310 research outputs found
Inhibitors of antibiotic resistance mechanisms: clinical applications and future perspectives
Bacterial strains responsible for antibiotic resistant infections are increasing in an alarming way and the evolution
of resistance mechanisms seems to be unstoppable. In the past decade, many efforts have been made in order to
counteract this phenomenon but very few compounds have reached clinical trials. The development of new classes
of antibiotics able to overcome the main bacterial drug resistance mechanisms is urgently required to counter the
imminent danger of a postantibiotic era
Recent Developments in the Inhibition of Bacterial Adhesion as Promising Anti-Virulence Strategy
Infectious diseases caused by antimicrobial-resistant strains have become a serious threat to global health, with a high social and economic impact. Multi-resistant bacteria exhibit various mechanisms at both the cellular and microbial community levels. Among the different strategies proposed to fight antibiotic resistance, we reckon that the inhibition of bacterial adhesion to host surfaces represents one of the most valid approaches, since it hampers bacterial virulence without affecting cell viability. Many different structures and biomolecules involved in the adhesion of Gram-positive and Gram-negative pathogens can be considered valuable targets for the development of promising tools to enrich our arsenal against pathogens
NUOVI DERIVATI 2-ACETAMMIDOBENZAMMIDICI: ATTIVITÀ ANTIPROLIFERATIVA E POSSIBILE MECCANISMO DI AZIONE
Le cinnammido benzammidi rappresentano una classe di sostanze biologicamente attive di grande interesse farmaceutico. Nonostante siano state descritte per svariate attivitÃ
biologiche, nessun dato è stato riportato sulla loro attivita antitumorale. Inizialmente
una serie di 2-cinammidobenzammidi variamente sostituite sono state sintetizzate e valutate per la loro attività antiproliferativa. Partendo dal derivato risultato più attivo, il
2-cinnammido-5-iodobenzammide, che ha mostrato una percentuale di inibizione della crescita sulle K562 del 74% a 10μM, sono stati sintetizzati una serie di derivati al fine di approfondirne la SAR.I composti così ottenuti sono risultati attivi nei confronti di numerose linee cellulari tumorali a concentrazioni micromolari e submicromololari inducendo un blocco del
ciclo cellulare delle K562 in fase G2M. Inoltre i derivati sintetizzati sono in grado di indurre apoptosi nelle cellule HEP G2
Citrus sinensis and Vitis vinifera Protect Cardiomyocytes from Doxorubicin-Induced Oxidative Stress: Evaluation of Onconutraceutical Potential of Vegetable Smoothies
The interest towards nutraceuticals able to counteract drug side effects is continuously growing in current chemotherapeutic protocols. In the present study, we demonstrated that smoothies containing mixtures of Citrus sinensis and Vitis vinifera L. cv. Aglianico N, two typical fruits of the Mediterranean diet, possess bioactive polyphenols that protect cardiomyocytes against
doxorubicin-induced oxidative stress. The polyphenolic extracts isolated from Citrus sinensis- and Vitis vinifera-based functional smoothies were deeply characterized by Liquid Chromatography-Mass Spectrometry methods. Subsequently, the functional smoothies and relative mixtures were tested to verify their ability to affect cellular viability and oxidative stress parameters in embryonic cardiomyocyte cells (H9c2), and human breast adenocarcinoma cell line (MCF-7) exposed to doxorubicin. Interestingly, we found that the mix resulting from Citrus sinensis and Vitis vinifera association in ratio 1:1 was able to reduce cardiomyocytes damage induced by anthracyclines, without significantly interfering with the pro-apoptotic activity of the drug on breast cancer cells. These results point out the potential use of vegetable smoothies as adjuvants functional foods for chemotherapeutic anticancer protocols
Novel [1,3,4]Thiadiazole[3,2-a]pyrimidin-5-ones as Promising Biofilm Dispersal Agents against Relevant Gram-Positive and Gram-Negative Pathogens
Biofilm-associated infections pose significant challenges in healthcare settings due to their resistance to conventional antimicrobial therapies. In the last decade, the marine environment has been a precious source of bioactive molecules, including numerous derivatives with antibiofilm activity. In this study, we reported the synthesis and the biological evaluation of a new series of twenty-two thiadiazopyrimidinone derivatives obtained by using a hybridization approach combining relevant chemical features of two important classes of marine compounds: nortopsentin analogues and Essramycin derivatives. The synthesized compounds were in vitro tested for their ability to inhibit biofilm formation and to disrupt mature biofilm in various bacterial strains. Among the tested compounds, derivative 8j exhibited remarkable dispersal activity against preformed biofilms of relevant Gram-positive and Gram-negative pathogens, as well as towards the fungus Candida albicans, showing BIC50 values ranging from 17 to 40 mu g/mL. Furthermore, compound 8j was in vivo assayed for its toxicity and the anti-infective effect in a Galleria mellonella model. The results revealed a promising combination of anti-infective properties and a favorable toxicity profile for the treatment of severe chronic biofilm-mediated infections
Functional Dissection of the PE Domain Responsible for Translocation of PE_PGRS33 across the Mycobacterial Cell Wall
PE are peculiar exported mycobacterial proteins over-represented in pathogenic mycobacterial species. They are characterized by an N-terminal domain of about 110 amino acids (PE domain) which has been demonstrated to be responsible for their export and localization. In this paper, we characterize the PE domain of PE_PGRS33 (PERv1818c), one of the best characterized PE proteins. We constructed several mutated proteins in which portions of the PE domain were deleted or subjected to defined mutations. These proteins were expressed in different mycobacterial species and their localization was characterized. We confirmed that the PE domain is essential for PE_PGRS33 surface localization, and demonstrated that a PE domain lacking its first 30 amino acids loses its function. However, single amino acid substitutions in two regions extremely well conserved within the N-terminal domain of all PE proteins had some effect on the stability of PE_PGRS33, but not on its localization. Using Mycobacterium marinum we could show that the type VII secretion system ESX-5 is essential for PE_PGRS33 export. Moreover, in M. marinum, but not in Mycobacterium bovis BCG and in Mycobacterium tuberculosis, the PE domain of PE_PGRS33 is processed and secreted into the culture medium when expressed in the absence of the PGRS domain. Finally, using chimeric proteins in which different portions of the PERv1818c domain were fused to the N-terminus of the green fluorescent protein, we could hypothesize that the first 30 amino acids of the PE domain contain a sequence that allows protein translocation
A synthetic derivative of antimicrobial peptide holothuroidin 2 from mediterranean sea cucumber (Holothuria tubulosa) in the control of Listeria monocytogenes
Due to the limited number of available antibiotics, antimicrobial peptides (AMPs) are considered antimicrobial candidates to fight difficult-to-treat infections such as those associated with biofilms. Marine environments are precious sources of AMPs, as shown by the recent discovery of antibiofilm properties of Holothuroidin 2 (H2), an AMP produced by the Mediterranean sea cucumber Holothuria tubulosa. In this study, we considered the properties of a new H2 derivative, named H2d, and we tested it against seven strains of the dangerous foodborne pathogen Listeria monocytogenes. This peptide was more active than H2 in inhibiting the growth of planktonic L. monocytogenes and was able to interfere with biofilm formation at sub-minimum inhibitory concentrations (MICs). Atomic-level molecular dynamics (MD) simulations revealed insights related to the enhanced inhibitory activity of H2d, showing that the peptide is characterized by a more defined tertiary structure with respect to its ancestor. This allows the peptide to better exhibit an amphipathic character, which is an essential requirement for the interaction with cell membranes, similarly to other AMPs. Altogether, these results support the potential use of our synthetic peptide, H2d, as a template for the development of novel AMP-based drugs able to fight foodborne that are resistant to conventional antibiotics
1,3,4-Oxadiazole and 1,3,4-Thiadiazole Nortopsentin Derivatives against Pancreatic Ductal Adenocarcinoma: Synthesis, Cytotoxic Activity, and Inhibition of CDK1
A new series of nortopsentin analogs, in which the central imidazole ring of the natural lead was replaced by a 1,3,4-oxadiazole or 1,3,4-thiadiazole moiety, was efficiently synthesized. The antiproliferative activity of all synthesized derivatives was evaluated against five pancreatic ductal adenocarcinoma (PDAC) cell lines, a primary culture and a gemcitabine-resistant variant. The five more potent compounds elicited EC50 values in the submicromolar-micromolar range, associated with a significant reduction in cell migration. Moreover, flow cytometric analysis after propidium iodide staining revealed an increase in the G2-M and a decrease in G1-phase, indicating cell cycle arrest, while a specific ELISA demonstrated the inhibition of CDK1 activity, a crucial regulator of cell cycle progression and cancer cell proliferation
A New Oxadiazole-Based Topsentin Derivative Modulates Cyclin-Dependent Kinase 1 Expression and Exerts Cytotoxic Effects on Pancreatic Cancer Cells
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer characterized
by drug resistance, urging new therapeutic strategies. In recent years, protein kinases have emerged
as promising pharmacological targets for the treatment of several solid and hematological tumors.
Interestingly, cyclin-dependent kinase 1 (CDK1) is overexpressed in PDAC tissues and has been
correlated to the aggressive nature of these tumors because of its key role in cell cycle progression
and resistance to the induction of apoptosis. For these reasons, CDK1 is one of the main causes
of chemoresistance, representing a promising pharmacological target. In this study, we report the
synthesis of new 1,2,4-oxadiazole compounds and evaluate their ability to inhibit the cell growth of
PATU-T, Hs766T, and HPAF-II cell lines and a primary PDAC cell culture (PDAC3). Compound 6b
was the most active compound, with IC50 values ranging from 5.7 to 10.7 M. Molecular docking
of 6b into the active site of CDK1 showed the ability of the compound to interact effectively with
the adenosine triphosphate binding pocket. Therefore, we assessed its ability to induce apoptosis
(which increased 1.5- and 2-fold in PATU-T and PDAC3 cells, respectively) and to inhibit CDK1
expression, which was reduced to 45% in Hs766T. Lastly, compound 6b passed the ADME prediction,
showing good pharmacokinetic parameters. These data demonstrate that 6b displays cytotoxic
activity, induces apoptosis, and targets CDK1, supporting further studies for the development of
similar compounds against PDAC
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