Mechanisms Of Multidrug Resistance Research Articles

Class 1 integrons and multiple mobile genetic elements in clinical isolates of the Klebsiella pneumoniae complex from a tertiary hospital in eastern China.

The emergence of highly drug-resistant K. pneumoniae, has become a major public health challenge. In this work, we aim to investigate the diversity of species and sequence types (STs) of clinical Klebsiella isolates and to characterize the prevalence and structure of class 1 integrons. Based on the whole genome sequencing, species identification was performed by 16S rRNA gene homology and average nucleotide identity (ANI) analysis. STs were determined in accordance with the international MLST schemes for K. pneumoniae and K. variicola. Integron characterization and comparative genomic analysis were performed using various bioinformatic tools. Species identification showed that the 167 isolates belonged to four species: K. pneumoniae, K. variicola subsp. variicola, K. quasipneumoniae and K. aerogenes. Thirty-six known and 5 novel STs were identified in K. pneumoniae, and 10 novel STs were identified in K. variicola subsp. variicola. Class 1 integrons were found in 57.49% (96/167) of the isolates, and a total of 169 resistance gene cassettes encoding 19 types of resistance genes, including carbapenem resistance gene (bla IPM-4) and class D β-lactamases gene (bla OXA-1 and bla OXA-10), were identified. Among the 17 complete genomes, 29 class 1 integrons from 12 groups were found, only 1 group was encoded on chromosomes. Interestingly, one plasmid (pKP167-261) carrying two copies of approximately 19-kb IS26-Int1 complex resistance region that contains an integron and a multidrug resistance gene fragment. The results of this work demonstrated that the species and STs of the clinical Klebsiella isolates were more complex by the whole genome sequence analysis than by the traditional laboratory methods. Finding of the new structure of MGEs related to the resistance genes indicates the great importance of deeply exploring the molecular mechanisms of bacterial multidrug resistance.

Whole genome sequencing of multidrug-resistant Proteus mirabilis strain PM1162 recovered from a urinary tract infection in China

Proteus mirabilis is an important opportunistic Gram-negative pathogen. This study reports the whole genome sequence of multidrug-resistant (MDR) P. mirabilis PM1162 and explores its antibiotic resistance genes (ARGs) and their genetic environments. P. mirabilis PM1162 was isolated from a urinary tract infection in China. Antimicrobial susceptibility was determined, and whole genome sequencing (WGS) was performed. ARGs, insertion sequence (IS) elements, and prophages were identified using ResFinder, ISfinder, and PHASTER software, respectively. Sequence comparisons and map generation were performed using BLAST and Easyfig, respectively. On its chromosome, P. mirabilis PM1162 harboured 15 ARGs, including cat, tet(J), blaCTX-M-14 (three copies), aph(3')-Ia, qnrB4, blaDHA-1, qacE, sul1, armA, msr(E), mph(E), aadA1, and dfrA1. We focused our analysis on the four related MDR regions: (1) genetic contexts associated with blaCTX-M-14; (2) the prophage containing blaDHA-1, qnrB4, and aph(3')-Ia; (3) genetic environments associated with mph(E), msr(E), armA, sul, and qacE; and (4) the class II integron harbouring dfrA1, sat2, and aadA1. This study reported the whole genome sequence of MDR P. mirabilis PM1162 and the genetic context of its ARGs. This comprehensive genomic analysis of MDR P. mirabilis PM1162 provides a deeper understanding of its MDR mechanism and elucidates the horizontal spread of its ARGs, thus providing a basis for the containment and treatment of the bacteria.

Research Progress on the Anti-Tumor Mechanism and Reversal of Multidrug Resistance of Zuojin Pill and its Main Components, Evodiamine and Berberine

Background Cancer is one of the most serious diseases worldwide that threatens human health and leads to death. Chemotherapy is the main clinical method to treat tumors, but, despite the development of new chemotherapeutic drugs, the multidrug resistance (MDR) of cancer cells to conventional chemotherapeutic drugs remains a major cause of failure in cancer prevention and treatment. Therefore, overcoming this resistance has become a major challenge in cancer prevention and treatment. Method With the in-depth study of traditional Chinese medicines (TCMs) for the treatment of tumors, many such medicines have been found that can reverse MDR and enhance the sensitivity of chemotherapy. ZJW is a famous traditional medicine formula from China, recorded first in an ancient medicine book named Danxi Xinfa. It is composed of Huanglian and Wuzhuyu in a ratio of 6:1 by mass. Conclusion ZJW can inhibit proliferation, induce apoptosis, inhibit invasion and metastasis, and reverse MDR of tumor cells through multiple pathways and multiple targets. In this paper, we briefly review recent research on ZJW and its main components, evodiamine and berberine, in the anti-tumor mechanism and reversal of multidrug resistance.

Photodynamic Therapy with PLGA-Lipid Hybrid Nanoparticles to Overcome the Diverse Mechanisms of Multidrug Resistance in Lung Cancer Cells

Photodynamic Therapy with PLGA-Lipid Hybrid Nanoparticles to Overcome the Diverse Mechanisms of Multidrug Resistance in Lung Cancer Cells

Hybrid Magnetic Lipid-Based Nanoparticles for Cancer Therapy.

Cancer is one of the major public health problems worldwide. Despite the advances in cancer therapy, it remains a challenge due to the low specificity of treatment and the development of multidrug resistance mechanisms. To overcome these drawbacks, several drug delivery nanosystems have been investigated, among them, magnetic nanoparticles (MNP), especially superparamagnetic iron oxide nanoparticles (SPION), which have been applied for treating cancer. MNPs have the ability to be guided to the tumor microenvironment through an external applied magnetic field. Furthermore, in the presence of an alternating magnetic field (AMF) this nanocarrier can transform electromagnetic energy in heat (above 42 °C) through Néel and Brown relaxation, which makes it applicable for hyperthermia treatment. However, the low chemical and physical stability of MNPs makes their coating necessary. Thus, lipid-based nanoparticles, especially liposomes, have been used to encapsulate MNPs to improve their stability and enable their use as a cancer treatment. This review addresses the main features that make MNPs applicable for treating cancer and the most recent research in the nanomedicine field using hybrid magnetic lipid-based nanoparticles for this purpose.

The Use and Effectiveness of Ceftazidime-Avibactam in Real-World Clinical Practice: EZTEAM Study.

Ceftazidime-avibactam has proven activity against multidrug-resistant (MDR) bacteria in clinical trials and real-world studies. This study was conducted to describe the patterns of use of ceftazidime-avibactam (including indications and associated antibiotics), and the effectiveness and safety of ceftazidime-avibactam in real-world clinical practice. This non-interventional medical chart review study was conducted in 11 countries across the European and Latin American (LATAM) regions. Consecutive patients treated in clinical practice with at least one dose of ceftazidime-avibactam for an approved indication per country label since 01January2018 (or launch date in the country if posterior) were enrolled. Effectiveness analyses were conducted in patients treated with ceftazidime-avibactam for at least 72h. Of the 569 eligible patients enrolled, 516 (90.7%) were treated for at least 72h (354 patients from Europe and 162 patients from LATAM); 390 patients (75.7%) had switched from another antibiotic line for Gram-negative coverage. Infection sources were intra-abdominal, urinary, respiratory, bloodstream infections, and other infections (approximately 20% each). K.pneumoniae was the most common microorganism identified in the latest microbiological evaluation before starting ceftazidime-avibactam (59.3%). Two-thirds of microorganisms tested for susceptibility were MDR, of which 89.3% were carbapenem-resistant. The common MDR mechanisms for K.pneumoniae were carbapenemase (33.9%), oxacillinase 48 (25.2%), extended-spectrum beta-lactamase (21.5%), or metallo-beta-lactamase (14.2%) production. Without prior patient exposure, 17 isolates (mostly K.pneumoniae) were resistant to ceftazidime-avibactam. Treatment success was achieved in 77.3% of patients overall (88.3% among patients with urinary infection), regardless of first or second treatment line. In-hospital mortality rate was 23.1%. Adverse events were reported for six of the 569 patients enrolled. This study provides important real-world evidence on treatment patterns, effectiveness, and safety of ceftazidime-avibactam in clinical practice through its recruitment in the European and LATAM regions. Ceftazidime-avibactam is one of the antibiotics to consider for treatment of MDR bacteria. ClinicalTrials.gov identifier, NCT03923426.

Special AT-rich sequence binding protein 1 promotes multidrug resistance in gastric cancer by regulation of Ezrin to alter subcellular localization of ATP-binding cassette transporters.

Multidrug resistance is a primary factor in the poor response to chemotherapy and subsequent death in gastric cancer patients. However, the molecular mechanisms involved remain unclear. In this study, the high expression of special AT-rich sequence binding protein 1 (SATB1) in gastric cancer was found to be associated with reduced sensitivity to various chemotherapy drugs. Our results demonstrate that SATB1 can promote chemotherapy resistance in gastric cancer in vitro and in vivo. SATB1 exerts its effect by enhancing the activity of multiple ATP-binding cassette (ABC) transporters (P-glycoprotein, multidrug resistance-associated protein, and breast cancer resistance protein) in gastric cancer cell lines. We also found that SATB1 affects ABC transporters by altering the subcellular localization of the ABC transporter rather than its expression. Subsequently, we confirmed that Ezrin binds to various ABC transporters and affects their subcellular localization. In addition, we found that SATB1 can also bind to the Ezrin promoter and regulate its expression. In the present study, we elucidate the mechanism of SATB1-mediated multidrug resistance in gastric cancer, providing a basis for SATB1 as a potential target for reversal of resistance.

Repurposing Antidepressants and Phenothiazine Antipsychotics as Efflux Pump Inhibitors in Cancer and Infectious Diseases.

Multidrug resistance (MDR) is a major obstacle in the therapy of infectious diseases and cancer. One of the major mechanisms of MDR is the overexpression of efflux pumps (EPs) that are responsible for extruding antimicrobial and anticancer agents. EPs have additional roles of detoxification that may aid the development of bacterial infection and the progression of cancer. Therefore, targeting EPs may be an attractive strategy to treat bacterial infections and cancer. The development and discovery of a new drug require a long timeline and may come with high development costs. A potential alternative to reduce the time and costs of drug development is to repurpose already existing drugs. Antidepressants and antipsychotic agents are widely used in clinical practice in the treatment of psychiatric disorders and some somatic diseases. Antidepressants and antipsychotics have demonstrated various beneficial activities that may be utilized in the treatment of infections and cancer. This review aims to provide a brief overview of antibacterial and anticancer effects of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and phenothiazine antipsychotics, while focusing on EPs. However, it should be noted that the antimicrobial activity of a traditionally non-antibiotic drug may have clinical implications regarding dysbiosis and bacterial MDR.

Taxonomic Assignment-Based Genome Reconstruction from Apical Periodontal Metagenomes to Identify Antibiotic Resistance and Virulence Factors.

Primary apical periodontitis occurs due to various insults to the dental pulp including microbial infections, physical and iatrogenic trauma, whereas inadequate elimination of intraradicular infection during root canal treatment may lead to secondary apical periodontitis. We explored the complex intra-radicular microbial communities and their functional potential through genome reconstruction. We applied shotgun metagenomic sequencing, binning and functional profiling to identify the significant contributors to infection at the acute and chronic apical periodontal lesions. Our analysis revealed the five classified clusters representing Enterobacter, Enterococcus, Lacticaseibacillus, Pseudomonas, Streptococcus and one unclassified cluster of contigs at the genus level. Of them, the major contributors were Pseudomonas, with 90.61% abundance in acute conditions, whereas Enterobacter followed by Enterococcus with 69.88% and 15.42% abundance, respectively, in chronic conditions. Enterobacter actively participated in antibiotic target alteration following multidrug efflux-mediated resistance mechanisms, predominant in the chronic stage. The prediction of pathways involved in the destruction of the supportive tissues of the tooth in Enterobacter and Pseudomonas support their crucial role in the manifestation of respective disease conditions. This study provides information about the differential composition of the microbiome in chronic and acute apical periodontitis. It takes a step to interpret the role of a single pathogen, solely or predominantly, in establishing endodontic infection types through genome reconstruction following high throughput metagenomic DNA analysis. The resistome prediction sheds a new light on the therapeutic treatment guidelines for endodontists. However, it needs further conclusive research to support this outcome using a larger number of samples with similar etiological conditions, but different demographic origin.

Elucidating the mechanism of antimicrobial resistance in Mycobacterium tuberculosis using gene interaction networks.

Antimicrobial resistance (AMR) in microorganisms is an urgent global health threat. AMR of Mycobacterium tuberculosis is associated with significant morbidity and mortality. It is of great importance to underpin the resistance pathways involved in the mechanisms of AMR and identify the genes that are directly involved in AMR. The focus of the current study was the bacteria M. tuberculosis, which carries AMR genes that give resistance that lead to multidrug resistance. We, therefore, built a network of 43 genes and examined for potential gene-gene interactions. Then we performed a clustering analysis and identified three closely related clusters that could be involved in multidrug resistance mechanisms. Through the bioinformatics pipeline, we consistently identified six-hub genes (dnaN, polA, ftsZ, alr, ftsQ, and murC) that demonstrated the highest number of interactions within the clustering analysis. This study sheds light on the multidrug resistance of MTB and provides a protocol for discovering genes that might be involved in multidrug resistance, which will improve the treatment of resistant strains of TB.

QSAR modeling and molecular docking studies of 2-oxo-1, 2-dihydroquinoline-4- carboxylic acid derivatives as p-glycoprotein inhibitors for combating cancer multidrug resistance

Multidrug resistance (MDR) proteins related to the ATP-binding cassette family are found in a very wide range of human tumors and result in therapeutic failure. The overexpression of efflux pumps such as ABCB1 is one of the mechanisms of MDR. This paper aims to develop a reliable quantitative structure-activity relationship (QSAR) model that best describes the correlation between the activity and the molecular structures in order to predict the inhibitory biological activity towards ABCB1. In this regard, a series of quinoline derivatives of 18 compounds were analyzed using different linear and non-linear machine learning (ML) regression methods including k-nearest neighbors (KNN), decision tree (DT), back propagation neural networks (BPNN) and gradient boosting-based (GB) methods. Their aim is to explain the origin of the activity of these investigated compounds and therefore, design new quinoline derivatives with higher effect on ABCB1. A total of 16 ML predictive models were developed on different number of 2D and 3D descriptors and were evaluated using the coefficient of determination (R2) and the root mean squared error (RMSE) statistical metrics. Among all developed models, A GB-based model in particular catboost achieved the highest predictive quality, with one descriptor, expressed by R2 and RMSE of 95% and 0.283 respectively. Molecular docking studies against the target crystal structure of the outward-facing p-glycoprotein (6C0V) revealed significant binding affinities via both hydrophobic and H-bond interactions with the relevant compounds. The 17 has shown the highest binding energy of −9.22 kcal/mol. Therefore, it can suggest that 17 may prove to be a valuable potential lead structure for the design and synthesis of more potent P-glycoprotein inhibitors for combination used with anti-cancer drugs for cancer multidrug resistance management.

Pharmacological Strategies for Overcoming Multidrug Resistance to Chemotherapy.

Actual mechanisms of multidrug resistance (MDR) to chemotherapy in oncology are considered. ABC-transporters such as P-glycoprotein, BCRP protein, and MRP proteins take part in the development of resistance. The review presents the main classes of chemosensitizers, i.e., inhibitors of ABC transporters of the 1st-4th generations. Plant polyphenols, i.e., flavonoids, are commonly referred to as the last (4th) generation of MDR inhibitors. Chemosensitizers of different classes should be chosen with allowance for the patient mutation-expression profile and the receptor status of a particular tumor. The appropriate dosage of the chemosensitizer and the administration schedule can enhance the process of counteracting MDR.

Recent advances in access to overcome cancer drug resistance by nanocarrier drug delivery system.

Cancer is currently one of the most intractable diseases causing human death. Although the prognosis of tumor patients has been improved to a certain extent through various modern treatment methods, multidrug resistance (MDR) of tumor cells is still a major problem leading to clinical treatment failure. Chemotherapy resistance refers to the resistance of tumor cells and/or tissues to a drug, usually inherent or developed during treatment. Therefore, an urgent need to research the ideal drug delivery system to overcome the shortcoming of traditional chemotherapy. The rapid development of nanotechnology has brought us new enlightenments to solve this problem. The novel nanocarrier provides a considerably effective treatment to overcome the limitations of chemotherapy or other drugs resulting from systemic side effects such as resistance, high toxicity, lack of targeting, and off-target. Herein, we introduce several tumor MDR mechanisms and discuss novel nanoparticle technology applied to surmount cancer drug resistance. Nanomaterials contain liposomes, polymer conjugates, micelles, dendrimers, carbon-based, metal nanoparticles, and nucleotides which can be used to deliver chemotherapeutic drugs, photosensitizers, and small interfering RNA (siRNA). This review aims to elucidate the advantages of nanomedicine in overcoming cancer drug resistance and discuss the latest developments.

Different Aspects of Nano-material and Biodegradable Polymers for Cancer Diagnosis and Treatment: A Review

Cancer, one of the most prevalent causes of death and disease, has a convoluted pathophysiology. Chemotherapy, immunotherapy and radiation therapy are examples of traditional cancer treatments. However, lack of selectivity, restrictions such cytotoxicity, and Drug resistance is a significant barrier to successful cancer treatment. With the development of nanotechnology, the study of cancer treatment has undergone a revolution. For treatment of cancer Nanoparticles can be used because of their special advantages, less toxicity, more good stability, stronger permeability, and exact placement. There are several varieties of nanoparticles. The innovative nanoparticle based drug delivery system makes advantage of characteristics of the tumour and its surroundings. Nanoparticles overcomes the disadvantages of conventional treatment of cancer in addition to avoiding multiple drug resistance. As additional multidrug resistance mechanisms are found and examined, nanoparticle research is also being pursued actively. The therapy includes consequences of Nano formulation have provided fresh perspectives on cancer treatment. The biggest chunk of studies, however, is restricted to in vivo and in vitro experiments, and the number of authorized Nano drugs has not increased significantly over time. This study covers a wide range of nanoparticle kinds, targeting strategies, and authorized Nanotherapy includes use in the cancer treatment. We also provide a summary of the pros, disadvantages, and present state of clinical translation.

Monocarbonyl Curcumin Analogues as Potent Inhibitors against Human Glutathione Transferase P1-1.

The isoenzyme of human glutathione transferase P1-1 (hGSTP1-1) is involved in multi-drug resistance (MDR) mechanisms in numerous cancer cell lines. In the present study, the inhibition potency of two curcuminoids and eleven monocarbonyl curcumin analogues against hGSTP1-1 was investigated. Demethoxycurcumin (Curcumin II) and three of the monocarbonyl curcumin analogues exhibited the highest inhibitory activity towards hGSTP1-1 with IC50 values ranging between 5.45 ± 1.08 and 37.72 ± 1.02 μM. Kinetic inhibition studies of the most potent inhibitors demonstrated that they function as non-competitive/mixed-type inhibitors. These compounds were also evaluated for their toxicity against the prostate cancer cells DU-145. Interestingly, the strongest hGSTP1-1 inhibitor, (DM96), exhibited the highest cytotoxicity with an IC50 of 8.60 ± 1.07 μΜ, while the IC50 values of the rest of the compounds ranged between 44.59-48.52 μΜ. Structural analysis employing molecular docking, molecular dynamics (MD) simulations, and binding-free-energy calculations was performed to study the four most potent curcumin analogues as hGSTP1-1 inhibitors. According to the obtained computational results, DM96 exhibited the lowest binding free energy, which is in agreement with the experimental data. All studied curcumin analogues were found to form hydrophobic interactions with the residue Gln52, as well as hydrogen bonds with the nearby residues Gln65 and Asn67. Additional hydrophobic interactions with the residues Phe9 and Val36 as well as π-π stacking interaction with Phe9 contributed to the superior inhibitory activity of DM96. The van der Waals component through shape complementarity was found to play the most important role in DM96-inhibitory activity. Overall, our results revealed that the monocarbonyl curcumin derivative DM96 acts as a strong hGSTP1-1 inhibitor, exerts high prostate cancer cell cytotoxicity, and may, therefore, be exploited for the suppression and chemosensitization of cancer cells. This study provides new insights into the development of safe and effective GST-targeted cancer chemosensitizers.

Nanoenabled Tumor Energy Metabolism Disorder via Sonodynamic Therapy for Multidrug Resistance Reversal and Metastasis Inhibition.

Cancer multidrug resistance (MDR) is an important reason that results in chemotherapy failure. As a main mechanism of MDR, overexpressed P-glycoprotein (P-gp) utilizes adenosine triphosphate (ATP) to actively pump chemotherapy drugs out of cells. In addition, metabolic reprogramming of drug-resistant tumor cells (DRTCs) exacerbates the specific hypoxic microenvironment and promotes tumor metastasis and recurrence. Therefore, we propose a novel sonodynamic therapy (SDT) paradigm to induce energy metabolism disorder and drug resistance change of DRTCs. A US-controlled "Nanoenabled Energy Metabolism Jammer" (TL@HPN) is designed using perfluoropentane (PFP) adsorbing oxygen in the core, and a targeting peptide (CGNKRTR) is attached to the liposome as the delivery carrier shell to incorporate hematoporphyrin monomethyl ether (HMME) and paclitaxel (PTX). The TL@HPN with ultrasonic/photoacoustic imaging (PAI/USI) precisely controlled the release of drugs and oxygen after being triggered by ultrasound (US), which attenuated the hypoxic microenvironment. SDT boosted the reactive oxygen species (ROS) content in tumor tissues, preferentially inducing mitochondrial apoptosis and maximizing immunogenic cell death (ICD). Persistently elevated oxidative stress levels inhibited ATP production and downregulated P-gp expression by disrupting the redox balance and electron transfer of the respiratory chain. We varied the effect of TL@HPN combined with PD-1/PD-L1 to activate autoimmunity and inhibit tumor metastasis, providing a practical strategy for expanding the use of SDT-mediated tumor energy metabolism.

Molecular Epidemiology, Clinical Characteristics and Risk Factors for Bloodstream Infection of Multidrug-Resistant Klebsiella pneumoniae Infections in Pediatric Patients from Tianjin, China.

The data on pediatrics with Multidrug-Resistant (MDR) Klebsiella pneumoniae infections are scarce. This study aims to investigate the molecular epidemiology of MDR Klebsiella pneumoniae, detect the mechanism of drug resistance, and determine the clinical risk factors for carbapenem-resistant Klebsiella pneumonia (CRKP) bloodstream infections (BSIs) in a children's hospital. A total of 62 strains were collected from Tianjin Children's Hospital. Carba NP and polymerase chain reactions (PCR) were performed to detect MDR mechanisms. Multilocus sequence typing (MLST) was used for analyzing strain homology. Clinical data were collected and logistic regression was used for BSI risk factors. ST11 was the principal ST among the CRKP isolates clinically, accounting for 56.45% (35/62); there were also 57.14% (20/35) ST11 CRKP strains co-carrying bla NDM-5 and bla KPC-2, which were resistant to most of the tested antibiotics, being susceptible only to cotrimoxazole and tigecycline. The clinical data showed that 72.73% (40/55) of children with CRKP infection had serious underlying diseases; 20.00% (11/55) patients developed BSIs with the potential to cause multiple organ failure, shock and death. The logistic regression showed that the risk of BSIs caused by CRKP strain infections in children with hematological malignancies after chemotherapy was 7 times that of other children (95%Cl: 1.298-45.415, P=0.025). ST11 was the prevalent clone in our hospital. The emergence of ST11 CRKP co-carrying bla NDM-5 and bla KPC-2 should be a cause for alarm as they were resistant to most of the tested antibiotics. CRKP strain infections are mainly occurring in young immunocompromised patients and the chemotherapy for hematological malignancies is an independent risk factor for BSIs.

Gibberellin derivative GA-13315 overcomes multidrug resistance in breast cancer by up-regulating BMP6 expression.

Chemoresistance represents a major obstacle in breast cancer treatment. Bone morphogenetic protein 6 (BMP6) was reported to participate in the occurrence and development of various tumors. In the present study, the results of transcriptome sequencing, qRT-PCR and western blot analysis revealed that BMP6 was down-regulated in multidrug resistant MCF-7/Adr breast cancer cells and BMP6 overexpression sensitized MCF-7/Adr cells to chemotherapeutic drugs, indicating that BMP6 downregulation was involved in the mechanisms of multidrug resistance (MDR) of MCF-7/Adr breast cancer cells. GA-13315 (GA5) is a new tetracyclic diterpenoid selected from a series of gibberellin derivatives. Here, we found that GA5 exhibited more potent anti-tumor activity in multidrug resistant MCF-7/Adr breast cancer cells and xenografts, indicating that GA5 could overcome MDR. Mechanistically, GA5 increased BMP6 expression, and BPM6 knockdown partially reversed the inhibitory effect of GA5 on cell proliferation. Furthermore, we found that ERK phosphorylation and P-gp expression were increased in MCF-7/Adr cells when compared with MCF-7 cells. Either overexpression of BMP6 or treatment the cells with GA5 significantly decreased ERK phosphorylation and P-gp expression, indicating that GA5 reversed MDR of MCF-7/Adr cells by upregulating BMP6, thereby inhibiting the activation of ERK signaling pathway and reducing P-gp expression. Collectively, our present study demonstrated that the MDR of MCF-7/Adr cells was closely related to the low expression of BMP6, and revealed the molecular mechanisms by which GA5 overcame MDR in breast cancer, providing evidence in supporting the development of GA5 to be a promising agent for overcoming MDR in clinical cancer therapy in the future.

Bim downregulation by activation of NF-κB p65, Akt, and ERK1/2 is associated with adriamycin and dexamethasone resistance in multiple myeloma cells.

Multiple myeloma (MM) frequently acquires multidrug resistance (MDR), which is due to poor prognosis. Our previous study indicated that high expression of Survivin and multidrug resistance protein 1 (MDR1) and decreased expression of Bim are associated with MDR in adriamycin- and dexamethasone-resistant cells. However, the fundamental mechanism of MDR in adriamycin- and dexamethasone-resistant MM cells is still unidentified. In this study, we examined the MDR mechanism in adriamycin- and dexamethasone-resistant cells. RPMI8226/ADM, ARH-77/ADM, RPMI8226/DEX, and ARH-77/DEX cells exhibited enhanced nuclear factor κB (NF-κB) p65, Akt, and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Combination treatment with NF-κB p65, phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinase 1/2 (MEK1/2) inhibitors resensitized to adriamycin and dexamethasone via increased Bim expression. Although treatment with MDR1 or Survivin siRNA did not overcome adriamycin and dexamethasone resistance in RPMI8226/ADM and RPMI8226/DEX cells, administration of Bim siRNA induced adriamycin and dexamethasone resistance in RPMI8226 cells. Moreover, low expression of Bim was related to poor prognosis in MM patients. These results indicate that activation of NF-κB p65, Akt, and ERK1/2 is associated with adriamycin and dexamethasone resistance via decreasing Bim expression, and these signal inhibitor combinations overcome drug resistance in MM. These findings suggest that combination treatment with these inhibitors and adriamycin or dexamethasone may be a promising therapy for adriamycin- and dexamethasone-resistant MM.

Biocide-Resistant Escherichia coli ST540 Co-Harboring ESBL, dfrA14 Confers QnrS-Dependent Plasmid-Mediated Quinolone Resistance.

Emerging sequence types of pathogenic bacteria have a dual ability to acquire resistance islands/determinants, and remain renitent towards disinfection practices; therefore, they are considered "critical risk factors" that contribute significantly to the global problem of antimicrobial resistance. Multidrug-resistant Escherichia coli was isolated, its genome sequenced, and its susceptibilities characterized, in order to understand the genetic basis of its antimicrobial resistance.The draft genome sequencing of E. coli ECU32, was performed with Illumina NextSeq 500, and annotated using a RAST server. The antibiotic resistome, genomic island, insertion sequences, and prophages were analyzed using bioinformatics tools. Subsequently, analyses including antibiotic susceptibility testing, E-test, bacterial growth, survival, and efflux inhibition assays were performed.The draft genome of E. coli ECU32 was 4.7 Mb in size, the contigs were 107, and the G+C content was 50.8%. The genome comprised 4658 genes, 4543 CDS, 4384 coding genes, 115 RNA genes, 88 tRNAs, and 3 CRISPR arrays. The resistome characterization of ST540 E. coli ECU32 revealed the presence of ESBL, APH(6)-Id, APH(3')-IIa, dfrA14, and QnrS1, with broad-spectrum multidrug and biocide resistance. Comparative genome sequence analysis revealed the presence of transporter and several virulence genes. Efflux activity and growth inhibition assays, which were performed with efflux substrates in the presence of inhibitor PAβN, exhibited significant reduced growth relative to its control.This study discusses the genotypic and phenotypic characterization of the biocide-tolerant multidrug-resistant E. coli O9:H30 strain, highlighting the contributory role of qnrS-dependent plasmid-mediated quinolone resistance, in addition to innate enzymatic modes of multidrug resistance mechanisms.