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Nature Communications Jun 2024Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for...
Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance. We screen clinically relevant small molecules for DSBR inhibition with the aim of identifying improved GBM combination therapy regimens. We identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor that suppresses radiation-induced phosphorylation of DSBR proteins, blocks DSB end resection, and enhances the cytotoxic effects of TMZ in treatment-naïve and treatment-resistant GBMs with TP53 mutation. We further show that a combination of G2/M checkpoint deficiency and reliance upon ATM-dependent DSBR renders TP53 mutant GBMs hypersensitive to TMZ/AZD1390 and radiation/AZD1390 combinations. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.
Topics: Humans; Ataxia Telangiectasia Mutated Proteins; Glioblastoma; Tumor Suppressor Protein p53; DNA Breaks, Double-Stranded; Temozolomide; Cell Line, Tumor; Mutation; Drug Resistance, Neoplasm; DNA Repair; Brain Neoplasms; Animals; DNA End-Joining Repair; Mice; Phosphorylation
PubMed: 38906885
DOI: 10.1038/s41467-024-49316-8 -
PloS One 2024Lung cancer, a relentless and challenging disease, demands unwavering attention in drug design research. Single-target drugs have yielded limited success, unable to...
Unrevealing the multitargeted potency of 3-1-BCMIYPPA against lung cancer structural maintenance and suppression proteins through pharmacokinetics, QM-DFT, and multiscale MD simulation studies.
Lung cancer, a relentless and challenging disease, demands unwavering attention in drug design research. Single-target drugs have yielded limited success, unable to effectively address this malignancy's profound heterogeneity and often developed resistance. Consequently, the clarion call for lung cancer drug design echoes louder than ever, and multitargeted drug design emerges as an imperative approach in this landscape, which is done by concurrently targeting multiple proteins and pathways and offering a beacon of hope. This study is focused on the multitargeted drug designing approach by identifying drug candidates against human cyclin-dependent kinase-2, SRC-2 domains of C-ABL, epidermal growth factor and receptor extracellular domains, and insulin-like growth factor-1 receptor kinase. We performed the multitargeted molecular docking studies of Drug Bank compounds using HTVS, SP and XP algorithms and poses filter with MM\GBSA against all proteins and identified DB02504, namely [3-(1-Benzyl-3-Carbamoylmethyl-2-Methyl-1h-Indol-5-Yloxy)-Propyl-]-Phosphonic Acid (3-1-BCMIYPPA) as multitargeted lead with docking and MM\GBSA score range from -8.242 to -6.274 and -28.2 and -44.29 Kcal/mol, respectively. Further, the QikProp-based pharmacokinetic computations and QM-based DFT showed acceptance results against standard values, and interaction fingerprinting reveals that THR, MET, GLY, VAL, LEU, GLU and ASP were among the most interacting residues. The NPT ensemble-based 100ns MD simulation in a neutralised state with an SPC water model has also shown a stable performance and produced deviation and fluctuations <2Å with huge interactions, making it a promising multitargeted drug candidate-however, experimental studies are suggested.
Topics: Humans; Lung Neoplasms; Molecular Dynamics Simulation; Molecular Docking Simulation; Antineoplastic Agents; Drug Design; Indoles; Density Functional Theory
PubMed: 38905286
DOI: 10.1371/journal.pone.0303784 -
PloS One 2024The battle against viral drug resistance highlights the need for innovative approaches to replace time-consuming and costly traditional methods. Deep generative models...
The battle against viral drug resistance highlights the need for innovative approaches to replace time-consuming and costly traditional methods. Deep generative models offer automation potential, especially in the fight against Human immunodeficiency virus (HIV), as they can synthesize diverse molecules effectively. In this paper, an application of an LSTM-based deep generative model named "LSTM-ProGen" is proposed to be tailored explicitly for the de novo design of drug candidate molecules that interact with a specific target protein (HIV-1 protease). LSTM-ProGen distinguishes itself by employing a long-short-term memory (LSTM) architecture, to generate novel molecules target specificity against the HIV-1 protease. Following a thorough training process involves fine-tuning LSTM-ProGen on a diverse range of compounds sourced from the ChEMBL database. The model was optimized to meet specific requirements, with multiple iterations to enhance its predictive capabilities and ensure it generates molecules that exhibit favorable target interactions. The training process encompasses an array of performance evaluation metrics, such as drug-likeness properties. Our evaluation includes extensive silico analysis using molecular docking and PCA-based visualization to explore the chemical space that the new molecules cover compared to those in the training set. These evaluations reveal that a subset of 12 de novo molecules generated by LSTM-ProGen exhibit a striking ability to interact with the target protein, rivaling or even surpassing the efficacy of native ligands. Extended versions with further refinement of LSTM-ProGen hold promise as versatile tools for designing efficacious and customized drug candidates tailored to specific targets, thus accelerating drug development and facilitating the discovery of new therapies for various diseases.
Topics: HIV Protease Inhibitors; Drug Design; Humans; HIV Protease; HIV-1; Acquired Immunodeficiency Syndrome; Molecular Docking Simulation
PubMed: 38905197
DOI: 10.1371/journal.pone.0303597 -
Briefings in Bioinformatics May 2024The inherent heterogeneity of cancer contributes to highly variable responses to any anticancer treatments. This underscores the need to first identify precise...
The inherent heterogeneity of cancer contributes to highly variable responses to any anticancer treatments. This underscores the need to first identify precise biomarkers through complex multi-omics datasets that are now available. Although much research has focused on this aspect, identifying biomarkers associated with distinct drug responders still remains a major challenge. Here, we develop MOMLIN, a multi-modal and -omics machine learning integration framework, to enhance drug-response prediction. MOMLIN jointly utilizes sparse correlation algorithms and class-specific feature selection algorithms, which identifies multi-modal and -omics-associated interpretable components. MOMLIN was applied to 147 patients' breast cancer datasets (clinical, mutation, gene expression, tumor microenvironment cells and molecular pathways) to analyze drug-response class predictions for non-responders and variable responders. Notably, MOMLIN achieves an average AUC of 0.989, which is at least 10% greater when compared with current state-of-the-art (data integration analysis for biomarker discovery using latent components, multi-omics factor analysis, sparse canonical correlation analysis). Moreover, MOMLIN not only detects known individual biomarkers such as genes at mutation/expression level, most importantly, it correlates multi-modal and -omics network biomarkers for each response class. For example, an interaction between ER-negative-HMCN1-COL5A1 mutations-FBXO2-CSF3R expression-CD8 emerge as a multimodal biomarker for responders, potentially affecting antimicrobial peptides and FLT3 signaling pathways. In contrast, for resistance cases, a distinct combination of lymph node-TP53 mutation-PON3-ENSG00000261116 lncRNA expression-HLA-E-T-cell exclusions emerged as multimodal biomarkers, possibly impacting neurotransmitter release cycle pathway. MOMLIN, therefore, is expected advance precision medicine, such as to detect context-specific multi-omics network biomarkers and better predict drug-response classifications.
Topics: Humans; Breast Neoplasms; Female; Machine Learning; Biomarkers, Tumor; Algorithms; Antineoplastic Agents; Computational Biology; Genomics
PubMed: 38904542
DOI: 10.1093/bib/bbae300 -
Microbiology Spectrum Jun 2024serovar Typhimurium is an important foodborne pathogen associated with human salmonellosis worldwide. A retrospective screening was performed to elucidate the...
UNLABELLED
serovar Typhimurium is an important foodborne pathogen associated with human salmonellosis worldwide. A retrospective screening was performed to elucidate the prevalence, antimicrobial resistance, and phylogenomic characterization of this pathogen in Shanghai, China. . Typhimurium isolates were selected from 2,211 serotyped isolates collected during 2007-2019. Two hundred and seventy-seven . Typhimurium isolates were detected in 15 of 16 districts in Shanghai. It was noted that 214 (77.3%) isolates were multi-drug resistant and 32 (11.6%) isolates were resistant to ciprofloxacin and 5 (1.8%) isolates were further resistant to ceftriaxone. Poisson generalized linear mixed model results showed that the multi-drug resistance (MDR) in 2017 and 2018 was significantly higher than that in 2010 (<0.05), highlighting an increase in the risk of MDR. Phylogenetic results showed that a global data set of 401 sequenced . Typhimurium isolates was classified into four clones (ST36, ST313, ST19, and ST34), which appeared in international clonal dissemination. The ST34 isolates from China fell into two clades, ST34C1 and ST34C2, the latter of which might originate from Shanghai, and then expanded nationally, accompanied by extended-spectrum β-lactamase gene and a mutation in quinolone resistance-determining region of the A 87 site. Furthermore, linking to IS upstream and ΔIS downstream was found in IncI (Gamma)-like plasmids, and the plasmid conjugation contributed to its horizontal transmission. To our knowledge, it is the first report of the epidemiological and phylogenetic characterization for . Typhimurium including the emerged clade ST34C2 in Shanghai, warranting the necessity of surveillance for this high-risk pathogen.
IMPORTANCE
Our study uncovered a widespread distribution of serovar Typhimurium isolates in Shanghai accompanied by the increase in antimicrobial resistance (AMR) especially MDR during a 10-year period, which filled in the gap about a long period of continuous monitoring of AMR in this pathogen in Shanghai. Meanwhile, we identified a new clade ST34C2 of . Typhimurium with the acquisition of IncI (Gamma)-like plasmids mediated by extended-spectrum β-lactamase gene as well as A 87 mutation, which had not been reported before. It was noted that IncI (Gamma)-like plasmids were reported in . Typhimurium for the first time and conjugation could accelerate the spread of antimicrobial resistance gene . These findings on the epidemic, antimicrobial resistance, and phylogenomic characterization for . Typhimurium provide valuable insights into its potential risk to public health and also the basis for AMR prevention and control strategies in Shanghai in the future.
PubMed: 38904374
DOI: 10.1128/spectrum.00262-24 -
Microbiology Spectrum Jun 2024To analyze the characteristics of as well as macrolide antibiotic resistance through whole-genome sequencing and comparative genomics. Thirteen clinical strains...
To analyze the characteristics of as well as macrolide antibiotic resistance through whole-genome sequencing and comparative genomics. Thirteen clinical strains isolated from 2003 to 2019 were selected, 10 of which were resistant to erythromycin (MIC >64 µg/mL), including 8 P1-type I and 2 P1-type II. Three were sensitive (<1 µg/mL) and P1-type II. One resistant strain had an A→G point mutation at position 2064 in region V of the 23S rRNA, the others had it at position 2063, while the three sensitive strains had no mutation here. Genome assembly and comparative genome analysis revealed a high level of genome consistency within the P1 type, and the primary differences in genome sequences concentrated in the region encoding the P1 protein. In P1-type II strains, three specific gene mutations were identified: C162A and A430G in L4 gene and T1112G mutation in the CARDS gene. Clinical information showed seven cases were diagnosed with severe pneumonia, all of which were infected with drug-resistant strains. Notably, BS610A4 and CYM219A1 exhibited a gene multi-copy phenomenon and shared a conserved functional domain with the DUF31 protein family. Clinically, the patients had severe refractory pneumonia, with pleural effusion, necessitating treatment with glucocorticoids and bronchoalveolar lavage. The primary variations between strains occur among different P1-types, while there is a high level of genomic consistency within P1-types. Three mutation loci associated with specific types were identified, and no specific genetic alterations directly related to clinical presentation were observed.IMPORTANCE is an important pathogen of community-acquired pneumonia, and macrolide resistance brings difficulties to clinical treatment. We analyzed the characteristics of as well as macrolide antibiotic resistance through whole-genome sequencing and comparative genomics. The work addressed primary variations between strains that occur among different P1-types, while there is a high level of genomic consistency within P1-types. In P1-type II strains, three specific gene mutations were identified: C162A and A430G in L4 gene and T1112G mutation in the CARDS gene. All the strains isolated from severe pneumonia cases were drug-resistant, two of which exhibited a gene multi-copy phenomenon, sharing a conserved functional domain with the DUF31 protein family. Three mutation loci associated with specific types were identified, and no specific genetic alterations directly related to clinical presentation were observed.
PubMed: 38904371
DOI: 10.1128/spectrum.03615-23 -
Frontiers in Cellular and Infection... 2024is a prominent genus owing to its dual nature. Species of this genus have many applications in industry and agriculture as plant growth-promoting rhizobacteria and...
INTRODUCTION
is a prominent genus owing to its dual nature. Species of this genus have many applications in industry and agriculture as plant growth-promoting rhizobacteria and microbial biological control agents, whereas species such as are considered one of the leading gram-negative multi-drug-resistant bacterial pathogens because of their high contribution to the increase in crude mortality and significant clinical challenge. Pathogenic species and most clinical isolates belong to the complex (SMc). However, a strain highly homologous to was isolated from a patient with pulmonary tuberculosis (TB), which aroused our interest, as belongs to a relatively distant clade from SMc and there have been no human association reports.
METHODS
The pathogenicity, immunological and biochemical characteristics of 610A2 were systematically evaluated.
RESULTS
610A2 is a new species of genus , which is named as sp. nov. for its obvious brown water-soluble pigment. 610A2 is pathogenic and caused significant weight loss, pulmonary congestion, and blood transmission in mice because it has multiple virulence factors, haemolysis, and strong biofilm formation abilities. In addition, the cytokine response induced by this strain was similar to that observed in patients with TB, and the strain was resistant to half of the anti-TB drugs.
CONCLUSIONS
The pathogenicity of 610A2 may not be weaker than that of . Its isolation extended the opportunistic pathogenic species to all 3 major clades of the genus , indicating that the clinical importance of species of other than and potential risks to biological safety associated with the use of require more attention.
Topics: Stenotrophomonas; Animals; Phylogeny; Gram-Negative Bacterial Infections; Biofilms; Mice; Virulence Factors; RNA, Ribosomal, 16S; Humans; DNA, Bacterial; Sequence Analysis, DNA; Disease Models, Animal; Hemolysis; Bacterial Typing Techniques
PubMed: 38903940
DOI: 10.3389/fcimb.2024.1410385 -
Frontiers in Cellular and Infection... 2024Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant , particularly those that are carbapenem resistant. CZA resistance in producing PER, a class A...
INTRODUCTION
Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant , particularly those that are carbapenem resistant. CZA resistance in producing PER, a class A extended-spectrum β-lactamase, has been well documented . However, data regarding clinical isolates are scarce. Our aim was to analyze the contribution of PER to CZA resistance in non-carbapenemase-producing clinical isolates that were ceftazidime and/or carbapenem non-susceptible.
METHODS
Antimicrobial susceptibility was determined through agar dilution and broth microdilution, while gene was screened through PCR. All PER-positive isolates and five PER-negative isolates were analyzed through Whole Genome Sequencing. The mutational resistome associated to CZA resistance was determined through sequence analysis of genes coding for PBPs 1b, 3 and 4, MexAB-OprM regulators MexZ, MexR, NalC and NalD, AmpC regulators AmpD and AmpR, and OprD porin. Loss of gene was induced in a PER-positive isolate by successive passages at 43°C without antibiotics.
RESULTS
Twenty-six of 287 isolates studied (9.1%) were CZA-resistant. Thirteen of 26 CZA-resistant isolates (50%) carried . One isolate carried but was CZA-susceptible. PER-producing isolates had significantly higher MICs for CZA, amikacin, gentamicin, ceftazidime, meropenem and ciprofloxacin than non-PER-producing isolates. All PER-producing isolates were ST309 and their gene was associated to ISCR1, an insertion sequence known to mobilize adjacent DNA. PER-negative isolates were classified as ST41, ST235 (two isolates), ST395 and ST253. PER-negative isolates carried genes for narrow-spectrum β-lactamases and the mutational resistome showed that all isolates had one major alteration in at least one of the genes analyzed. Loss of gene restored susceptibility to CZA, ceftolozane/tazobactam and other β-lactamsin the evolved isolate.
DISCUSSION
PER-3-producing ST309 is a successful multidrug-resistant clone with gene implicated in resistance to CZA and other β-lactams.
Topics: Ceftazidime; Pseudomonas aeruginosa; Azabicyclo Compounds; Microbial Sensitivity Tests; Humans; Drug Combinations; beta-Lactamases; Anti-Bacterial Agents; Pseudomonas Infections; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Chile; Whole Genome Sequencing; Mutation
PubMed: 38903939
DOI: 10.3389/fcimb.2024.1410834 -
Frontiers in Microbiology 2024has strong drug resistance and can tolerate a variety of antibiotics, which is a major problem in the management of antibiotic-resistant infections. Direct prediction...
OBJECTIVE
has strong drug resistance and can tolerate a variety of antibiotics, which is a major problem in the management of antibiotic-resistant infections. Direct prediction of multi-drug resistance (MDR) resistance phenotypes of isolates and clinical samples by genotype is helpful for timely antibiotic treatment.
METHODS
In the study, whole genome sequencing (WGS) data of 494 isolates were used to screen key anti-microbial resistance (AMR)-associated genes related to imipenem (IPM), meropenem (MEM), piperacillin/tazobactam (TZP), and levofloxacin (LVFX) resistance in by comparing genes with copy number differences between resistance and sensitive strains. Subsequently, for the direct prediction of the resistance of to four antibiotics by the AMR-associated features screened, we collected 74 positive sputum samples to sequence by metagenomics next-generation sequencing (mNGS), of which 1 sample with low quality was eliminated. Then, we constructed the resistance prediction model.
RESULTS
We identified 93, 88, 80, 140 AMR-associated features for IPM, MEM, TZP, and LVFX resistance in . The relative abundance of AMR-associated genes was obtained by matching mNGS and WGS data. The top 20 features with importance degree for IPM, MEM, TZP, and LVFX resistance were used to model, respectively. Then, we used the random forest algorithm to construct resistance prediction models of , in which the areas under the curves of the IPM, MEM, TZP, and LVFX resistance prediction models were all greater than 0.8, suggesting these resistance prediction models had good performance.
CONCLUSION
In summary, mNGS can predict the resistance of by directly detecting AMR-associated genes, which provides a reference for rapid clinical detection of drug resistance of pathogenic bacteria.
PubMed: 38903781
DOI: 10.3389/fmicb.2024.1413434 -
Health Science Reports Jun 2024as an opportunistic pathogen produces several virulence factors. This study evaluated the relative frequency of exoenzymes () A, U and S genes and integron classes (I,...
BACKGROUND
as an opportunistic pathogen produces several virulence factors. This study evaluated the relative frequency of exoenzymes () A, U and S genes and integron classes (I, II, and III) among multi-drug-resistant clinical isolates from burn patients in Ahvaz, southwest of Iran.
METHODS
In this cross-sectional study isolates were recovered from 355 wound samples. The antimicrobial susceptibility test was done by disk agar diffusion method on Muller-Hinton agar according to the Clinical and Laboratory Standards Institute. MDR isolates were defined if they showed simultaneous resistance to 3 antibiotics. Extensively drug-resistant was defined as nonsusceptibility to at least one agent in all but two or fewer antimicrobial categories. The presence of class I, II, and III integrons and virulence genes was determined using a PCR assay on extracted DNA.
RESULTS
Overall, 145 clinical isolates were confirmed with biochemical and PCR tests. Overall, 35% (52/145) of the isolates were taken from males and 64% (93/145) from female hospitalized burn patients. The highest resistance rates of isolates to antibiotics were related to piperacillin 59% ( = 86/145) and piperacillin-tazobactam 57% ( = 83/145). A total of 100% of isolates were resistant to at least one antibiotic. MDR and XDR had a frequency of 60% and 29%, respectively. The prevalence of integron classes I, II, and III in was 60%, 7.58%, and 3.44%, respectively. was more common in MDR and XDR isolates. In addition, 70(48%) of isolates did not harbor integron genes. Besides, , and in had a frequency of 55%, 55%, and 56%, respectively.
CONCLUSION
It was found that as a potent pathogen with strong virulence factors and high antibiotic resistance in the health community can cause refractory diseases in burn patients.
PubMed: 38903659
DOI: 10.1002/hsr2.2164