Multiple drug resistance in Candida albicans.

By functional complementation of a PDR 5 (pleiotropic drug resistance) null mutant of S. cerevisiae, we have recently cloned and sequenced a multidrug resistance gene CDR 1 (Candida Drug Resistance). Transformation by CDR 1 of a PDR 5 disrupted host hypersensitive to cycloheximide and chloramphenicol resulted in resistance to these as well as other unrelated drugs. The nucleotide sequence of CDR 1 revealed that, like PDR 5, it encodes a putative membrane pump belonging to the ABC superfamily. CDR 1 encodes a protein of 169.9 kDa whose predicted structural organisation is characterised by two homologous halves, each comprising a hydrophobic region, with a set of six transmembrane stretches, preceded by a hydrophilic binding fold. We now have evidence to suggest that there are several PDR homologues present in C. albicans which display multidrug resistance and a collateral sensitivity pattern different from PDR 5 and CDR 1. The functions of such genes and their products in the overall physiology of C. albicans is not yet established.

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Isolation, Molecular Identification and Multidrug Resistance Profiling of Bacteria Causing Clinical Mastitis in Cows

Agricultural Science Digest - A Research Journal ◽

10.18805/ag.d-5220 ◽

2020 ◽

Author(s):

D.J. Vatalia ◽

B.B. Bhanderi ◽

V.R. Nimavat ◽

M.K. Jhala

Keyword(s):

Drug Resistance ◽

Antibiotic Resistance ◽

Multiple Drug Resistance ◽

Bacterial Species ◽

Research Work ◽

Resistance Index ◽

Diffusion Method ◽

Multiple Drug ◽

Milk Samples ◽

Sensitivity Pattern

Background: Mastitis, the inflammation of parenchyma of mammary gland is frequently considered to be costliest and complex disease prevalent in India. Mastitis is caused by pathogens like Staphylococcus spp., Streptococcus spp., Mycoplasma bovis, E. coli, Klebsiella spp., Citrobacter spp., Enterobacter spp. and Entercoccus. The treatment of mastitis in animals is carried out using antibiotics. Treatment failure in mastitis is due to increased antibiotic resistance of mastitis pathogens and also due to indiscriminate use of antibiotics without testing in vitro antibiotic sensitivity test against causal organisms. In comparison to cultural method, PCR assays takes less time for detection of bacteria from the mastitis milk samples. Present research work was carried out regarding isolation, identification and multiple drug resistance profile of clinical bovine mastitis associated pathogens using conventional as well as molecular approach. Methods: In the present study, 73 mastitis milk samples were collected from Anand and Panchmahal district of Gujarat. The milk samples were subjected for cultural isolation and DNA extraction for identification of bacteria by cultural and PCR method. Antimicrobial sensitivity pattern of the isolates were carried by disc diffusion method and isolates were categorized in multiple drug resistant. Result: In the present study, Out of 73 mastitis milk samples collected from cows 48 (65.75%) cows were positive for bacterial isolation and S. aureus was the most predominant bacterial species. PCR from the mastitis milk additionally detected bacteria in culturally negative milk samples. Most sensitive drug was gentamicin and most of the isolates (90.19%) showed the multiple drug resistance for the two to nine drugs with 0.1 to 0.6 multiple antibiotic resistance index.

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Different Efflux Transporter Affinity and Metabolism of 99mTc-2-methoxyisobutylisonitrile and 99mTc-Tetrofosmin for Multidrug Resistance Monitoring in Cancer Cells

10.20944/preprints201808.0267.v1 ◽

2018 ◽

Author(s):

Masato Kobayashi ◽

Takafumi Tsujiuchi ◽

Yuya Okui ◽

Asuka Mizutani ◽

Kodai Nishi ◽

...

Keyword(s):

Drug Resistance ◽

Multidrug Resistance ◽

Cancer Cells ◽

Human Liver ◽

High Stability ◽

Multiple Drug Resistance ◽

Multiple Drug ◽

Labeled Compounds ◽

Cancer Resistance ◽

99Mtc Mibi

Objectives: Little is known about the affinity of 99mTc-labeled 2-methoxyisobutylisonitrile (99mTc-MIBI) and tetrofosmin (99mTc-TF) for multiple drug resistance in cancer cells. Additionally, if 99mTc-labeled compounds are metabolized immediately after injection, imaging with these compounds may not allow monitoring of multiple drug resistance in cancer cells. We examined the affinity of 99mTc-labeled compounds for these transporters and their stability in vivo. Methods: 99mTc-MIBI or 99mTc-TF was incubated in vesicles expressing P-glycoprotein (MDR1), multidrug resistance-associated protein (MRP)1-4, or breast cancer resistance protein with and without verapamil (MDR1 inhibitor) or MK-571 (MRP inhibitor). Time activity curves of 99mTc-labeled compounds were established using SK-N-SH neuroblastoma, SK-MEL-28 melanoma, and PC-3 prostate adenocarcinoma cell lines, and transporter expression of multiple drug resistance was measured in these cells. The stability of 99mTc-labeled compounds was evaluated in mice and human liver S9 fractions. Results: In vesicles, 99mTc-labeled compounds had affinity for MDR1 and MRP1. 99mTc-TF had additional affinity for MRP2 and MRP3. In SK-N-SH cells expressing MDR1 and MRP1, MK-571 produced the highest uptake of both 99mTc-labeled compounds. 99mTc-MIBI uptake with inhibitors was higher than 99mTc-TF uptake with inhibitors. 99mTc-TF was taken up more in SK-MEL-28 cells expressing MRP1 and MRP2 than PC-3 cells expressing MRP1 and MRP3. 99mTc-MIBI was metabolized after a 30-min incubation in SK-N-SH cells, mouse liver, human liver S9 fractions, and plasma. 99mTc-TF had high stability. Conclusion: 99mTc-MIBI is exported via MDR1 and MRP1 (MRP1 > MDR1) at greater levels and more quickly compared to 99mTc-TF, which is exported via MDR1 and MRP1-3 (MRP1 > MDR1; MRP1, 2 > MRP3). Although 99mTc-MIBI is metabolized, clinical imaging for monitoring MDR and shorter examination times may be possible with an earlier scanning time on late phase imaging. 99mTc-TF has high stability and accurately reflects the function of MDR1 and MRP1-3.

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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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Mutations in the yeast PDR3, PDR4, PDR7 and PDR9 pleiotropic (multiple) drug resistance loci affect the transcript level of an ATP binding cassette transporter encoding gene, PDR5.

Genetics ◽

10.1093/genetics/136.2.505 ◽

1994 ◽

Vol 136 (2) ◽

pp. 505-515 ◽

Cited By ~ 11

Author(s):

D Dexter ◽

W S Moye-Rowley ◽

A L Wu ◽

J Golin

Keyword(s):

Drug Resistance ◽

Leucine Zipper ◽

Multiple Drug Resistance ◽

State Level ◽

Transcript Level ◽

Multiple Drug ◽

Pleiotropic Drug Resistance ◽

Positive Regulator ◽

Multiple Drug Resistance Gene ◽

Chromosome Ii

Abstract The yeast pleiotropic (multiple drug) resistance gene PDR5 encodes a product with homology to a large number of membrane transport proteins including the mammalian multiple drug resistance family. In this study, we identified four genes on chromosome II that affect the steady-state level of PDR5 transcript in addition to a previously identified positive regulator, PDR1. The genes in question are PDR3, PDR4, PDR7 and PDR9. We also analyzed the interaction between PDR5 and YAP1. YAP1 encodes a positive regulator with a leucine zipper motif that causes pleiotropic drug resistance when overproduced. YAP1-mediated pleiotropic drug resistance is not dependent on the presence of PDR5 and must act through other genes.

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Antibiotic resistance among bacteria isolated from seawater and penguin fecal samples collected near Palmer Station, AntarcticaThis article is one of a selection of papers in the Special Issue on Polar and Alpine Microbiology.

Canadian Journal of Microbiology ◽

10.1139/w08-119 ◽

2009 ◽

Vol 55 (1) ◽

pp. 37-45 ◽

Cited By ~ 50

Author(s):

Robert V. Miller ◽

Katharine Gammon ◽

Martin J. Day

Keyword(s):

Drug Resistance ◽

Antibiotic Resistance ◽

Multidrug Resistance ◽

Multiple Drug Resistance ◽

Multiple Drug ◽

Antarctic Waters ◽

Colony Forming Units ◽

Palmer Station ◽

Human Habitation ◽

The Antarctic

Antibiotic resistance in aquatic bacteria has increased steadily as a consequence of the widespread use of antibiotics, but practice and international treaty should have limited antibiotic contamination in Antarctica. We estimated antibiotic resistance in microorganisms isolated from the Antarctic marine waters and a penguin rookery, for 2 reasons: (i) as a measure of human impact and (ii) as a potential “snapshot” of the preantibiotic world. Samples were taken at 4 established sampling sites near Palmer Station, which is situated at the southern end of the Palmer Archipelago (64°10′S, 61°50′W). Sites were chosen to provide different potentials for human contamination. Forty 50 mL samples of seawater were collected and colony-forming units (CFU)/mL were determined at 6 and 20 °C. For this study, presumed psychrophiles (growth at 6 °C) were assumed to be native to Antarctic waters, whereas presumed mesophiles (growth at 20 °C but not at 6 °C) were taken to represent introduced organisms. The 20–6 °C CFU/mL ratio was used as a measure of the relative impact to the ecosystem of presumably introduced organisms. This ratio was highest at the site nearest to Palmer Station and decreased with distance from it, suggesting that human presence has impacted the natural microbial flora of the site. The frequency of resistance to 5 common antibiotics was determined in each group of isolates. Overall drug resistance was higher among the presumed mesophiles than the presumed psychrophiles and increased with proximity to Palmer Station, with the presumed mesophiles showing higher frequencies of single and multiple drug resistance than the psychrophile population. The frequency of multidrug resistance followed the same pattern. It appears that multidrug resistance is low among native Antarctic bacteria but is increased by human habitation.

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Multiple-drug-resistance phenomenon in the yeast Saccharomyces cerevisiae: involvement of two hexose transporters.

Molecular and Cellular Biology ◽

10.1128/mcb.17.9.5453 ◽

1997 ◽

Vol 17 (9) ◽

pp. 5453-5460 ◽

Cited By ~ 76

Author(s):

A Nourani ◽

M Wesolowski-Louvel ◽

T Delaveau ◽

C Jacq ◽

A Delahodde

Keyword(s):

Saccharomyces Cerevisiae ◽

Drug Resistance ◽

Multidrug Resistance ◽

Abc Transporters ◽

Multiple Drug Resistance ◽

Kluyveromyces Lactis ◽

Major Facilitator Superfamily ◽

Multiple Drug ◽

Yeast Saccharomyces Cerevisiae ◽

Hexose Transporters

In the yeast Saccharomyces cerevisiae, multidrug resistance to unrelated chemicals can result from overexpression of ATP-binding cassette (ABC) transporters such as Pdr5p, Snq2p, and Yor1p. Expression of these genes is under the control of two homologous zinc finger-containing transcription regulators, Pdr1p and Pdr3p. Here, we describe the isolation, by an in vivo screen, of two new Pdr1p-Pdr3p target genes: HXT11 and HXT9. HXT11 and HXT9, encoding nearly identical proteins, have a high degree of identity to monosaccharide transporters of the major facilitator superfamily (MFS). In this study, we show that the HXT11 product, which allows glucose uptake in a glucose permease mutant (rag1) strain of Kluyveromyces lactis, is also involved in the pleiotropic drug resistance process. Loss of HXT11 and/or HXT9 confers cycloheximide, sulfomethuron methyl, and 4-NQO (4-nitroquinoline-N-oxide) resistance. Conversely, HXT11 overexpression increases sensitivity to these drugs in the wild-type strain, an effect which is more pronounced in a strain having both PDR1 and PDR3 deleted. These data show that the two putative hexose transporters Hxt11p and Hxt9p are transcriptionally regulated by the transcription factors Pdr1p and Pdr3p, which are known to regulate the production of ABC transporters required for drug resistance in yeast. We thus demonstrate the existence of genetic interactions between genes coding for two classes of transporters (ABC and MFS) to control the multidrug resistance process.

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Genes of multidrug resistance in haematological malignancies

Biologia ◽

10.2478/s11756-006-0046-4 ◽

2006 ◽

Vol 61 (3) ◽

Cited By ~ 2

Author(s):

Jozef Hatok ◽

Peter Račay ◽

Jan Hudeček ◽

Dušan Dobrota

Keyword(s):

Drug Resistance ◽

Multidrug Resistance ◽

Multiple Drug Resistance ◽

Multiple Drug ◽

Refractory Disease ◽

Haematological Malignancies ◽

Reversal Agents ◽

Lung Resistance Protein ◽

Impact On Survival ◽

The Impact

AbstractSince the early 1970s, multiple drug resistance has been known to exist in cancer cells and is thought to be attributable to a membrane-bound, energy-dependent pump protein (P-glycoprotein [P-gp]) capable of extruding various related and unrelated chemotherapeutic drugs. The development of refractory disease in haematological malignancies is frequently associated with the expression of one or several multidrug resistance (MDR) genes. MDR1, multidrug resistance-associated protein (MRP) and lung-resistance protein (LRP) have been identified as important adverse prognostic factors. Recently it has become possible to reverse clinical MDR by blocking P-gp-mediated drug efflux. The potential relevance of these reversal agents of MDR as well as the potential new approaches to treat the refractory disease are discussed in this article. In addition, an array of different molecules and mechanisms by which resistant cells can escape the cytotoxic effect of anticancer drugs has now been identified. These molecules and mechanisms include apoptosis-related proteins and drug inactivation enzymes. Resistance to chemotherapy is believed to cause treatment failure in more than 50% patients. Clearly, if drug resistance could be overcome, the impact on survival would be highly significant. This review focuses on molecular mechanism of drug resistance in haematological malignancies with emphasis on molecules involved in MDR. In addition, it brings the survey of methods involved in determination of MDR, in particular P-gp/MDR1, MRP and LRP.

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