Drug Resistance Updates最新文献

{"title":"Ultrastructural, metabolic and genetic characteristics of determinants facilitating the acquisition of macrolide resistance by Streptococcus pneumoniae","authors":"","doi":"10.1016/j.drup.2024.101138","DOIUrl":"10.1016/j.drup.2024.101138","url":null,"abstract":"<div><h3>Aims</h3><p>To investigate the molecular events associated with acquiring macrolide resistance genes [<em>mefE</em>/<em>mel</em> (Mega) or <em>ermB</em>] in <em>Streptococcus pneumoniae</em> (<em>Spn</em>) during nasopharyngeal colonization.</p></div><div><h3>Methods and results</h3><p>Genomic analysis of 128 macrolide-resistant <em>Spn</em> isolates revealed recombination events in genes of the conjugation apparatus, or the competence system, in strains carrying Tn<em>916</em>-related elements. Studies using confocal and electron microscopy demonstrated that during the transfer of Tn<em>916</em>-related elements in nasopharyngeal cell biofilms, pneumococcal strains formed clusters facilitating their acquisition of resistance determinants at a high recombination frequency (rF). Remarkably, these aggregates comprise both encapsulated and nonencapsulated pneumococci that span extracellular and intracellular compartments. rF assessments showed similar rates regardless Mega was associated with large integrative and conjugative elements (ICEs) (&gt;23 kb) or not (∼5.4 kb). The rF for Mega Class IV(c) insertion region (∼53 kb) was three orders of magnitude higher than the transformation of the capsule locus. Metabolomics studies of the microenvironment created by colonization of human nasopharyngeal cells revealed a link between the acquisition of ICEs and the pathways involving nicotinic acid and sucrose.</p></div><div><h3>Conclusions</h3><p>Pneumococcal clusters, both extracellular and intracellular, facilitate macrolide resistance acquisition, and ICEs were acquired at a higher frequency than the capsule locus. Metabolic changes could serve as intervention targets.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142012656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability","authors":"","doi":"10.1016/j.drup.2024.101141","DOIUrl":"10.1016/j.drup.2024.101141","url":null,"abstract":"<div><h3>Aims</h3><p>The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating <em>FPGS</em> mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL.</p></div><div><h3>Methods</h3><p>We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution. The drug sensitivity assay was used to determine the impact of relapse-specific <em>FPGS</em> mutations on sensitivity to different antifolates and chemotherapeutics in ALL cells. We used liquid chromatography-mass spectrometry (LC-MS) to quantify MTX and folate polyglutamate levels in folylpoly-γ-glutamate synthetase (FPGS) mutant ALL cells. Enzymatic activity and protein degradation assays were also conducted to characterize the catalytic properties and protein stabilities of FPGS mutants. An ALL cell line-derived mouse leukemia xenograft model was used to evaluate the <em>in vivo</em> impact of <em>FPGS</em> inactivation on leukemogenesis and sensitivity to the polyglutamatable antifolate MTX as well as non-polyglutamatble lipophilic antifolate trimetrexate (TMQ).</p></div><div><h3>Results</h3><p>We found a significant decrease in folate polyglutamylation network activities during ALL relapse using RNA-seq data. Supported by functional evidence, we identified multifactorial mechanisms of <em>FPGS</em> inactivation in relapsed ALL, including its decreased network activity and gene expression, focal gene deletion, impaired catalytic activity, and increased protein degradation. These deleterious <em>FPGS</em> alterations induce MTX resistance and inevitably cause marked intracellular folate shrinkage, which could be efficiently targeted by a polyglutamylation-independent lipophilic antifolate TMQ <em>in vitro</em> and <em>in vivo</em>.</p></div><div><h3>Conclusions</h3><p>MTX resistance in relapsed ALL relies on <em>FPGS</em> inactivation, which inevitably induces a folate metabolic vulnerability, allowing for an efficacious antifolate ALL treatment strategy that is based upon TMQ, thereby surmounting chemoresistance in relapsed ALL.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142049364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The key role of iroBCDN-lacking pLVPK-like plasmid in the evolution of the most prevalent hypervirulent carbapenem-resistant ST11-KL64 Klebsiella pneumoniae in China","authors":"","doi":"10.1016/j.drup.2024.101137","DOIUrl":"10.1016/j.drup.2024.101137","url":null,"abstract":"<div><h3>Aims</h3><p>Hypervirulent carbapenem-resistant <em>Klebsiella pneumoniae</em> (hv-CRKP), coharboring hypervirulence and carbapenem-resistance genes mediated by plasmids, causes infections with extremely high mortality and seriously impacts public health. Exploring the transfer mechanisms of virulence/carbapenem-resistance plasmids, as well as the formation and evolution pathway of hv-CRKP is of great significance to the control of hv-CRKP infections.</p></div><div><h3>Methods</h3><p>In this study, we identified the predominant clone of hv-CRKP in China and elucidated its genomic characteristics and formation route based on 239 multicenter clinical <em>K. pneumoniae</em> isolates and 1014 GenBank genomes by using comparative genomic analysis. Further, we revealed the factors affecting the transfer of virulence plasmids, and explained the genetic foundation for the prevalence of Chinese predominant hv-CRKP clone.</p></div><div><h3>Results</h3><p>ST11-KL64 is the predominant clone of hv-CRKP in China and primarily evolved from ST11-KL64 CRKP by acquiring the pLVPK-like virulence plasmid from hvKP. Significantly, the virulence gene cluster <em>iroBCDN</em> was lost in the virulence plasmid of ST11-KL64 hv-CRKP but existed in that of hvKP. Moreover, the absence of <em>iroBCDN</em> didn’t decrease the virulence of hv-CRKP, which was proved by bacterial test, cell-interaction test and mice infection model. On the contrary, loss of <em>iroBCDN</em> was observed to regulate virulence/carbapenem-resistance plasmid transfer and oxidative stress-related genes in strains and thus promoted the mobilization of nonconjugative virulence plasmid from hvKP into ST11-KL64 CRKP, forming hv-CRKP which finally had elevated antioxidant capacity and enhanced survival capacity in macrophages. The loss of <em>iroBCDN</em> increased the survival ability of hv-CRKP without decreasing its virulence, endowing it with an evolutionary advantage.</p></div><div><h3>Conclusions</h3><p>Our work provides new insights into the key role of <em>iroBCDN</em> loss in convergence of CRKP and hvKP, and the genetic and biological foundation for the widespread prevalence of ST11-KL64 hv-CRKP in China.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000955/pdfft?md5=eabe17f35a7d1fc472d7ca2a4d2fd49b&pid=1-s2.0-S1368764624000955-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142040453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CBX4 counteracts cellular senescence to desensitize gastric cancer cells to chemotherapy by inducing YAP1 SUMOylation","authors":"","doi":"10.1016/j.drup.2024.101136","DOIUrl":"10.1016/j.drup.2024.101136","url":null,"abstract":"<div><h3>Aims</h3><p>As our comprehension of the intricate relationship between cellular senescence and tumor biology continues to evolve, the therapeutic potential of cellular senescence is gaining increasing recognition. Here, we identify chromobox 4 (CBX4), a Small Ubiquitin-related Modifier (SUMO) E3 ligase, as an antagonist of cellular senescence and elucidate a novel mechanism by which CBX4 promotes drug resistance and malignant progression of gastric cancer (GC).</p></div><div><h3>Methods</h3><p><em>In vitro</em> and <em>in vivo</em> models were conducted to investigate the manifestation and impact of CBX4 on cellular senescence and chemoresistance. High-throughput sequencing, chromatin immunoprecipitation, and co-immunoprecipitation techniques were utilized to identify the upstream regulators and downstream effectors associated with CBX4, revealing its intricate regulatory network.</p></div><div><h3>Results</h3><p>CBX4 diminishes the sensitivity of GC cells to cellular senescence, facilitating chemoresistance and GC development by deactivating the senescence-related Hippo pathway. Mechanistically, low-dose cisplatin transcriptionally downregulates CBX4 through CEBPB. In addition, CBX4 preserves the stability and cytoplasm-nuclear transport of YAP1, the key player of Hippo pathway, by inducing SUMO1 modification at K97 and K280, which competitively inhibits YAP1-S127 phosphorylation.</p></div><div><h3>Conclusions</h3><p>Our study highlights the anti-senescence role of CBX4 and suggests that CBX4 inhibition in combination with low-dose cisplatin has the potential to overcome chemoresistance and effectively restrict GC progression.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: ABC transporters and drug resistance","authors":"","doi":"10.1016/j.drup.2024.101135","DOIUrl":"10.1016/j.drup.2024.101135","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142044781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional relay between Mph(A) enzyme and Mrx efflux pump mediates azithromycin resistance, a novel mechanism of bacterial antimicrobial resistance","authors":"","doi":"10.1016/j.drup.2024.101127","DOIUrl":"10.1016/j.drup.2024.101127","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142044780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular and molecular mechanisms of gastrointestinal cancer liver metastases and drug resistance","authors":"","doi":"10.1016/j.drup.2024.101125","DOIUrl":"10.1016/j.drup.2024.101125","url":null,"abstract":"<div><p>Distant metastases and drug resistance account for poor survival of patients with gastrointestinal (GI) malignancies such as gastric cancer, pancreatic cancer, and colorectal cancer. GI cancers most commonly metastasize to the liver, which provides a unique immunosuppressive tumour microenvironment to support the development of a premetastatic niche for tumor cell colonization and metastatic outgrowth. Metastatic tumors often exhibit greater resistance to drugs than primary tumors, posing extra challenges in treatment. The liver metastases and drug resistance of GI cancers are regulated by complex, intertwined, and tumor-dependent cellular and molecular mechanisms that influence tumor cell behavior (e.g. epithelial-to-mesenchymal transition, or EMT), tumor microenvironment (TME) (e.g. the extracellular matrix, cancer-associated fibroblasts, and tumor-infiltrating immune cells), tumor cell-TME interactions (e.g. through cytokines and exosomes), liver microenvironment (e.g. hepatic stellate cells and macrophages), and the route and mechanism of tumor cell dissemination (e.g. circulating tumor cells). This review provides an overview of recent advances in the research on cellular and molecular mechanisms that regulate liver metastases and drug resistance of GI cancers. We also discuss recent advances in the development of mechanism-based therapy for these GI cancers. Targeting these cellular and molecular mechanisms, either alone or in combination, may potentially provide novel approaches to treat metastatic GI malignancies.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142012657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"crVDAC3 alleviates ferroptosis by impeding HSPB1 ubiquitination and confers trastuzumab deruxtecan resistance in HER2-low breast cancer","authors":"","doi":"10.1016/j.drup.2024.101126","DOIUrl":"10.1016/j.drup.2024.101126","url":null,"abstract":"<div><h3>Aims</h3><p>With the wide application of trastuzumab deruxtecan (T-DXd), the survival of HER2-low breast cancer patients is dramatically improved. However, resistance to T-DXd still exists in a subset of patients, and the molecular mechanism remains unclear.</p></div><div><h3>Methods</h3><p>An <em>in vivo</em> shRNA lentiviral library functional screening was performed to identify potential circular RNA (crRNA) that mediates T-DXd resistance. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation assays were conducted to investigate the molecular mechanism. Ferroptosis was detected using C11-BODIPY, Liperfluo, FerroOrange staining, glutathione quantification, malondialdehyde quantification, and transmission electron microscopy. Molecular docking, virtual screening, and patient-derived xenograft (PDX) models were used to validate therapeutic agents.</p></div><div><h3>Results</h3><p>VDAC3-derived crRNA (crVDAC3) ranked first in functional shRNA library screening. Knockdown of crVDAC3 increased the sensitivity of HER2-low breast cancer cells to T-DXd treatment. Further mechanistic research revealed that crVDAC3 specifically binds to HSPB1 protein and inhibits its ubiquitination degradation, leading to intracellular accumulation and increased levels of HSPB1 protein. Notably, suppression of crVDAC3 dramatically increases excessive ROS levels and labile iron pool accumulation. Inhibition of crVDAC3 induces ferroptosis in breast cancer cells by reducing HSPB1 expression, thereby mediating T-DXd resistance. Through virtual screening and experimental validation, we identified that paritaprevir could effectively bind to crVDAC3 and prevent its interaction with HSPB1 protein, thereby increasing ubiquitination degradation of HSPB1 protein to overcome T-DXd resistance. Finally, we validated the enhanced therapeutic efficacy of T-DXd by paritaprevir in a HER2-low PDX model.</p></div><div><h3>Conclusion</h3><p>This finding reveals the molecular mechanisms underlying T-DXd resistance in HER2-low breast cancer. Our study provides a new strategy to overcome T-DXd resistance by inhibiting the interaction between crVDAC3 and HSPB1 protein.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An increased prevalence of carbapenem-resistant hypervirulent Klebsiella pneumoniae associated with the COVID-19 pandemic","authors":"","doi":"10.1016/j.drup.2024.101124","DOIUrl":"10.1016/j.drup.2024.101124","url":null,"abstract":"<div><h3>Background</h3><p><em>Klebsiella pneumoniae</em> (Kp) is a common community-acquired and nosocomial pathogen. Carbapenem-resistant and hypervirulent (CR-hvKp) variants can emerge rapidly within healthcare facilities and impacted by other infectious agents such as COVID-19 virus.</p></div><div><h3>Methods</h3><p>To understand the impact of COVID-19 virus on the prevalence of CR-hvKp, we accessed Kp genomes with corresponding metadata from GenBank. Sequence types (STs), antimicrobial resistance genes, and virulence genes, and those scores and CR-hvKp were identified. We analyzed population diversity and phylogenetic characteristics of five most common STs, measured the prevalence of CR-hvKp, identified CR-hvKp subtypes, and determined associations between carbapenem resistance gene subtypes with STs and plasmid types. These variables were compared pre- and during the COVID-19 pandemic.</p></div><div><h3>Findings</h3><p>The proportion of CR-hvKp isolates increased within multiple STs in different continents during the COVID-19 pandemic and persistent CR-hvKp subtypes were found in common STs. <em>bla</em>_KPC was dominant in CG258, <em>bla</em>_KPC-2 was detected in 97 % of the ST11 CR-hvKp, <em>bla</em>_NDM subtypes were prominent in ST147 (87.4 %) and ST307 (70.8 %); <em>bla</em>_OXA-48 and its subtypes were prevalent in ST15 (80.5 %). The possession of carbapenemase genes was different among subclades from different origins in different periods of time within each ST. IncFIB/IncHI1B hybrid plasmids contained virulence genes and carbapenemase genes and were predominant in ST147 (67.37 %) and ST307 (56.25 %).</p></div><div><h3>Interpretation</h3><p>The prevalence of CR-hvKp increased during the COVID-19 pandemic, which was evident by an increase in local endemic clones. This process was facilitated by the convergence of plasmids containing carbapenemase genes and virulence genes. These findings have implications for the appropriate use of antimicrobials and infection prevention and control during outbreaks of respiratory viruses and pandemic management.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emergence of silent NDM-1 carbapenemase gene in carbapenem-susceptible Klebsiella pneumoniae: Clinical implications and epidemiological insights","authors":"","doi":"10.1016/j.drup.2024.101123","DOIUrl":"10.1016/j.drup.2024.101123","url":null,"abstract":"<div><p>The global dissemination of carbapenemase genes, particularly <em>bla</em>_NDM-1, poses a significant threat to public health. While research has mainly focused on strains with phenotypic resistance, the impact of silent resistance genes has been largely overlooked. This study documents the first instance of silent <em>bla</em>_NDM-1 in a cluster of clonally related carbapenem-susceptible <em>K. pneumoniae</em> strains from a single patient. Despite initial effectiveness of carbapenem therapy, the patient experienced four recurrent lung infections over five months, indicating persistent <em>K. pneumoniae</em> infection. Genomic sequencing revealed all strains harbored <em>bla</em>_NDM-1 on the epidemic IncX3 plasmid. A deletion within the upstream promoter region (P_{IS<em>Aba125</em>}) of <em>bla</em>_NDM-1 hindered its expression, resulting in phenotypic susceptibility to carbapenems. However, in vitro bactericidal assays and a mouse infection model showed that <em>K. pneumoniae</em> strains with silent <em>bla</em>_NDM-1 exhibited significant tolerance to carbapenem-mediated killing. These findings demonstrate that silent <em>bla</em>_NDM-1 can mediate both phenotypic susceptibility and antibiotic tolerance. In silico analysis of 1986 <em>bla</em>_NDM sequences showed that 1956 (98.5%) retained the original promoter P_{IS<em>Aba125</em>}. Given that previous genomic sequencing typically targets carbapenem-resistant strains, accurately assessing the prevalence of silent <em>bla</em>_NDM remains challenging. This study highlights the hidden threat of silent resistance genes to clinical antimicrobial therapy and calls for enhanced clinical awareness and laboratory detection.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}