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At least 19 recordsLinked to original sources
PubMed2026

Patterns of Drug Resistance, Drug Resistance Conferring Mutations and Genomic DNA Methylation Revealed in Mycobacterium tuberculosis From South Africa.

Tuberculosis remains a major public health threat globally, with drug-resistant strains undermining treatment efficacy. We analyzed 126 Mycobacterium tuberculosis (M. tuberculosis) isolates with diverse drug resistance spectra and selected 35 for whole genome sequencing (WGS) using Illumina NextSeq, SMRT PacBio Onso and SMRT PacBio Revio sequencing platforms. The study aimed to characterize drug resistance profiles, compare short- and long-read sequencing performance, identify lineages among South African isolates, detect known drug resistance mutations and their lineage-specific patterns, and utilize long-read SMRT platforms for epigenetic profiling. Multiple drug resistance mutations were identified, some lineage-specific, and notably, East-African-Indian (EAI) Lineage 1 isolates often considered less pathogenic, showed significant potential for multidrug-resistance development, including higher fluoroquinolone resistance as compared to other lineages. Three DNA motifs with methylated adenines, namely CACGCaG, CtCCaG and GaTNNNNRtAC, were detected, with methylation patterns varying by lineage and strain due to mutations in the corresponding methyltransferases (MTases). A particularly notable finding was the stable maintenance of a genetic heterogeneity in the mamB MTase, performing methylation at CACGCaG motifs. These results highlight the combined role of genetic and epigenetic variation in M. tuberculosis adaptive evolution and underscore the value of integrating long-read sequencing into TB surveillance and research.

Mycobacterium tuberculosis↗
PubMed1986

Tumor heterogeneity and drug resistance.

Drug resistance has long been identified as a major reason for therapy failure in cancer patients. Concurrently, work from many laboratories in the past 10 years has established tumor heterogeneity as a phenomenon of critical importance in the natural history of individual neoplasms. The two most sinister aspects of intraneoplastic diversity in human solid tumors are the genesis of clones with metastatic potential, and the existence of drug-resistant variants in primary cancers and their metastases. Thus, recent investigations on drug resistance and on tumor heterogeneity have converged to focus attention on the clonal organization of primary tumors and their metastases as the underlying basis for anticancer drug resistance. This review examines the degree of heterogeneity observed within tumors and the relationship of this diversity to resistance that might be anticipated for any given agent. A question critical to our discussion is "How many subpopulations are there?" The impact of multiple tumor clones on therapy is next discussed in relationship to normal tissue tolerance, the barrier clinicians face regardless of the specific agent used in treatment. Finally, laboratory and clinical approaches are presented for addressing a drug resistance problem that is seemingly overwhelming because of its complex biological roots.

Antineoplastic Agents↗
PubMed1989

Effect of erythromycin and tumour necrosis factor on the drug resistance of multidrug-resistant cells: reversal of drug resistance by erythromycin.

WEHI 164 murine fibrosarcoma cells were rendered multidrug-resistant (MDR) by culture in the presence of actinomycin D. In addition to resistance to actinomycin D, the cells acquired resistance to doxorubicin, mitomycin, vincristine and cycloheximide. The fact that development of resistance to one type of lipophilic chemotherapeutic drug also results in resistance to other structurally unrelated lipophilic drugs suggests that non-toxic lipophilic agents may interfere with drug resistance by saturating the pathway by which MDR-cells inhibit drug cytotoxicity. We show that the antibiotic erythromycin significantly reverses the resistance of MDR WEHI 164 cells to doxorubicin and actinomycin D. In addition to cross-resistance to chemotherapeutic drugs, 3 out of 4 actinomycin D-resistant WEHI 164 cell lines also showed higher resistance to tumour necrosis factor (TNF) than the parental WEHI 164 cells. However, whereas verapamil, a calcium antagonist known to reverse multidrug-resistance, rendered resistant cells more sensitive to chemotherapeutic drugs, it protected the cells from killing by TNF, suggesting that drug resistance and TNF resistance may not be directly connected. A synergistic cytotoxic effect of TNF and actinomycin D was obtained on both the parental and the MDR cells. However, higher concentrations of TNF and actinomycin D were required to obtain a cytotoxic effect in the MDR cells, reflecting actinomycin D and TNF resistance in these cells.

Animals↗
PubMed1989

Immunohistochemical detection and quantitation of P-glycoprotein in multiple drug-resistant human myeloma cells: association with level of drug resistance and drug accumulation.

Using several multiple drug-resistant human myeloma cell lines as standards, we developed an immunohistochemical staining technique and means of quantitating P-glycoprotein in individual myeloma cells. The level of staining intensity for P-glycoprotein in individual myeloma cells was quantitated by measuring the average optical density of each cell with a microscopic computerized cell analysis system. Using this system, we observed that the level of P-glycoprotein for individual cells within a cell population of known drug sensitivity was very homogeneous (coefficient of variation less than or equal to 13%). Analysis of cell lines with gradually increasing levels of multidrug resistance (8226/S, 8226/Dox6 and 8226/Dox40) demonstrated a close association between the level of resistance to doxorubicin, defined by the mean lethal dose (D0) and the amount of P-glycoprotein on individual cells determined by the optical density (r = 0.82, P less than 0.0005). Intracellular doxorubicin (DOX) accumulation in the individual cell lines was inversely related to the level of drug resistance expressed as D0. P-glycoprotein was also detected in the marrow-derived myeloma cells of patients with drug refractory disease using immunohistochemical staining. The amount of P-glycoprotein in the cells of one patient was directly compared to the amount found in the simultaneously stained standard cell lines (8226/Dox6 and 8226/Dox40) by comparing the optical densities for individual cells. Using this immunohistochemical technique to detect and quantitate P-glycoprotein in patient myeloma cells and comparing it to standard multidrug resistant myeloma cell lines may be of value in determining the contribution of P-glycoprotein to clinical drug resistance in patients with multiple myeloma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1979

Ara-C metabolism: implications for drug resistance and drug interactions.

Clinical studies of resistance to cytosine arabinoside have not produced agreement as to the specific biochemical lesions responsible for altered sensitivity, although experimental and clinical work supports the concept that a decreased ability to generate ara-CTP must be the ultimate effect of this lesion. 3-deazauridine, an inhibitor of CTP synthetase, was found to enhance ara-CTP production in murine tumor cells, and in the present study, was shown to inhibit deamination of ara-C at both the nucleoside and nucleotide level. Enhanced ara-CTP formation was observed in cells lacking cytidine deaminase (L1 210 and HL60), indicating that 3-deazauridine inhibition of deoxycytidylate deaminase may be important in this drug interaction.

3-Deazauridine↗
PubMed1992

Cross-resistance of drug-resistant murine P388 leukemias to taxol in vivo.

The antimicrotubule agent taxol (NSC 125973) has shown clinical antitumor activity against several classically refractory tumors. We developed a drug-resistance profile for taxol using ten drug-resistant P388 leukemias to identify potentially useful guides for patient selection for further clinical trials of taxol and possible non-cross-resistant drug combinations with taxol. Multidrug-resistant P388 leukemias exhibited either clear (leukemia resistant to amsacrine) or marginal cross-resistance (leukemias resistant to doxorubicin, actinomycin D, and mitoxantrone) to taxol. Leukemias resistant to vincristine (non-multidrug-resistant leukemia), camptothecin, melphalan, cisplatin, 1-beta-D-arabinofuranosylcytosine, and methotrexate were not cross-resistant to taxol. The data suggest that (1) it may be important to exclude or to monitor with extra care patients who have previously been treated with amsacrine, doxorubicin, actinomycin D, or mitoxantrone and (2) a combination of one of the non-cross-resistant drugs and taxol might exhibit therapeutic synergism.

Animals↗
PubMed1990

Trypanosoma congolense: an in vitro assay to distinguish drug-resistant from drug-sensitive populations.

An in vitro assay to distinguish drug-resistant from drug-sensitive populations of Trypanosoma congolense has been developed. The incorporation of radiolabelled hypoxanthine by procyclic trypanosomes in vitro was measured after 48 h exposure to different concentrations of trypanocides. In the presence of either isometamidium chloride (Samorin) or diminazene aceturate (Berenil), the ability of procyclics of a drug-sensitive stock (TREU 1627) to incorporate hypoxanthine at 28 degrees C was impaired to a much greater extent than that of procyclics of a drug-resistant stock (TREU 1467), when compared with control organisms grown in the absence of drugs. Serum from a rabbit given 1 mg/kg Samorin also inhibited incorporation of radiolabel in TREU 1627 procyclics more severely than in TREU 1467 procyclics, although the difference between stocks was not substantial. When used with cultured blood-stream forms maintained at 35 degrees C, the assay could distinguish the stocks in the presence of Samorin, but no difference was detected between the populations in their incorporation of hypoxanthine after exposure to Berenil.

Amidines↗
PubMed1990

Antiviral drug resistance.

Antiviral drug resistance is an area of increasing importance in acquired immunodeficiency syndrome (AIDS), not only in terms of the human immunodeficiency virus (HIV), but also opportunistic pathogens such as herpes simplex virus (HSV) and human cytomegalovirus (CMV). Studies of drug resistance in these and other viruses have proven valuable both for the molecular dissection of drug mechanisms and drug targets and for predicting the features of drug resistance in clinical settings: Drug-resistance mutations arise readily, due in part to a lack of fidelity of viral polymerase. Both biochemical and genetic analyses are generally required to understand the basis of drug resistance. Novel drug targets, such as a CMV gene product that contributes to ganciclovir phosphorylation, can be identified by analysis of such mutations. Regions of drug targets that are involved in drug recognition can be identified by sequencing of drug-resistance mutations. Analysis of drug-resistant viruses, obtained either in the laboratory or from patients, reveals a broad spectrum of alterations and points to the importance of heterogeneous populations of virus in resistance and pathogenesis.

Animals↗
PubMed1979

Primary drug resistance in children. Drug susceptibility of strains of Mycobacterium tuberculosis isolated from children during the years 1973 through 1977 at the Kings County Hospital Center of Brooklyn.

A continuing study of the frequency of primary drug resistance among children treated at the Kings County Hospital Center of Brooklyn during the years 1973 through 1977 showed a high incidence of primary drug resistance to isoniazid (8.8 per cent) and to streptomycin (12.3 per cent). In contrast, there were no strains resistant to cycloserine, viomycin, ethambutol, or rifampin, and only one of 57 strains (1.8 per cent) was resistant to ethionamide, and one (1.8 per cent) was resistant to para-aminosalicylic acid. Comparison with previous studies begun in 1961 showed no significant increase in resistance to isoniazid during 3 prior periods of study and no increase in resistance to streptomycin during the last 2 periods of study. It must be emphasized that these findings relate only to the children of a local community, and do not reflect the prevalence of primary drug resistance elsewhere in this country or among different age groups.

Adolescent↗
PubMed1977

Drug resistance and plasmid mediated transfer of drug resistance in Escherichia coli isolated from various districts of the human organism. A possible relationship with the antimicrobial drug concentrations during therapy.

The study of the prevalence of drug resistances and of the frequency of R factors among resistant strains, in E. coli isolated respectively from the respiratory, intestinal and urinary tracts of patients, during 1976, has shown that the frequency of drug resistances is highest among E. coli strains isolated from the respiratory tract and lowest among the E. coli strains isolated from urines. The frequency of R factors, among resistant strains, follows an exactly opposite distribution. This behaviour could be related to the gradient of antimicrobial drug concentrations achieved in the various compartments during ordinary antimicrobial therapy.

Anti-Bacterial Agents↗
PubMed1992

Transport of isometamidium (Samorin) by drug-resistant and drug-sensitive Trypanosoma congolense.

The uptake kinetics of a 14C-labelled trypanocidal compound isometamidium chloride (Samorin, RMB Animal Health Ltd, UK) was measured in drug-resistant and drug-sensitive Trypanosoma congolense. It was established that drug uptake was significantly more rapid and quantitatively greater in drug-sensitive parasites. There was clear evidence that drug uptake in both the resistant and sensitive trypanosomes was by a specific, receptor-mediated process. This specific drug transport was energy-dependent, being sensitive to metabolic inhibition with SHAM/glycerol. Significant differences in drug transport were observed which could be correlated with resistance to isometamidium. The optimal pH for drug accumulation was lowered in the resistant trypanosomes; this finding, along with an observed change in specificity for the related compound homidium bromide, suggested that the specific receptor for isometamidium is altered in the resistant trypanosomes, possibly resulting in a reduction in drug uptake. In addition to these alterations in drug uptake, efflux of isometamidium also appears to occur in the resistant trypanosomes. Both a reduction in incubation temperature and metabolic inhibition increased the level of trypanosome-associated isometamidium in the resistant parasites. This was in contrast to observations using drug-sensitive parasites. Furthermore, the addition of calcium flux-modulating agents to the incubation medium also resulted in an increase in accumulation by the resistant parasites.

Animals↗
PubMed1991

Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance.

In this report, we investigate several examples of hypoxia-induced drug resistance and compare them with P-glycoprotein associated multidrug resistance (MDR). EMT6/Ro cells exposed to drugs in air immediately after hypoxic treatment developed resistance to adriamycin, 5-fluorouracil, and actinomycin D. However, these cells did not develop resistance to colchicine, vincristine or cisplatin. When the cells were returned to a normal oxygen environment, they lost resistance. There was no correlation between the content of adriamycin and the development of adriamycin resistance induced by hypoxia. There was no difference between the efflux of adriamycin from aerobic cells and that from hypoxia-treated cells. The mRNA for P-glycoprotein was not detected in the hypoxia-treated cells. These results suggest that hypoxia-induced drug resistance is different from P-glycoprotein associated multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1986

Primary drug-resistant tuberculosis in children. Emergence of primary drug-resistant strains of M. tuberculosis to rifampin.

A prospective study of primary drug-resistant strains of Mycobacterium tuberculosis among children was begun at the Kings County Hospital Medical Center of Brooklyn in 1961 and reported at 5 4-yr periods through 1980. The present report extends our observations of primary drug-resistant tuberculosis in children through 1984. The salient finding in the present report was the increase in primary drug resistance to rifampin, 3 of 19 strains resistant in the last period of study (1981 to 1984) as compared with 1 of 96 strains isolated in the previous 3 periods of study (1969 to 1980). This increase was significant (p less than 0.02) even though the number of strains isolated was small. There were continued low resistance rates to ethambutol and para-aminosalicylic acid and stable resistance rates for isoniazid and streptomycin.

Adolescent↗