scholarly journals Homologous recombination repair creates mutations in the non-coding genome that alter Topoisomerase-1 cleavage sites & orchestrates irinotecan resistance

2021 ◽  
Author(s):  
Santosh Kumar ◽  
Valid Gahramanov ◽  
Julia Yaglom ◽  
Shivani Patel ◽  
Lukasz Kaczmarczyk ◽  
...  
Keyword(s):  
Cancer Biology ◽  
De Novo ◽  
Resistance Mechanism ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Cleavage Sites ◽  
Dna Breaks ◽  
Adaptive Mutations ◽  
Recurrent Mutations ◽  
Selection Of

The selection of drug-resistant mammalian cell mutants requires multiple drug exposures. When cloned genetically identical cells are exposed to the drug, resistance is unlikely to result from the selection of pre-existent mutations. Therefore, adaptation must involve the generation of drug-resistant mutations de-novo. Understanding how adaptive mutations are generated and protect cells is important for our knowledge of cancer biology and evolution. Here, we studied the adaptation of cancer cells to topoisomerase (Top1) inhibitor irinotecan, which triggers DNA breaks, resulting in cytotoxicity. The resistance mechanism was based on the gradual accumulation of hundreds of thousands of recurrent mutations in non-coding DNA at sequence-specific Top1 cleavage sites. Repair of DSBs at these sites following initial irinotecan exposures created mutant sequences that were resistant to further Top1 cleavage. Therefore, by creating DNA breaks Top1 increases the rate of highly protective mutations specifically at such spots, thus explaining a puzzling need of dose escalation in resistance development.

scholarly journals The plasmid system ofEscherichia colistrain UR12644: Identification and molecular characteristics of transposons involved in the generation of endogenous R-plasmids

1979 ◽  
Vol 34 (3) ◽  
pp. 287-301 ◽  
Author(s):  
F. Schöffl ◽  
A. Pühler
Keyword(s):  
Escherichia Coli ◽  
Molecular Characteristics ◽  
Multiple Drug ◽  
Restriction Map ◽  
Drug Resistant ◽  
Cleavage Sites ◽  
A Value ◽  
Multiple Drug Resistant ◽  
R Plasmids

SUMMARYTwo spontaneously formed R-plasmids (pFS401 and pFS402) originating from the multiple drug-resistantEscherichia colistrain UR12644 were found to carry transposable drug-resistance elements. Incompatibility between these two plasmids was used to select for transposition. An ampicillin transposon (Tn1781) residing on pFS401 and a tetracycline transposon (Tn1771) present on pFS402 were independently translocated to the endogenous RTF-plasmid pFS2. Molecular weight determinations of pFS2::Tn1781(Ap) and pFS2::Tn1771(Tc) revealed a value of 2·9 Mdal for Tn1781 and 7·1 Mdal for Tn1771. The arrangement of 3PstI and 1BamHI restriction endonuclease sites was found to be characteristic for the ampicillin transposon whereas the restriction map of Tn1771 features a nearly symmetrical location of 3EcoRI cleavage sites, two of them close to the termini and one in the middle of the transposon. A model is presented suggesting the existence of repetitive DNA-segments at these positions which represent the structural preconditions for the genetic properties of Tn1771. The role of a cryptic plasmid involved in the generation of the endogenous R-plasmids pFS401 and pFS402 is discussed.

scholarly journals Selection of a Multiple Drug-Resistant Hepatitis B Virus Strain in a Liver-Transplanted Patient

2006 ◽  
Vol 131 (4) ◽  
pp. 1253-1261 ◽  
Author(s):  
Stéphanie Villet ◽  
Christian Pichoud ◽  
Jean-Pierre Villeneuve ◽  
Christian Trépo ◽  
Fabien Zoulim
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Virus Strain ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Multiple Drug Resistant ◽  
B Virus ◽  
Selection Of

scholarly journals Connecting the Missing Dots: ncRNAs as Critical Regulators of Therapeutic Susceptibility in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2698
Author(s):  
Elena-Georgiana Dobre ◽  
Sorina Dinescu ◽  
Marieta Costache
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
De Novo ◽  
Multiple Drug Resistance ◽  
Therapeutic Targets ◽  
Prognostic Biomarkers ◽  
Multiple Drug ◽  
Therapeutic Success ◽  
Relevant Evidence ◽  
Selection Of

Whether acquired or de novo, drug resistance remains a significant hurdle in achieving therapeutic success in breast cancer (BC). Thus, there is an urge to find reliable biomarkers that will help in predicting the therapeutic response. Stable and easily accessible molecules such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are regarded as valuable prognostic biomarkers and therapeutic targets since they act as crucial regulators of the various mechanisms involved in BC drug resistance. Here, we reviewed the current literature on ncRNAs as mediators of resistance to systemic therapies in BC. Interestingly, upon integrating data results from individual studies, we concluded that miR-221, miR-222, miR-451, Urothelial Carcinoma Associated 1 (UCA1), and Growth arrest-specific 5 (GAS5) are strong candidates as prognostic biomarkers and therapeutic targets since they are regulating multiple drug resistance phenotypes in BC. However, further research around their clinical implications is needed to validate and integrate them into therapeutic applications. Therefore, we believe that our review may provide relevant evidence for the selection of novel therapeutic targets and prognostic biomarkers for BC and will serve as a foundation for future translational research in the field.

scholarly journals Synergistic Interactions of Antimicrobials to Counteract the Drug-Resistant Microorganisms

2021 ◽  
Vol 12 (1) ◽  
pp. 861-872
Keyword(s):  
Efflux Pump ◽  
Multiple Drug Resistance ◽  
Resistance Mechanism ◽  
Synergistic Interaction ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Synergistic Interactions ◽  
Major Threat ◽  
Herbal Compound ◽  
Efflux Pump Inhibitors

The development of multiple drug resistance organisms (MDR) is a major threat, and due to this emergence, it is found that it is difficult to treat many infectious diseases. Synergistic interaction means combining existing antimicrobials with any component that says it can be a herbal compound, phytochemicals, essential oils, antibiotics, antimicrobial peptides, and even any other antimicrobial. With the help of antimicrobial and phytochemical blending, this effective resistance conversion will neutralize the resistance mechanism, which makes the drug effective in resistant organisms. Microbes have developed several strategies, such as efflux pump inhibitors or inhibition of drug degrading enzymes. This combination interaction has shown promising abatement in minimum inhibitory concentrations and upturn of susceptibility of drug-resistant microorganisms. This synergistic interaction is brought into play because it is very difficult to develop new antimicrobials. There are already only limited antimicrobials that are segregated into classes and cannot be used all the time. So this synergistic effect can bring about a change like it can be used to increase antimicrobials' effect and prevent resistance in the organisms. Thus, it might be helpful in the effective treatment against various infections.

Posttransplant CMV infection and the role of immunosuppression (Sponsor: Novartis Pharma GmbH, Nürnberg)

2016 ◽  
Vol 04 (01) ◽  
pp. 4-10
Keyword(s):  
Lower Incidence ◽  
Paradigm Shift ◽  
Mtor Inhibitor ◽  
De Novo ◽  
Expert Panel ◽  
Risk Of Infection ◽  
Cmv Infection ◽  
Expert Meeting ◽  
Selection Of

AbstractImmunosuppression permits graft survival after transplantation and consequently a longer and better life. On the other hand, it increases the risk of infection, for instance with cytomegalovirus (CMV). However, the various available immunosuppressive therapies differ in this regard. One of the first clinical trials using de novo everolimus after kidney transplantation [1] already revealed a considerably lower incidence of CMV infection in the everolimus arms than in the mycophenolate mofetil (MMF) arm. This result was repeatedly confirmed in later studies [2–4]. Everolimus is now considered a substance with antiviral properties. This article is based on the expert meeting “Posttransplant CMV infection and the role of immunosuppression”. The expert panel called for a paradigm shift: In a CMV prevention strategy the targeted selection of the immunosuppressive therapy is also a key element. For patients with elevated risk of CMV, mTOR inhibitor-based immunosuppression is advantageous as it is associated with a significantly lower incidence of CMV events.

scholarly journals trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zachary D. Aron ◽  
Atousa Mehrani ◽  
Eric D. Hoffer ◽  
Kristie L. Connolly ◽  
Pooja Srinivas ◽  
...  
Keyword(s):  
Oral Dose ◽  
Neisseria Gonorrhoeae ◽  
Multiple Drug ◽  
Specific Inhibition ◽  
Drug Resistant ◽  
Peptidyl Transfer ◽  
Bacterial Ribosome ◽  
Multiple Drug Resistant ◽  
Unique Site

AbstractBacterial ribosome rescue pathways that remove ribosomes stalled on mRNAs during translation have been proposed as novel antibiotic targets because they are essential in bacteria and are not conserved in humans. We previously reported the discovery of a family of acylaminooxadiazoles that selectively inhibit trans-translation, the main ribosome rescue pathway in bacteria. Here, we report optimization of the pharmacokinetic and antibiotic properties of the acylaminooxadiazoles, producing MBX-4132, which clears multiple-drug resistant Neisseria gonorrhoeae infection in mice after a single oral dose. Single particle cryogenic-EM studies of non-stop ribosomes show that acylaminooxadiazoles bind to a unique site near the peptidyl-transfer center and significantly alter the conformation of ribosomal protein bL27, suggesting a novel mechanism for specific inhibition of trans-translation by these molecules. These results show that trans-translation is a viable therapeutic target and reveal a new conformation within the bacterial ribosome that may be critical for ribosome rescue pathways.

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