecific mode of action. Interestingly, colistin behaved antagonistically to BP214 whenpmrABandlpxCmutants were challenged.

Download Full-text

Yeast Increases Resistance in Arabidopsis Against Pseudomonas syringae and Botrytis cinerea by Salicylic Acid-Dependent as Well as -Independent Mechanisms

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-19-1138 ◽

2006 ◽

Vol 19 (10) ◽

pp. 1138-1146 ◽

Cited By ~ 25

Author(s):

Ines C. Raacke ◽

Uta von Rad ◽

Martin J. Mueller ◽

Susanne Berger

Keyword(s):

Cell Wall ◽

Botrytis Cinerea ◽

Pseudomonas Syringae ◽

Mode Of Action ◽

Systemic Acquired Resistance ◽

Virulent Strain ◽

Acquired Resistance ◽

Defense Responses ◽

Symptom Development ◽

Yeast Suspension

Cell-wall and glucopeptide components of yeast have been reported to exhibit elicitor activity. The mode of action of defense activation by yeast is not known so far. In this study, we used the model plant Arabidopsis to investigate the activation of defense responses by yeast, the effect on resistance against different pathogens, and the mode of action. Treatment of Arabidopsis plants with an autoclaved yeast suspension induced the expression of systemic acquired resistance-related genes and accumulation of the phytoalexin camalexin. Symptom development and bacterial growth after infection with a virulent strain of the pathogen Pseudomonas syringae was reduced in yeast-pretreated plants. No protection was detectable in mutants affected in the salicylate pathway, while mutants in the jasmonate or camalexin pathway were protected by yeast, indicating that the salicylate pathway is necessary for the yeast-induced resistance against P. syringae. Yeast also reduced symptom development after challenge with Botrytis cinerea. This protection was detectable in all mutants tested, indicating that it is independent of the salicylate, jasmonate, and camalexin pathway.

Download Full-text

FGF2 Dual Warhead Conjugate with Monomethyl Auristatin E and α-Amanitin Displays a Cytotoxic Effect towards Cancer Cells Overproducing FGF Receptor 1

International Journal of Molecular Sciences ◽

10.3390/ijms19072098 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2098 ◽

Cited By ~ 7

Author(s):

Karolina Świderska ◽

Anna Szlachcic ◽

Łukasz Opaliński ◽

Małgorzata Zakrzewska ◽

Jacek Otlewski

Keyword(s):

Cancer Cells ◽

Mode Of Action ◽

Cytotoxic Effect ◽

Acquired Resistance ◽

Cancer Cell Line ◽

Lung Cancer Cell Line ◽

Cytotoxic Drugs ◽

Cancer Resistance ◽

Fgf Receptor ◽

High Cytotoxicity

In the rapidly developing field of targeted cancer therapy there is growing interest towards therapeutics combining two or more compounds to achieve synergistic action and minimize the chance of cancer resistance to treatment. We developed a fibroblast growth factor 2 (FGF2)-conjugate bearing two cytotoxic drugs with independent mode of action: α-amanitin and monomethyl auristatin E. Drugs are covalently attached to the targeting protein in a site-specific manner via maleimide-thiol conjugation and Cu(I)-catalyzed alkyne-azide cycloaddition. The dual warhead conjugate binds to FGF receptor 1 (FGFR1) and utilizes receptor-mediated endocytosis for selective internalization into cancer cells with FGFR1. The developed conjugate displays high cytotoxicity towards all tested FGFR1-positive cell lines. Most importantly, the improved cytotoxic effect of both drugs is observed for lung cancer cell line NCI-H446. The single drug-FGF2 conjugates have no impact on the viability of NCI-H446 cells, whereas the dual warhead-FGF2 conjugate selectively and efficiently kills these FGFR1 positive cancer cells. Due to the diversified mode of action the dual warhead-FGF2 conjugate may overcome the potential acquired resistance of FGFR1-overproducing cancer cells towards single cytotoxic drugs.

Download Full-text

Assessment of the Efficacy and Mode of Action of Benzo(1,2,3)-Thiadiazole-7-Carbothioic Acid S-Methyl Ester (BTH) and Its Derivatives in Plant Protection Against Viral Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20071598 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1598 ◽

Cited By ~ 4

Author(s):

Patryk Frąckowiak ◽

Henryk Pospieszny ◽

Marcin Smiglak ◽

Aleksandra Obrępalska-Stęplowska

Keyword(s):

Methyl Ester ◽

Mode Of Action ◽

Systemic Acquired Resistance ◽

Plant Protection ◽

Acquired Resistance ◽

Viral Disease ◽

Plant Performance ◽

Marker Genes ◽

Plant Responses ◽

Pr Genes

Systemic acquired resistance (SAR) induction is one of the primary defence mechanisms of plants against a broad range of pathogens. It can be induced by infectious agents or by synthetic molecules, such as benzo(1,2,3)-thiadiazole-7-carbothioic acid S-methyl ester (BTH). SAR induction is associated with increases in salicylic acid (SA) accumulation and expression of defence marker genes (e.g., phenylalanine ammonia-lyase (PAL), the pathogenesis-related (PR) protein family, and non-expressor of PR genes (NPR1)). Various types of pathogens and pests induce plant responses by activating signalling pathways associated with SA, jasmonic acid (JA) and ethylene (ET). This work presents an analysis of the influence of BTH and its derivatives as resistance inducers in healthy and virus-infected plants by determining the expression levels of selected resistance markers associated with the SA, JA, and ET pathways. The phytotoxic effects of these compounds and their influence on the course of viral infection were also studied. Based on the results obtained, the best-performing BTH derivatives and their optimal concentration for plant performance were selected, and their mode of action was suggested. It was shown that application of BTH and its derivatives induces increased expression of marker genes of both the SA- and JA-mediated pathways.

Download Full-text

Effects of 5-5'-Diphenyl-2-thiohydantoin (DPTH) and Thyroxine on the Ultrastructure and Chemical Composition of Rat Liver

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100066917 ◽

1971 ◽

Vol 29 ◽

pp. 570-571

Author(s):

E. A. Elfont ◽

R. B. Tobin ◽

D. G. Colton ◽

M. A. Mehlman

Keyword(s):

Chemical Composition ◽

Rat Liver ◽

Future Study ◽

Mode Of Action ◽

Liver Mitochondria ◽

Rat Liver Mitochondria ◽

Effective Inhibitor ◽

Biochemical Effects ◽

Glycerophosphate Dehydrogenase ◽

Stimulation Of

Summary5,-5'-diphenyl-2-thiohydantoin (DPTH) is an effective inhibitor of thyroxine (T4) stimulation of α-glycerophosphate dehydrogenase in rat liver mitochondria. Because this finding indicated a possible tool for future study of the mode of action of thyroxine, the ultrastructural and biochemical effects of DPTH and/or thyroxine on rat liver mere investigated.Rats were fed either standard or DPTH (0.06%) diet for 30 days before T4 (250 ug/kg/day) was injected. Injection of T4 occurred daily for 10 days prior to sacrifice. After removal of the liver and kidneys, part of the tissue was frozen at -50°C for later biocheailcal analyses, while the rest was prefixed in buffered 3.5X glutaraldehyde (390 mOs) and post-fixed in buffered 1Z OsO4 (376 mOs). Tissues were embedded in Araldlte 502 and the sections examined in a Zeiss EM 9S.Hepatocytes from hyperthyroid rats (Fig. 2) demonstrated enlarged and more numerous mitochondria than those of controls (Fig. 1). Glycogen was almost totally absent from the cytoplasm of the T4-treated rats.

Download Full-text