361 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
Prevalent pH Controls the Capacity of Galdieria maxima to Use Ammonia and Nitrate as a Nitrogen Source
Cyclin dependent kinase-1 (Cdk-1) inhibition as a novel therapeutic strategy against pancreatic ductal adenocarcinoma (pdac)
The role of CDK1 in PDAC onset and development is two-fold. Firstly, since CDK1 activity regulates the G2/M cell cycle checkpoint, overexpression of CDK1 can lead to progression into mitosis even in cells with DNA damage, a potentially tumorigenic process. Secondly, CDK1 overexpression leads to the stimulation of a range of proteins that induce stem cell properties, which can contribute to the development of cancer stem cells (CSCs). CSCs promote tumor-initiation and metastasis and play a crucial role in the development of PDAC. Targeting CDK1 showed promising results for PDAC treatment in different preclinical models, where CDK1 inhibition induced cell cycle arrest in the G2/M phase and led to induction of apoptosis. Next to this, PDAC CSCs are uniquely sensitive to CDK1 inhibition. In addition, targeting of CDK1 has shown potential for combination therapy with both ionizing radiation treatment and conventional chemotherapy, through sensitizing tumor cells and reducing resistance to these treatments. To conclude, CDK1 inhibition induces G2/M cell cycle arrest, stimulates apoptosis, and specifically targets CSCs, which makes it a promising treatment for PDAC. Screening of patients for CDK1 overexpression and further research into combination treatments is essential for optimizing this novel targeted therapy
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
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
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
Discovery of the 3-Amino-1,2,4-triazine-Based Library as Selective PDK1 Inhibitors with Therapeutic Potential in Highly Aggressive Pancreatic Ductal Adenocarcinoma
Pyruvate dehydrogenase kinases (PDKs) are serine/threonine kinases, that are directly involved in altered cancer cell metabolism, resulting in cancer aggressiveness and resistance. Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Building upon a molecular hybridization approach, a small library of 3-amino-1,2,4-triazine derivatives has been designed, synthesized, and characterized for their PDK inhibitory activity using in silico, in vitro, and in vivo assays. Biochemical screenings showed that all synthesized compounds are potent and subtype-selective inhibitors of PDK. Accordingly, molecular modeling studies revealed that a lot of ligands can be properly placed inside the ATP-binding site of PDK1. Interestingly, 2D and 3D cell studies revealed their ability to induce cancer cell death at low micromolar doses, being extremely effective against human pancreatic KRAS mutated cancer cells. Cellular mechanistic studies confirm their ability to hamper the PDK/PDH axis, thus leading to metabolic/redox cellular impairment, and to ultimately trigger apoptotic cancer cell death. Remarkably, preliminary in vivo studies performed on a highly aggressive and metastatic Kras-mutant solid tumor model confirm the ability of the most representative compound 5i to target the PDH/PDK axis in vivo and highlighted its equal efficacy and better tolerability profile with respect to those elicited by the reference FDA approved drugs, cisplatin and gemcitabine. Collectively, the data highlights the promising anticancer potential of these novel PDK-targeting derivatives toward obtaining clinical candidates for combatting highly aggressive KRAS-mutant pancreatic ductal adenocarcinomas
HIV-1-induced nuclear invaginations mediated by VAP-A, ORP3, and Rab7 complex explain infection of activated T cells
The mechanism of human immunodeficiency virus 1 (HIV-1) nuclear entry, required for productive infection, is not fully understood. Here, we report that in HeLa cells and activated CD4+ T cells infected with HIV-1 pseudotyped with VSV-G and native Env protein, respectively, Rab7+ late endosomes containing endocytosed HIV-1 promote the formation of nuclear envelope invaginations (NEIs) by a molecular mechanism involving the VOR complex, composed of the outer nuclear membrane protein VAP-A, hyperphosphorylated ORP3 and Rab7. Silencing VAP-A or ORP3 and drug-mediated impairment of Rab7 binding to ORP3-VAP-A inhibited the nuclear transfer of the HIV-1 components and productive infection. In HIV-1-resistant quiescent CD4+ T cells, ORP3 was not hyperphosphorylated and neither VOR complex nor NEIs were formed. This new cellular pathway and its molecular players are potential therapeutic targets, perhaps shared by other viruses that require nuclear entry to complete their life cycle
3-[4-(1H-indol-3-yl)-1,3-thiazol-2-yl]-1H-pyrrolo[2,3-b]pyridines, nortopsentin Analogues with antiproliferative activity
A new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and the indole unit bound to position 2 of the thiazole ring was substituted by a 7-azaindole moiety, was efficiently synthesized. Two of the new nortopsentin analogues showed good antiproliferative effect against the totality of the NCI full panel of human tumor cell lines ( 3c60) having GI50 values ranging from low micromolar to nanomolar level. The mechanism of the antiproliferative effect of these derivatives, investigated on human hepatoma HepG2 cells, was pro-apoptotic, being associated with externalization of plasma membrane phosphatidylserine and mitochondrial dysfunction. Moreover, the compounds induced a concentration-dependent accumulation of cells in the subG0/G1phase, while confined viable cells in G2/M phase
- …