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PubMed2006

In vitro activity of tigecycline against multiple-drug-resistant, including pan-resistant, gram-negative and gram-positive clinical isolates from Greek hospitals.

The in vitro activities of tigecycline and selected antimicrobials were evaluated against a variety of multiple-drug-resistant clinical isolates, including extended-spectrum beta-lactamase- and/or metallo-beta-lactamase-producing gram-negative strains, colistin-resistant strains, vancomycin- and/or linezolid-resistant enterococci, and methicillin-resistant Staphylococcus aureus (MRSA). Tigecycline showed excellent activity against a collection of difficult-to-treat pathogens currently encountered in the hospital setting.

Anti-Bacterial Agents↗
PubMed1995

Circumvention of P-glycoprotein-mediated multiple drug resistance by phosphorylation modulators is independent of protein kinases.

Expression of P-glycoprotein by tumor cells confers resistance to multiple natural product drugs because of its ability to export these compounds. This transporter is a substrate for several protein kinases; however, the functional significance of its phosphorylation is not defined. We examined the effects of many activators and inhibitors of protein kinases on the activity of P-glycoprotein in drug-resistant human breast carcinoma cells (MCF-7/ADR). Several phorbol esters sensitized these cells to P-glycoprotein substrate drugs; however, there was no correlation with activation of protein kinase C. The 4 alpha- and 4 beta-isomers of phorbol 12-myristate 13-acetate were equally potent in sensitizing the cells to actinomycin D and daunomycin and in increasing the intracellular accumulation of [3H]vinblastine. These effects of 4 beta-phorbol myristate acetate required much higher concentrations than were needed to increase P-glycoprotein phosphorylation and were not antagonized by staurosporine. Similar to verapamil, the phorbol esters did not sensitize MCF-7/ADR cells to cisplatin, nor parental MCF-7 cells to any of the anticancer drugs. Mezerein, K-252a, and H-89 sensitized MCF-7/ADR cells, increased intracellular accumulation of [3H]vinblastine, and antagonized photolabeling of P-glycoprotein by [3H]azidopine. Therefore, phosphorylation does not appear to play a significant role in regulating P-glycoprotein activity in MCF-7/ADR cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Relationship between expression of multiple drug resistance proteins and p53 tumor suppressor gene proteins in human brain astrocytes.

Multiple drug resistance occurs when cells fail to respond to chemotherapy. Although it has been established that the drug efflux protein P-glycoprotein protects the brain from xenobiotics, the mechanisms involved in the regulation of expression of multiple drug resistance genes and proteins are not fully understood. Re-entry into the cell cycle and integrity of the p53 signaling pathway have been proposed as triggers of multiple drug resistance expression in tumor cells. Whether this regulation occurs in non-tumor CNS tissue is not known. Since multiple drug resistance overexpression has been reported in glia and blood vessels from epileptic brain, we investigated the level of expression of multidrug resistance protein, multidrug resistance-associated proteins and lung resistance protein in endothelial cells and astrocytes isolated from epileptic patients or studied in situ in surgical tissue samples by double label immunocytochemistry. Reverse transcriptase-polymerase chain reaction and Western blot analyses revealed that multiple drug resistance, multidrug resistance protein, and lung resistance protein are expressed in these cells. Given that lung resistance proteins have been reported to be preferentially expressed by tumors, we investigated expression of tumor suppressor genes in epileptic cortices. The pro-apoptotic proteins p53 and p21 could not be detected in "epileptic" astrocytes, while endothelial cells from the same samples readily expressed these proteins, as did normal brain astroglia and normal endothelial cells. Other apoptotic markers were also absent in epileptic glia. Our results suggest a possible link between loss of p53 function and expression of multiple drug resistance in non-tumor CNS cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Molecular mechanisms of multiple drug resistance in clinical isolates of Mycobacterium tuberculosis.

The molecular mechanisms of resistance to streptomycin, rifampin, and isoniazid in 53 Mycobacterium tuberculosis clinical isolates were examined. Twenty-five of 44 streptomycin-resistant strains had mutations in the rpsL gene and 5 of these had rrs gene perturbations. The region of the rpoB gene that is associated with resistance to rifampin was altered in 28 of 29 rifampin-resistant strains. Mutations in known genetic markers of isoniazid resistance were detected in 25 of 42 isoniazid-resistant isolates: 20 strains had katG gene alterations and 5 had perturbations in the inhA operon. Of the 20 multiply resistant strains with reduced sensitivity to streptomycin, rifampin, and isoniazid, 11 had mutations in genetic markers associated with resistance to each of these three drugs. These studies suggest that the primary mechanism of multiple drug resistance in tuberculosis is the accumulation of mutations in individual drug target genes.

Antitubercular Agents↗
PubMed1998

Rapid detection and evaluation of clinical characteristics of emerging multiple-drug-resistant gram-negative rods carrying the metallo-beta-lactamase gene blaIMP.

Gram-negative rods (GNR) carrying the transferable carbapenem resistance gene blaIMP, including Pseudomonas aeruginosa and Serratia marcescens, have been isolated from more than 20 hospitals in Japan. Although the emergence of such multiple-drug-resistant bacteria is of utmost clinical concern, little information in regard to the distribution of blaIMP-positive GNR in hospitals and the clinical characteristics of infected patients is available. To address this, a system for the rapid detection of the blaIMP gene with a simple DNA preparation and by enzymatic detection of PCR products was developed. A total of 933 ceftazidime-resistant strains of GNR isolated between 1991 and 1996 at Nagasaki University Hospital, Nagasaki, Japan, were screened for the blaIMP gene; 80 isolates were positive, including 53 P. aeruginosa isolates, 13 other glucose-nonfermenting bacteria, 13 S. marcescens isolates, and 1 Citrobacter freundii isolate. Most of the patients from whom blaIMP-positive organisms were isolated had malignant diseases (53. 8%). The organisms caused urinary tract infections, pneumonia, or other infections in 46.3% of the patients, while they were just colonizing the other patients evaluated. It was possible that blaIMP-positive P. aeruginosa strains contributed to the death of four patients, while the other infections caused by GNR carrying blaIMP were not lethal. DNA fingerprinting analysis by pulsed-field gel electrophoresis suggested the cross transmission of strains within the hospital. The isolates were ceftazidime resistant and were frequently resistant to other antibiotics. Although no particular means of pathogenesis of blaIMP-positive GNR is evident at present, the rapid detection of such strains is necessary to help with infection control practices for the prevention of their dissemination and the transmission of the resistance gene to other pathogenic bacteria.

DNA Fingerprinting↗
PubMedDate not supplied

Characterization of naturally acquired multiple-drug resistance of Yoshida rat ascites hepatoma AH66 cell line.

Characteristics of multiple-drug resistance of rat ascites hepatoma AH66, a cell line induced by dimethylaminoazobenzene and established as a transplantable tumor, were compared with those of AH66F, a drug sensitive line obtained from AH66. The AH66 cell line was resistant to vinblastine, adriamycin, SN-38 an active form of camptothesine, etoposide, and clorambucil by 10-fold or more than the AH66F cell line. The resistance of AH66 cells to vinblastine, adriamycin, and SN-38 was closely related to P-glycoprotein overexpression in the plasma membrane, because the resistance was significantly inhibited by verapamil. AH66 cells contained much glutahione and had a high activity of glutathione S-transferase P-form (GST-P), compared with AH66F cells, and resistance to clorambucil was decreased by treatment with buthionine sulfoximine, an inhibitor of glutathione synthesis. AH66 cells have a similar topoisomerase I activity, but about 6 times lower topoisomerase II activity than AH66F cells. Therefore, the resistance to etoposide and a part of the resistance to adriamycin of AH66 cells seems to depend upon this low topoisomerase II activity. These results, show that the AH66 cell line has high multiple-drug resistance compared with the AH66F cell line, by several mechanisms. Consequently, the AH66 and AH66F cell lines are useful to study naturally acquired multiple-drug resistance of hepatomas.

Animals↗
PubMed1997

A city-wide outbreak of a multiple-drug-resistant strain of Mycobacterium tuberculosis in New York.

SETTING: Incident patients with active tuberculosis (TB) resistant to two or more drugs in New York City hospitals in 1992. OBJECTIVE: To examine the New York-wide distribution of Public Health Research Institute (PHRI) strain W of Mycobacterium tuberculosis, an extremely drug-resistant strain identified by a 17-band Southern hybridization pattern using IS6110, during the peak tuberculosis year of 1992. We also compared strain W with other strains frequently observed in New York. DESIGN: Blinded retrospective study of stored M. tuberculosis cultures by restriction fragment length polymorphism (RFLP) DNA fingerprinting, and chart review. RESULTS: We found 112 cultures with the strain W fingerprint and 8 variants in 21 hospitals among incident patients hospitalized in 1992. Almost all isolates were resistant to four first-line drugs and kanamycin. This single strain made up at least 22% of New York City multiple-drug-resistant (MDR) TB in 1992, far more than any other strain. Almost all W-strain cases were acquired immune deficiency syndrome (AIDS) patients. The cluster is the most drug-resistant cluster identified in New York and the largest IS6110 fingerprint cluster identified anywhere to date. CONCLUSION: Because recommended four-drug therapy will not sterilise this very resistant strain, there was a city-wide nosocomial outbreak of W-strain TB in the early 1990s among New York AIDS patients. Other frequently seen strains were either also very resistant, or, surprisingly, pansusceptible. Individual MDR strains can be spread widely in situations where AIDS and TB are both common.

Adult↗
PubMed1969

Recombination between a thermosensitive kanamycin resistance factor and a nonthermosensitive multiple-drug resistant factor.

The thermosensitive kanamycin (KM) resistance factor, R(KM)(t), and a nonthermosensitive multiple-drug resistance factor, R(100), were simultaneously introduced into Escherichia coli and Salmonella typhimurium. The temperature sensitivity of both R factors remained unchanged as long as they replicated independently. Under certain conditions, however, a new thermosensitive R factor harboring resistance markers for kanamycin, streptomycin (SM), and sulfanilamide (SA) was obtained by recombination between the R(KM)(t) and R(100) factors. R factors carrying resistance markers for KM and SA, or for SM and SA, were obtained from the recombinant R(KM SA SM)(t) by spontaneous segregation. Though the R(100) factor has been known as an fi(+) (positive for F-mediated fertility inhibition of its host) type and it does not restrict any coexisting phages, the thermosensitive recombinants of R(100) with R(KM)(t) and their segregants were found to be fi(-) and to restrict the replication of all T-even phages, as does the R(KM)(t) factor. Double infection immunity was not observed between the R(KM)(t) and R(100) factors.

Chloramphenicol↗
PubMed2001

Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy.

PURPOSE: It has been suggested that altered drug permeability across the blood-brain barrier (BBB) may be involved in pharmacoresistance to antiepileptic drugs (AEDs). To test this hypothesis further, we measured multiple drug resistance (MDR) gene expression in endothelial cells (ECs) isolated from temporal lobe blood vessels of patients with refractory epilepsy. ECs from umbilical cord or temporal lobe vessels obtained from aneurysm surgeries were used as comparison tissue. METHODS: cDNA arrays were used to determine MDR expression. MDR protein (MRP1) immunocytochemistry and Western blot analysis were used to confirm cDNA array data. RESULTS: We found overexpression of selected MDR and significantly higher P-glycoprotein levels in "epileptic" versus "control" ECs. Specifically, MDR1, cMRP/MRP2, and MRP5 were upregulated in epileptic tissue, whereas Pgp3/MDR3 levels were comparable to those measured in comparison tissue. The gene encoding cisplatin resistance--associated protein (hCRA-alpha) also was overexpressed in epileptic tissue. Immunocytochemical analysis revealed that MDR1 immunoreactivity was localized primarily in ECs; MRP1 protein levels also were significantly higher in epileptic tissue. CONCLUSIONS: Complex MDR expression changes may play a role in AEDs pharmacoresistance by altering the permeability of AEDs across the BBB.

Adult↗
PubMed1997

The MRD1 (P-glycoprotein) and MRP (P-190) transporters do not play a major role in the intrinsic multiple drug resistance of Jurkat T lymphocytes.

The response of T cells in relation to the cell cycle has not been extensively studied. We have attempted to address this question using Jurkat T cells treated with cytostatic drugs known to arrest cells at various transition points of their cycle. We tested various concentrations of drugs that act at G1/S (hydroxyurea, lovastatin, thymidine), early S [aphidicolin, cyclosporin A (CsA), rapamycin] or G2 + M (colchicine, nocodazole) in 24 h cultures. Cytofluorimetric analyses showed that cycling Jurkat cells were equally distributed between the G1 (44.9 +/- 6.5%) and S (42.3 +/- 8.0%) phases. Cell distribution in G2 + M was 12.7 +/- 2.8%. Hydroxyurea but not lovastatin increased the percentage of cells in S phase to ca 60-70% and both drugs decreased it to ca 30% in G1. Thymidine had no effects. Aphidicolin increased the distribution in S phase to ca 70% with a decrease in G1 to ca 30%. CsA and rapamycin increased the percentage of the cells in G1 to ca 70% and decreased it to ca 25% in S phase. Nocodazole increased cell distribution in G2 + M to ca 60% and induced a decrease in G1 to ca 10%. The effects of the drugs were not related to their toxicity and their limited efficiency raised the possibility that Jurkat cells possessed an intrinsic resistance to these xenobiotics. Time-course analysis showed (scanning electron microscopy) that the early morphological changes induced by colchicine were reversible. Drug efflux experiments (vinblastine) suggested that an ATP-dependent process could be involved. However, Northern blot analyses showed a weak signal for MDR1 (MDR, multiple drug resistance). In contrast, a probe for multidrug resistance-associated protein (P-190; MRP) showed a strong signal in Jurkat and peripheral lymphocytes. The presence of drugs (CsA, nocodazole, thymidine) (24 h) did not up-regulate its message and cell treatment with BSO only moderately affected the efficiency of the glutathione S-conjugate MRP transporter. Our data suggest that the intrinsic multidrug resistance of leukemic Jurkat T cells does not appear to involve the MDR1 and MRP members of the ABC family of reverse drug transporters and these observations raise the possibility of the involvement of multi-faceted mechanisms.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

[Intestinal colonization of newborns treated in intensive care units by multiple drug resistant microorganisms].

The aim of the study was to examine the digestive tract colonisation of the newborns by multiple drug resistant bacteria during hospitalization. On the day of admission, after 5 days of hospitalization and at the day of discharge swabs from the anus of the 31 newborns hospitalized in OITiPN were taken and cultured on nutrient and selective media for staphylococci, enterococci, gram negative bacilli and fungi. Susceptibility to antibiotics of bacteria was determined, with giving attention to such resistance mechanisms as: methicillin resistant staphylococci (MRS), high level aminoglycoside resistant (HLAR) and vancomycin resistant enterococci (VRE) and the production of extended spectrum beta-lactamases (type ESBL) by gram negative bacilli. On the day of admission in 7 newborns methicillin resistant staphylococci (MRSCN) were grown in 24 no multiple drug resistant bacteria were found. Among those in 23 already after 5 days of hospitalization, colonization by multiple drug resistant strains was determined: coagulase-negative methicillin resistant staphylococci (MRSCN) were found in 16 children, strains of enterococci (HLAR) in 3 newborns and gram negative ESBL (+) bacilli also in 3 cases. On the day of discharge from hospital (after 13-141 days) in 23 out of 24 newborns enteric tract colonization by multiple drug resistant strains was assessed. In the enteric tract of 3 newborns hospitalized up to 2 weeks coagulase-negative methicillin resistant staphylococci (MRSCN) and/or HLAR enterococci were found; gram negative bacilli that produce ESBL appeared in newborns hospitalized for longer than 14 days. They were isolated in 12 out of 21 newborns. Forming of the enteric tract bacterial flora of the long hospitalized newborns depends on the time of hospitalization as well as on the used therapy.

Drug Resistance, Multiple, Bacterial↗
PubMed1994

Reversal of multiple drug resistance by tolyporphin, a novel cyanobacterial natural product.

The effects of a novel porphyrin, tolyporphin, on P-glycoprotein-mediated multiple drug resistance in human ovarian and breast cell lines were characterized. Compared with parental SKOV3 and MCF-7 cells, the P-glycoprotein-overexpressing sublines SKVLB1 and MCF-7/ADR were 5- and 1.3-fold less sensitive to the cytotoxic effects of tolyporphin. Subtoxic doses of tolyporphin increased the sensitivity of the SKVLB1 and MCF-7/ADR cells to P-glycoprotein-transported drugs, but did not increase the antiproliferative effects of nontransported drugs. Tolyporphin also enhanced the accumulation of [3H]-vinblastine in SKVLB1 and MCF-7/ADR cells at doses approximately 10-fold lower than those required for similar responses to verapamil. In contrast, tolyporphin did not affect drug accumulation in SKOV3 or MCF-7 cells. Tolyporphin reduced [3H]-vinblastine efflux from SKVLB1 cells, reduced [3H]-vinblastine binding to membranes from SKVLB1 cells, and blocked the ability of [3H]-azidopine to photoaffinity-label P-glycoprotein in these membranes. These results indicate that tolyporphin binds to P-glycoprotein and inhibits the transport of cytotoxic natural product drugs. This novel natural product, and related compounds, may be useful for the reversal of multiple drug resistance and for further definition of the drug binding site(s) of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1983

Resistance-plasmid- and protease-independent murine virulence of a multiple-drug-resistant strain of Serratia marcescens.

The multiple-drug-resistant Serratia marcescens isolate SH 186 (serotype 06/014:H12, bacteriocin type 18) carried a 44 megadalton, nonconjugative resistance (R-) plasmid as demonstrated with 'curing' experiments and the DNA agarose gel electrophoresis technique. 'Cured' variants, which had lost part of or the entire R-plasmid, proved as virulent for outbred NMRI mice (intraperitoneal route) as the wild-type parent strain. Therefore, the virulence of this S. marcescens strain was plasmid-independent. Protease-deficient variants of this strain as well as protease-negative variants of two additional S. marcescens strains displayed comparable murine virulence. None of 19 representative S. marcescens strains, including isolate SH 186, gave rise to guinea pig keratoconjunctivitis (negative Anton-Sereny tests), i.e., were non-invasive; NMRI mice pretreated with either cyclophosphamide (leukopenia), type II carrageenan (blockade of macrophages) or with zymosan (depletion of complement) revealed essentially unaltered susceptibility to S. marcescens. However, mice pretreated with cyclophosphamide followed by zymosan were significantly more susceptible for 4 tests strains of S. marcescens, including isolate SH 186. Thus, neutrophil granulocytes and complement were required for murine defense against intraperitoneal infection with S. marcescens.

Animals↗
PubMed1996

MDL 201,307: a novel benzothiazepine modulator of multiple drug resistance.

A series of novel benzothiazepine derivatives were evaluated for their relative potential to reverse multiple drug resistance (MDR) phenotype in vitro as well as for their relative cardiovascular activity and neurotoxicity. Compounds were evaluated for antiMDR activity using Chinese hamster ovary cells with derived resistance to either vincristine or doxorubicin, or a human lymphoblastic leukemia line with resistance to vinblastine. Lead compounds with good antiMDR activity were further evaluated for their relative potential to exhibit cardiovascular and neurological pharmacodynamic activity. A single compound, MDL 201,307 with good antiMDR activity and low cardiovascular and neurologic activity was chosen for further study. In contrast to (R)-verapamil, MDL 201,307 showed only a weak potential to block calcium channels. Using a series of related murine fibrosarcoma cell lines (UV-2237M) with varying levels of resistance to doxorubicin, it was shown that MDL 201,307 augmented inhibition of growth due to doxorubicin. The antiMDR compound was also effective in enhancing the cytotoxicity of actinomycin-D and vinblastine although it was ineffective in increasing cytotoxicity of the nonMDR compound, 5FU. MDL 201,307 increased uptake and decreased efflux of doxorubicin suggesting that MDL 201,307 blocks the GP170-mediated efflux pump mechanism. MDL 201,307 represents a novel antiMDR agent with diminished potential for cardiovascular activity and neurologic interactions which presently limit many of the currently available first and second generations of antiMDR compounds.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Significance of MDR1 and multiple drug resistance in refractory human epileptic brain.

BACKGROUND: The multiple drug resistance protein (MDR1/P-glycoprotein) is overexpressed in glia and blood-brain barrier (BBB) endothelium in drug refractory human epileptic tissue. Since various antiepileptic drugs (AEDs) can act as substrates for MDR1, the enhanced expression/function of this protein may increase their active extrusion from the brain, resulting in decreased responsiveness to AEDs. METHODS: Human drug resistant epileptic brain tissues were collected after surgical resection. Astrocyte cell cultures were established from these tissues, and commercially available normal human astrocytes were used as controls. Uptake of fluorescent doxorubicin and radioactive-labeled Phenytoin was measured in the two cell populations, and the effect of MDR1 blockers was evaluated. Frozen human epileptic brain tissue slices were double immunostained to locate MDR1 in neurons and glia. Other slices were exposed to toxic concentrations of Phenytoin to study cell viability in the presence or absence of a specific MDR1 blocker. RESULTS: MDR1 was overexpressed in blood vessels, astrocytes and neurons in human epileptic drug-resistant brain. In addition, MDR1-mediated cellular drug extrusion was increased in human 'epileptic' astrocytes compared to 'normal' ones. Concomitantly, cell viability in the presence of cytotoxic compounds was increased. CONCLUSIONS: Overexpression of MDR1 in different cell types in drug-resistant epileptic human brain leads to functional alterations, not all of which are linked to drug pharmacokinetics. In particular, the modulation of glioneuronal MDR1 function in epileptic brain in the presence of toxic concentrations of xenobiotics may constitute a novel cytoprotective mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗