-
Molecular Therapy. Oncology Mar 2024The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic...
The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PIs) has revolutionized the treatment of MM. However, resistance to PIs is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461, has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here, we show that CX-5461 has potent anti-myeloma activity in PI-resistant MM preclinical models and . In addition to inhibiting ribosome biogenesis, CX-5461 causes topoisomerase II trapping and replication-dependent DNA damage, leading to G2/M cell-cycle arrest and apoptotic cell death. Combining CX-5461 with PI does not further enhance the anti-myeloma activity of CX-5461 . In contrast, CX-5461 shows synergistic interaction with the histone deacetylase inhibitor panobinostat in both the Vk∗MYC and the 5T33-KaLwRij mouse models of MM by targeting ribosome biogenesis and protein synthesis through distinct mechanisms. Our findings thus provide strong evidence to facilitate the clinical development of targeting the ribosome to treat relapsed and refractory MM.
PubMed: 38596309
DOI: 10.1016/j.omton.2024.200771 -
Revista Espanola de Quimioterapia :... Jun 2024Mycoplasma genitalium (MG) is a microorganism related to sexually transmitted infections. Antibiotic resistance of MG leads to an increase in treatment failure rates and...
OBJECTIVE
Mycoplasma genitalium (MG) is a microorganism related to sexually transmitted infections. Antibiotic resistance of MG leads to an increase in treatment failure rates and the persistence of the infection. The aim of this study was to describe the most frequent mutations associated with azithromycin and moxifloxacin resistance in our geographical area.
METHODS
A prospective study from May 2019 to May 2023 was performed. MG-positive samples were collected. Real-time PCRs (AllplexTM MG-AziR Assay and AllplexTM MG-MoxiR Assay, Seegene) were performed in MG positive samples to detect mutations in 23S rRNA V domain and parC gene.
RESULTS
A 37.1% of samples presented resistance determinants to azithromycin and the most common mutation detected was A2059G (57.9%). Resistance to moxifloxacin was studied in 72 azithromycin-resistant samples and 36.1% showed mutations, being G248T the most prevalent (73.1%).
CONCLUSIONS
The resistance to different lines of treat ment suggests the need for a targeted therapy and the performing of a test of cure afterwards.
Topics: Mycoplasma genitalium; Moxifloxacin; Azithromycin; Spain; Humans; Prospective Studies; Anti-Bacterial Agents; Drug Resistance, Bacterial; Mycoplasma Infections; Mutation; Female; Male; Microbial Sensitivity Tests; RNA, Ribosomal, 23S; Adult; DNA Topoisomerase IV
PubMed: 38591493
DOI: 10.37201/req/015.2024 -
Carbohydrate Research May 2024Herein, we report the development of a diastereoselective and efficient route to construct sugar-derived pyrano[3,2-c]quinolones utilizing 1-C-formyl glycal and...
Herein, we report the development of a diastereoselective and efficient route to construct sugar-derived pyrano[3,2-c]quinolones utilizing 1-C-formyl glycal and 4-hydroxy quinolone annulation. This methodology will open a route to synthesize nature inspired pyrano[3,2-c]quinolones. This is the first report for the stereoselective synthesis of sugar-derived pyrano[3,2-c]quinolones, where 100% stereoselectivity was observed. A total of sixteen compounds have been synthesized in excellent yields with 100% stereoselectivity. The molecular docking of the synthesized novel natural product analogues demonstrated their binding modes within the active site of type II topoisomerase. The results of the in-silico studies displayed more negative binding energies for the all the synthesized compounds in comparison to the natural product huajiosimuline A, indicating their affinity for the active pocket. Ten out of the sixteen novel synthesized compounds were found to have comparative or relatively more negative binding energy in comparison to the standard anti-cancer drug, doxorubicin. Additionally, the scalability and viability of this protocol was illustrated by the gram scale synthesis.
Topics: Biological Products; Stereoisomerism; Molecular Docking Simulation; Quinolones; DNA Topoisomerases, Type II
PubMed: 38583285
DOI: 10.1016/j.carres.2024.109105 -
Bioorganic Chemistry Jun 2024The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In...
The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In this study, a series of N-heteroaryl-substituted 4-hydroxy-2-quinolone-3-carboxamides were developed using the bioisosteric replacement strategy. As a result of our research, we discovered the two most potent GyrB inhibitors (WBX7 and WBX18), with IC values of 0.816 µM and 0.137 µM, respectively. Additional antibacterial activity screening indicated that WBX18 possesses the best antibacterial activity against MRSA, VISA, and VRE strains, with MIC values rangingbetween0.5and 2 µg/mL, which was 2 to over 32 times more potent than that of vancomycin. In vitro safety and metabolic stability, as well as in vivo pharmacokinetics assessments revealed that WBX18 is non-toxic to HUVEC and HepG2, metabolically stable in plasma and liver microsomes (mouse), and displays favorable in vivo pharmacokinetic properties. Finally, docking studies combined with molecular dynamic simulation showed that WBX18 could stably fit in the active site cavity of GyrB.
Topics: Anti-Bacterial Agents; Humans; DNA Gyrase; Topoisomerase II Inhibitors; Microbial Sensitivity Tests; Structure-Activity Relationship; Animals; Molecular Structure; Dose-Response Relationship, Drug; Mice; Hep G2 Cells; Molecular Docking Simulation; Microsomes, Liver
PubMed: 38581967
DOI: 10.1016/j.bioorg.2024.107314 -
Cell Reports Apr 2024In the search for much-needed new antibacterial chemical matter, a myriad of compounds have been reported in academic and pharmaceutical screening endeavors. Only a...
In the search for much-needed new antibacterial chemical matter, a myriad of compounds have been reported in academic and pharmaceutical screening endeavors. Only a small fraction of these, however, are characterized with respect to mechanism of action (MOA). Here, we describe a pipeline that categorizes transcriptional responses to antibiotics and provides hypotheses for MOA. 3D-printed imaging hardware PFIboxes) profiles responses of Escherichia coli promoter-GFP fusions to more than 100 antibiotics. Notably, metergoline, a semi-synthetic ergot alkaloid, mimics a DNA replication inhibitor. In vitro supercoiling assays confirm this prediction, and a potent analog thereof (MLEB-1934) inhibits growth at 0.25 μg/mL and is highly active against quinolone-resistant strains of methicillin-resistant Staphylococcus aureus. Spontaneous suppressor mutants map to a seldom explored allosteric binding pocket, suggesting a mechanism distinct from DNA gyrase inhibitors used in the clinic. In all, the work highlights the potential of this platform to rapidly assess MOA of new antibacterial compounds.
Topics: Topoisomerase II Inhibitors; DNA Gyrase; Anti-Bacterial Agents; Escherichia coli; Transcription, Genetic; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests
PubMed: 38578824
DOI: 10.1016/j.celrep.2024.114053 -
Brain Communications 2024Alzheimer's disease accounts for 60-70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to drug discovery. Recently,...
Alzheimer's disease accounts for 60-70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to drug discovery. Recently, in cancer, morphological profiling has been used in combination with high-throughput screening of small-molecule libraries in human cells . To test feasibility of this approach for Alzheimer's disease, we developed a cell morphology-based drug screen centred on the risk gene, (which encodes the protein SORLA). Increased Alzheimer's disease risk has been repeatedly linked to variants in , particularly those conferring loss or decreased expression of SORLA, and lower levels are observed in post-mortem brain samples from individuals with Alzheimer's disease. Consistent with its role in the endolysosomal pathway, deletion is associated with enlarged endosomes in neural progenitor cells and neurons. We, therefore, hypothesized that multi-parametric, image-based cell phenotyping would identify features characteristic of deletion. An automated morphological profiling method (Cell Painting) was adapted to neural progenitor cells and used to determine the phenotypic response of neural progenitor cells to treatment with compounds from a small internationally approved drug library (TargetMol, 330 compounds). We detected distinct phenotypic signatures for neural progenitor cells compared to isogenic wild-type controls. Furthermore, we identified 16 compounds (representing 14 drugs) that reversed the mutant morphological signatures in neural progenitor cells derived from three induced pluripotent stem cell sub-clones. Network pharmacology analysis revealed the 16 compounds belonged to five mechanistic groups: 20S proteasome, aldehyde dehydrogenase, topoisomerase I and II, and DNA synthesis inhibitors. Enrichment analysis identified DNA synthesis/damage/repair, proteases/proteasome and metabolism as key pathways/biological processes. Prediction of novel targets revealed enrichment in pathways associated with neural cell function and Alzheimer's disease. Overall, this work suggests that (i) a quantitative phenotypic metric can distinguish induced pluripotent stem cell-derived neural progenitor cells from isogenic wild-type controls and (ii) phenotypic screening combined with multi-parametric high-content image analysis is a viable option for drug repurposing and discovery in this human neural cell model of Alzheimer's disease.
PubMed: 38576795
DOI: 10.1093/braincomms/fcae101 -
Antimicrobial Agents and Chemotherapy May 2024) inherently displays resistance to most antibiotics, with the underlying drug resistance mechanisms remaining largely unexplored. Efflux pump is believed to play an...
) inherently displays resistance to most antibiotics, with the underlying drug resistance mechanisms remaining largely unexplored. Efflux pump is believed to play an important role in mediating drug resistance. The current study examined the potential of efflux pump inhibitors to reverse levofloxacin (LFX) resistance in . The reference strain of (ATCC19977) and 60 clinical isolates, including 41 subsp. and 19 . subsp. , were investigated. The drug sensitivity of against LFX alone or in conjunction with efflux pump inhibitors, including verapamil (VP), reserpine (RSP), carbonyl cyanide 3-chlorophenylhydrazone (CCCP), or dicyclohexylcarbodiimide (DCC), were determined by AlarmarBlue microplate assay. Drug-resistant regions of the and genes from the drug-resistant strains were sequenced. The transcription level of the efflux pump genes was monitored using qRT-PCR. All the tested strains were resistant to LFX. The drug-resistant regions from the and genes showed no mutation associated with LFX resistance. CCCP, DCC, VP, and RSP increased the susceptibility of 93.3% (56/60), 91.7% (55/60), 85% (51/60), and 83.3% (50/60) isolates to LFX by 2 to 32-fold, respectively. Elevated transcription of seven efflux pump genes was observed in isolates with a high reduction in LFX MIC values in the presence of efflux pump inhibitors. Efflux pump inhibitors can improve the antibacterial activity of LFX against . The overexpression of efflux-related genes in LFX-resistant isolates suggests that efflux pumps are associated with the development of LFX resistance in .
Topics: Levofloxacin; Anti-Bacterial Agents; Microbial Sensitivity Tests; Mycobacterium abscessus; Reserpine; Bacterial Proteins; Carbonyl Cyanide m-Chlorophenyl Hydrazone; DNA Gyrase; Membrane Transport Proteins; Drug Resistance, Bacterial; Humans; Verapamil
PubMed: 38572960
DOI: 10.1128/aac.01348-23 -
Chemistry & Biodiversity Jun 2024In order to develop novel antimicrobial agents, we prepared quinoline bearing pyrimidine analogues 2-7, 8 a-d and 9 a-d and their structures were elucidated by...
In order to develop novel antimicrobial agents, we prepared quinoline bearing pyrimidine analogues 2-7, 8 a-d and 9 a-d and their structures were elucidated by spectroscopic techniques. Furthermore, our second aim was to predict the interactions between the active compounds and enzymes (DNA gyrase and DHFR). In this work, fourteen pyrimido[4,5-b]quinoline derivatives were prepared and assessed for their antimicrobial potential by estimating zone of inhibition. All the screened candidates displayed antibacterial potential with zone of inhibition range of 9-24 mm compared with ampicillin (20-25 mm) as a reference drug. Moreover, the target derivatives 2 (ZI=16), 9 c (ZI=17 mm) and 9 d (ZI=16 mm) recorded higher antifungal activity against C. albicans to that exhibited by the antifungal drug amphotericin B (ZI=15 mm). Finally, the most potent pyrimidoquinoline compounds (2, 3, 8 c, 8 d, 9 c and 9 d) were docked inside DHFR and DNA gyrase active sites and they recorded excellent fitting within the active regions of DNA gyrase and DHFR. These outcomes revealed us that compounds (2, 3, 8 c, 8 d, 9 c and 9 d) could be lead compounds to discover novel antibacterial candidates.
Topics: Quinolines; DNA Gyrase; Microbial Sensitivity Tests; Molecular Docking Simulation; Tetrahydrofolate Dehydrogenase; Candida albicans; Anti-Bacterial Agents; Structure-Activity Relationship; Antifungal Agents; Pyrimidines; Molecular Structure; Topoisomerase II Inhibitors; Dose-Response Relationship, Drug
PubMed: 38570192
DOI: 10.1002/cbdv.202400200 -
ACS Infectious Diseases Apr 2024Beyond their requisite functions in many critical DNA processes, the bacterial type II topoisomerases, gyrase and topoisomerase IV, are the targets of fluoroquinolone... (Review)
Review
Beyond their requisite functions in many critical DNA processes, the bacterial type II topoisomerases, gyrase and topoisomerase IV, are the targets of fluoroquinolone antibacterials. These drugs act by stabilizing gyrase/topoisomerase IV-generated DNA strand breaks and by robbing the cell of the catalytic activities of these essential enzymes. Since their clinical approval in the mid-1980s, fluoroquinolones have been used to treat a broad spectrum of infectious diseases and are listed among the five "highest priority" critically important antimicrobial classes by the World Health Organization. Unfortunately, the widespread use of fluoroquinolones has been accompanied by a rise in target-mediated resistance caused by specific mutations in gyrase and topoisomerase IV, which has curtailed the medical efficacy of this drug class. As a result, efforts are underway to identify novel antibacterials that target the bacterial type II topoisomerases. Several new classes of gyrase/topoisomerase IV-targeted antibacterials have emerged, including novel bacterial topoisomerase inhibitors, gyrase inhibitors, triazaacenaphthylenes, spiropyrimidinetriones, and thiophenes. Phase III clinical trials that utilized two members of these classes, gepotidacin (triazaacenaphthylene) and zoliflodacin (spiropyrimidinetrione), have been completed with positive outcomes, underscoring the potential of these compounds to become the first new classes of antibacterials introduced into the clinic in decades. Because gyrase and topoisomerase IV are validated targets for established and emerging antibacterials, this review will describe the catalytic mechanism and cellular activities of the bacterial type II topoisomerases, their interactions with fluoroquinolones, the mechanism of target-mediated fluoroquinolone resistance, and the actions of novel antibacterials against wild-type and fluoroquinolone-resistant gyrase and topoisomerase IV.
Topics: DNA Topoisomerase IV; Fluoroquinolones; DNA Gyrase; Topoisomerase II Inhibitors; Anti-Bacterial Agents; DNA; Mycobacterium tuberculosis
PubMed: 38564341
DOI: 10.1021/acsinfecdis.4c00128 -
Breast Cancer (Tokyo, Japan) May 2024Patients with breast cancer (BC) at advanced stages have poor outcomes because of high rate of recurrence and metastasis. Biomarkers for predicting prognosis remain to...
BACKGROUND
Patients with breast cancer (BC) at advanced stages have poor outcomes because of high rate of recurrence and metastasis. Biomarkers for predicting prognosis remain to be explored. This study aimed to evaluate the relationships between circulating tumor cells (CTCs) and outcomes of BC patients.
PATIENTS AND METHODS
A total of 50 female were enrolled in this study. Their diagnoses were determined by clinical characteristics, image data, and clinical pathology. CTC subtypes and TOP2A gene expression on CTCs were detected by CanPatrol™ technology and triple color in situ RNA hybridization (RNA-ISH), which divided into epithelial CTCs (eCTCs), mesenchymal CTCs (MCTCs), and hybrid CTCs (HCTCs) based on their surface markers. Hormone receptor, including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression, was measured by immunohistochemistry (IHC) method before treatment. The risk factors for predicting recurrence and metastasis were calculated by COX risk regression model. The progression-free survival (PFS) of patients was determined using Kaplan-Meier survival curve.
RESULTS
The patients with a large tumor size (≥ 3 cm) and advanced tumor node metastasis (TNM) stages had high total CTCs (TCTCs) (P < 0.05). These patients also had high TOP2A expression level. COX risk regression analysis indicated that TOP2A expression levels in TCTCs, ER + , HER-2 + , and TNM stages were critical risk factors for recurrence and metastasis of patients (P < 0.05). The PFS of patients with ≥ 5 TCTCs, ≥ 3 HCTCs, and positive TOP2A expression in ≥ 3 TCTCs was significantly longer than that in patient with < 5 TCTCs, < 3 HCTCs, and TOP2A expression in < 3 TCTCs (P < 0.05). In contrast, the PFS of patients with positive hormone receptors (ER + , PR + , HER-2 +) also was dramatically lived longer than that in patients with negative hormone receptor expression.
CONCLUSIONS
High TCTC, HCTCs, and positive TOP2A gene expression on CTCs were critical biomarkers for predicting outcomes of BC patients. Positive hormone receptor expression in BC patients has significant favor PFS.
Topics: Humans; Female; Neoplastic Cells, Circulating; Breast Neoplasms; DNA Topoisomerases, Type II; Middle Aged; Drug Resistance, Neoplasm; Biomarkers, Tumor; Adult; Aged; Receptor, ErbB-2; Prognosis; Receptors, Estrogen; Poly-ADP-Ribose Binding Proteins; Neoplasm Recurrence, Local; Receptors, Progesterone; Gene Expression Regulation, Neoplastic; Progression-Free Survival; Kaplan-Meier Estimate
PubMed: 38561479
DOI: 10.1007/s12282-024-01553-x