Influence of multi-species biofilm formed in vitro from different environmental samples on the drug-resistance traits of resident bacteria

Present study was designed to investigate whether the formation of multi-species biofilm impart any effect on the enhancement of the antibiotic resistance of the planktonic cells residing in the general nutrient enriched environments. In this regard, surface water of pond, mud from agricultural field, pharmaceutical waste waters, municipal waste water, hospital waste water and the domestic waste samples were collected and were induced to form an in vitro multi-species biofilm. All samples were found to contain huge array of pathogenic bacteria. The pathogenic isolates both from the bulk samples and their corresponding biofilms were subjected to antibiogram assay using 13 commonly used antibiotics. An extended frequency of drug resistance was observed in case of biofilm isolates. The findings of present study revealed that a number of bacterial isolates which showed sensitivity towards antibiotics, acquired drug-resistance when they were isolated from biofilms. Bangladesh J Microbiol, Volume 35 Number 2 December 2018, pp 108-114

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Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

Nature Communications ◽

10.1038/s41467-021-21386-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jing Liu ◽

Ying Xie ◽

Jing Guo ◽

Xin Li ◽

Jingjing Wang ◽

...

Keyword(s):

Multiple Myeloma ◽

Drug Resistance ◽

Phase Separation ◽

Liquid Phase ◽

Liquid Phase Separation ◽

Acquired Drug Resistance ◽

Bortezomib Treatment ◽

Liquid Liquid Phase Separation

AbstractDevelopment of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.

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Synergistic inhibitory effects by the combination of gefitinib and genistein on NSCLC with acquired drug-resistance in vitro and in vivo

Molecular Biology Reports ◽

10.1007/s11033-011-1293-1 ◽

2011 ◽

Vol 39 (4) ◽

pp. 4971-4979 ◽

Cited By ~ 22

Author(s):

Hang Zhu ◽

Hua Cheng ◽

Yuan Ren ◽

Zhan Guo Liu ◽

Yi Fang Zhang ◽

...

Keyword(s):

Drug Resistance ◽

Inhibitory Effects ◽

Acquired Drug Resistance

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Deacetylation Induced Nuclear Condensation of HP1γ Promotes Multiple Myeloma Drug Resistance

10.21203/rs.3.rs-698350/v1 ◽

2021 ◽

Author(s):

Zhiqiang Liu ◽

Xin Li ◽

Sheng Wang ◽

Ying Xie ◽

Hongmei Jiang ◽

...

Keyword(s):

Multiple Myeloma ◽

Dna Damage ◽

Drug Resistance ◽

Heterochromatin Protein 1 ◽

Nuclear Condensation ◽

Repair Capacity ◽

Acquired Drug Resistance ◽

Histone Deacetylase 1

Abstract Acquired chemoresistance to proteasome inhibitors (PIs) is a major obstacle that results in failure to manage patients with multiple myeloma (MM) in the clinic; however, the key regulators and underlying mechanisms are still unclear. In this study, we found that high levels of a chromosomal modifier, heterochromatin protein 1 gamma (HP1γ), are accompanied by a low acetylation level in bortezomib-resistant (BR) MM cells, and aberrant DNA repair capacity is correlated with HP1γ overexpression. Mechanistically, the deacetylation of HP1γ at lysine 5 by histone deacetylase 1 (HDAC1) alleviates HP1γ ubiquitination, and the stabilized HP1γ recruits the mediator of DNA damage checkpoint 1 (MDC1) to induce DNA damage repair. Simultaneously, deacetylation modification and MDC1 recruitment enhance the nuclear condensate of HP1γ, which facilitates the chromatin accessibility of genes governing sensitivity to PIs, such as FOS, JUN and CD40. Thus, targeting HP1γ stability using the HDAC1/2 inhibitor, romidepsin, sensitizes PIs treatment and overcomes drug resistance both in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in the acquired drug resistance of MM and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in MM patients.

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In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v86.10.3861.bloodjournal86103861 ◽

1995 ◽

Vol 86 (10) ◽

pp. 3861-3868 ◽

Cited By ~ 148

Author(s):

E Klumper ◽

R Pieters ◽

AJ Veerman ◽

DR Huismans ◽

AH Loonen ◽

...

Keyword(s):

Drug Resistance ◽

Acute Lymphoblastic Leukemia ◽

Poor Prognosis ◽

De Novo ◽

Lymphoblastic Leukemia ◽

Childhood All ◽

Acquired Drug Resistance ◽

The Poor ◽

Response To Chemotherapy

Cellular drug resistance is thought to be an important cause of the poor prognosis for children with relapsed or refractory acute lymphoblastic leukemia (ALL), but it is unknown when, to which drugs, and to what extent resistance is present. We determined in vitro resistance to 13 drugs with the MTT assay. Compared with 141 children with initial ALL, cells from 137 children with relapsed ALL were significantly more resistant to glucocorticoids, L-asparaginase, anthracyclines, and thiopurines, but not to vinca-alkaloids, cytarabine, ifosfamide, and epipodophyllotoxins. Relapsed ALL cells expressed the highest level of resistance to glucocorticoids, with a median level 357- and >24-fold more resistant to prednisolone and dexamethasone, respectively, than initial ALL cells, whereas the resistance ratios for the other drugs differed from 0.8- to 1.9-fold, intraindividual comparisons between initial and relapsed samples from 16 children with ALL showed that both de novo and acquired drug resistance were involved. Specific in vitro drug-resistance profiles were associated with high-risk relapsed ALL groups. In vitro drug resistance was also related to the clinical response to chemotherapy in relapsed/refractory childhood ALL. We conclude that drug resistance may explain the poor prognosis for children with relapsed/refractory ALL. These day may be helpful to design alternative treatment regimens for relapsed childhood ALL.

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Midkine Mediates Intercellular Crosstalk between Drug-Resistant and Drug-Sensitive Neuroblastoma Cells In Vitro and In Vivo

ISRN Oncology ◽

10.1155/2013/518637 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12

Author(s):

Fei Chu ◽

Jessica A. Naiditch ◽

Sandra Clark ◽

Yi-Yong Qiu ◽

Xin Zheng ◽

...

Keyword(s):

Drug Resistance ◽

Chemotherapy Resistance ◽

Neuroblastoma Cells ◽

Cytotoxic Agents ◽

Drug Resistant ◽

Wild Type ◽

Cytoprotective Effect ◽

Acquired Drug Resistance

Resistance to cytotoxic agents has long been known to be a major limitation in the treatment of human cancers. Although many mechanisms of drug resistance have been identified, chemotherapies targeting known mechanisms have failed to lead to effective reversal of drug resistance, suggesting that alternative mechanisms remain undiscovered. Previous work identified midkine (MK) as a novel putative survival molecule responsible for cytoprotective signaling between drug-resistant and drug-sensitive neuroblastoma, osteosarcoma and breast carcinoma cells in vitro. In the present study, we provide further in vitro and in vivo studies supporting the role of MK in neuroblastoma cytoprotection. MK overexpressing wild type neuroblastoma cells exhibit a cytoprotective effect on wild type cells when grown in a co-culture system, similar to that seen with doxorubicin resistant cells. siRNA knockdown of MK expression in doxorubicin resistant neuroblastoma and osteosarcoma cells ameliorates this protective effect. Overexpression of MK in wild type neuroblastoma cells leads to acquired drug resistance to doxorubicin and to the related drug etoposide. Mouse studies injecting various ratios of doxorubicin resistant or MK transfected cells with GFP transfected wild type cells confirm this cytoprotective effect in vivo. These findings provide additional evidence for the existence of intercellular cytoprotective signals mediated by MK which contribute to chemotherapy resistance in neuroblastoma.

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Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma

Blood ◽

10.1182/blood-2007-12-129833 ◽

2008 ◽

Vol 111 (11) ◽

pp. 5350-5358 ◽

Cited By ~ 101

Author(s):

Luca Paoluzzi ◽

Mithat Gonen ◽

Jeffrey R. Gardner ◽

Jill Mastrella ◽

Dajun Yang ◽

...

Keyword(s):

Drug Resistance ◽

B Cell ◽

Cell Lymphoma ◽

Family Members ◽

B Cell Lymphoma ◽

B Cell Lymphomas ◽

In Vivo Models ◽

Acquired Drug Resistance ◽

Bh3 Mimetic

Abstract Overexpression of antiapoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying antiapoptotic function can potentially overcome this in-trinsic and acquired drug resistance. AT-101 is a BH3 mimetic known to be a potent inhibitor of antiapoptotic Bcl-2 family members including Bcl-2, Bcl-XL, and Mcl-1. In vitro, AT-101 exhibits concentration- and time-dependent cytotoxicity against lymphoma and multiple myeloma cell lines, enhancing the activity of cytotoxic agents. The IC50 for AT-101 is between 1 and 10 μM for a diverse panel of B-cell lymphomas. AT-101 was synergistic with carfilzomib (C), etoposide (E), doxorubicin (D), and 4-hydroxycyclophosphamide (4-HC) in mantle cell lymphoma (MCL) lines. In a transformed large B-cell lymphoma line (RL), AT-101 was synergistic when sequentially combined with 4-HC, but not when both drugs were added simultaneously. AT-101 also induced potent mitochondrial membrane depolarization (ΔΨm) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In severe combined immunodeficient (SCID) beige mouse models of drug-resistant B-cell lymphoma, 35 mg/kg per day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide (Cy) and rituximab (R) in a schedule-dependent manner enhanced the efficacy of the conventional therapy.

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Enhanced cohesion promotes chromosome stability and limits acquired drug resistance in non small cell lung cancer

10.1101/2020.07.10.197350 ◽

2020 ◽

Author(s):

Nicole M Hermance ◽

Elizabeth A Crowley ◽

Conor P Herlihy ◽

Amity L Manning

Keyword(s):

Lung Cancer ◽

Drug Resistance ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Tumor Heterogeneity ◽

Small Cell ◽

Tumor Evolution ◽

Small Cell Lung ◽

Acquired Drug Resistance

AbstractChromosome instability, or CIN, defined as a high frequency of whole chromosome gains and losses, is prevalent in many solid tumors. CIN has been shown to promote intra-tumor heterogeneity and correspond with tumor aggressiveness, drug resistance and tumor relapse. However, whether CIN promotes the acquisition of genomic changes responsible for drug resistance remain unclear. Here we assess the role of CIN in the acquisition of drug resistance in non small cell lung cancer. We show that impairment of centromeric cohesion underlies the generation of whole chromosome segregation errors and CIN in non small cell lung cancer cells. Further, we demonstrate that centromere-specific enhancement of chromosome cohesion strongly suppresses CIN and reduces intra-tumor heterogeneity. We demonstrate that suppression of CIN has no impact on NSCLC cell proliferation in vitro nor in tumor initiation in mouse xenograft models. However, suppression of CIN alters the timing and molecular mechanism that drive acquired drug resistance. These findings suggest mechanisms to suppress CIN may serve as effective co-therapies to limit tumor evolution and sustain drug response.

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Multidrug Therapy and Evolution of Antibiotic Resistance: When Order Matters

Applied and Environmental Microbiology ◽

10.1128/aem.01078-12 ◽

2012 ◽

Vol 78 (17) ◽

pp. 6137-6142 ◽

Cited By ~ 20

Author(s):

Gabriel G. Perron ◽

Sergey Kryazhimskiy ◽

Daniel P. Rice ◽

Angus Buckling

Keyword(s):

Drug Resistance ◽

Multidrug Resistance ◽

Pathogenic Bacteria ◽

Health Workers ◽

Multiple Drug Resistance ◽

Sequential Therapy ◽

Resistant Bacteria ◽

Multiple Drug ◽

Multidrug Therapy

ABSTRACTThe evolution of drug resistance among pathogenic bacteria has led public health workers to rely increasingly on multidrug therapy to treat infections. Here, we compare the efficacy of combination therapy (i.e., using two antibiotics simultaneously) and sequential therapy (i.e., switching two antibiotics) in minimizing the evolution of multidrug resistance. Usingin vitroexperiments, we show that the sequential use of two antibiotics againstPseudomonas aeruginosacan slow down the evolution of multiple-drug resistance when the two antibiotics are used in a specific order. A simple population dynamics model reveals that using an antibiotic associated with high costs of resistance first minimizes the chance of multidrug resistance evolution during sequential therapy under limited mutation supply rate. As well as presenting a novel approach to multidrug therapy, this work shows that costs of resistance not only influences the persistence of antibiotic-resistant bacteria but also plays an important role in the emergence of resistance.

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Radiosensitivity is an acquired vulnerability of PARPi-resistant BRCA1-deficient tumors

10.1101/370577 ◽

2018 ◽

Cited By ~ 1

Author(s):

Marco Barazas ◽

Alessia Gasparini ◽

Yike Huang ◽

Asli Küçükosmanoğlu ◽

Stefano Annunziato ◽

...

Keyword(s):

Drug Resistance ◽

Topoisomerase I ◽

Parp Inhibitors ◽

Mammary Cells ◽

Deficient Mouse ◽

Acquired Drug Resistance ◽

Dna Damaging Agents ◽

End Resection

ABSTRACTThe homologous recombination (HR) defect in BRCA1-associated cancers can be therapeutically exploited by the treatment with DNA-damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. We and others previously reported that BRCA1-deficient tumors are initially hypersensitive to the inhibition of topoisomerase I/II and PARP, but acquire drug resistance through restoration of HR activity by the loss of end-resection antagonists of the 53BP1/RIF1/REV7/Shieldin/CST pathway. Here, we identified radiotherapy as an acquired vulnerability of 53BP1;BRCA1-deficient cells in vitro and in vivo. In contrast to the radioresistance caused by HR restoration through BRCA1 reconstitution, HR restoration by 53BP1 pathway inactivation further increases radiosensitivity. This highlights the relevance of this pathway for the repair of radiotherapy-induced damage. Moreover, our data show that BRCA1-mutated tumors that acquired drug resistance due to BRCA1-independent HR restoration can be targeted by radiotherapy.STATEMENT OF SIGNIFICANCEIn this study, we uncovered radiosensitivity as a novel therapeutically exploitable vulnerability of BRCA1-deficient mouse mammary cells that have acquired drug resistance due to the loss of the 53BP1 pathway.

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Geraniol, a Potential Alternative to Antibiotics for Bovine Mastitis Treatment Without Disturbing the Host Microbial Community, Does Not Lead to Drug Residues or Induce Drug Resistance

10.21203/rs.3.rs-845781/v1 ◽

2021 ◽

Author(s):

Guo Wei ◽

Min Qiu ◽

Zhonghui Pu ◽

Nana Long ◽

Min Yang ◽

...

Keyword(s):

Drug Resistance ◽

Microbial Community ◽

Gut Microbiome ◽

Pathogenic Bacteria ◽

Bovine Mastitis ◽

Clinical Mastitis ◽

Inflammatory Factors ◽

Drug Residues ◽

Potential Alternative

Abstract BackgroundMastitis is one of the important diseases of the dairy cow. Currently, mastitis treatment in dairy cows is mainly based on antibiotics. However, the use of antibiotics causes adverse effects, including drug resistance, drug residues, host-microbiome destruction, and environmental pollution. Geraniol, extracted from Fructus Tsaoko, has demonstrated good antibacterial activity in mouse model. Geraniol and antibiotics were used to treat cows with clinical mastitis to test this possibility of geraniol as a potential alternative to antibiotics for bovine mastitis treatment. The effectiveness of treatment, improvement in inflammatory factors, the influence on microbiome, presence of drug residues, and induction of drug resistance were compared and analyzed.ResultsGeraniol demonstrated a better therapeutic rate than antibiotics on clinical mastitis of cows, with a longer course of treatment. Antibiotics and geraniol significantly reduced the abundance of pathogenic bacteria and restored the microbial community in milk. Meanwhile, geraniol increased the abundance of probiotics in milk. Interestingly, geraniol did not destroy the gut microbial community of cows, whereas antibiotics significantly reduced the diversity and destroyed the community structure of the gut microbiome in cows. Conversely, geraniol increased the diversity of the gut microbiome. Besides, no geraniol residue was detected in the milk four days after treatment discontinuation. However, antibiotic residues were detected in milk at the 7th day after drug withdrawal. In vitro experiments revealed that geraniol did not induce drug resistance in the Escherichia coli strain ATCC25922 after 120 generations of culturing, while antibiotics induced resistance after 10 generations. ConclusionsOur results suggest that geraniol has antibacterial and anti-inflammatory effects similar to antibiotics. Additionally, it retains the structure of the host-microbial community and does not lead to drug residues or induce drug resistance. Therefore, geraniol can be a potential substitute for antibiotics to treat mastitis and be widely used in the dairy industry.

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