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PubMed1985

Cross-resistance of vinblastine- and taxol-resistant mutants of Chinese hamster ovary cells to other anticancer drugs.

Stable mutants resistant to the anticancer drug vinblastine (VinR mutants) have been isolated after a single selection step from Chinese hamster ovary cells. Of the two types of VinR mutants which are obtained, one class exhibits specific cross-resistance to only some of the microtubule inhibitors. However, the second type of mutants, which is affected in membrane permeability, exhibits cross-resistance to a wide variety of unrelated compounds. Both classes of VinR mutants showed codominant expression in cell hybrids formed between resistant and sensitive cells. The cross-resistance patterns of the VinR mutants and a single-step mutant resistant to the anticancer drug taxol (TaxR mutant) toward various anticancer drugs have been determined. The mutants resistant to both of these drugs showed significantly increased resistance toward aclarubicin, dactinomycin, doxorubicin, bisantrene, bruceantin, chromomycin A3, demecolcine, colchicine, daunorubicin, ellipticine, emetine, ethidium bromide, maytansine, mithramycin, mitoxantrone, nitidine chloride, olivomycin, podophyllotoxin, puromycin, taxol, vinblastine, vincristine, vindesine, teniposide, and etoposide. Interestingly, either one or both of the above mutants exhibited somewhat enhanced sensitivity toward vidarabine, acivicin, bleomycin, cisplatin, cytarabine, alpha-difluoromethyl-ornithine, 5-FU, tegafur, and tiazofurin. For a number of other anticancer drugs which were examined (chlorambucil, mitolactol, IMPY, hexamethylmelamine, hydroxyurea, diglycoaldehyde, methotrexate, mitoguazone, mitomycin, nocodazole, and 6-thioguanine), the level of resistance of these mutants was found to be unaltered. The information regarding cross-resistance and collateral sensitivity patterns of VinR and TaxR mutants should prove to be very useful in the design of drug combinations which could prove more effective in cancer chemotherapy.

Alkaloids↗
PubMed1986

[Mechanism and overcoming of resistance in ACNU-resistant sublines of rat brain tumors].

One of the most serious problems in chemotherapy of brain tumors is that tumor cells are able to acquire resistance to initially effective cytotoxic agents. In order to study the mechanism of such resistance to ACNU and the means to overcome it, two variant cell lines (C6/ACNU and 9L/ACNU) resistant to ACNU were selected in vivo. Uptake and retention of ACNU in these resistant cells were studied with [14C] ACNU. The results indicated that the resistance exhibited by both sublines of C6/ACNU and 9L/ACNU were due to both reduced uptake and retention of the drug. In an attempt to clarify the more detailed biochemical mechanism of resistance in these cells, we surveyed various membrane-modifying agents which potentiate the sensitivity of these resistant cells to ACNU. Among a number of membrane-modifying agents, calcium antagonists, especially nicardipine and verapamil, were found to cause retention of ACNU in the resistant cells and to enhance the effect of ACNU on these resistant cell lines. It might therefore be concluded that ACNU resistance can be overcome by membrane-modifying agents, such as nicardipine and verapamil.

Animals↗
PubMed1987

Genetics of multidrug resistance: relationship of a cloned gene to the complete multidrug resistant phenotype.

Resistance to multiple chemotherapeutic agents remains the major cause of failure in cancer chemotherapy. Multidrug resistant cell lines developed in vitro have provided a useful model for analyzing this phenomenon. We describe a complementary DNA, lambda DR11, which is present in normal cells and overexpressed in multidrug resistant cell lines. We have placed this complementary DNA in an expression vector which uses the beta-actin promoter to drive transcription and introduced this vector via transfection into drug sensitive cells. Cells expressing increased levels of lambda DR11 are resistant to the same broad spectrum of chemotherapeutic agents which characterize the multidrug resistant phenotype. The expression of this complementary DNA in transfected clones is dependent upon the number of copies of lambda DR11 integrated in the genome as well as the amount of selective pressure placed on the clone during selection of the clone. Furthermore, the number of copies of lambda DR11 in the genome and the expression of lambda DR11 can be modulated by releasing an individual clone from selective pressure or by increasing the selective pressure on the clone. The endogenous sequences encoding the multidrug resistance gene are not amplified in transfected drug resistant clones. Finally, the drug resistant phenotype is reversed in the transfected clones by verapamil just as drug resistance is reversed in multidrug resistant cell lines.

Animals↗
PubMed1982

[Amplification of portions of the genome in mammalian somatic cells resistant to colchicine. II. Marker chromosomes with long homogeneously staining regions in colchicine-resistant cells of the Djungarian hamster].

The series of sublines 170-750 times more resistant to colchicine were obtained from 10 independent clones of Djungarian hamster cells possessing 16-22-fold resistance to the drug. From each clone, several sublines with different levels of colchicine-resistance were developed. The drug resistance was unstable. 2,7-4,0% of cells per population doubling lost resistance to selective dosages of colchicine. The loss of resistance was stepwise. The chromosomes stained by trypsin G-banding technique were studied in 17 sublines. 15 sublines derived from 9 independent clones contained chromosomes with long homogeneously staining regions (HSRs). These were, as a rule, primarily localized in the long arm of chromosome 4. During cultivation, HSRs were transferred from chromosome 4 into other chromosomes. Evidently, transposition of HSRs was due to translocations of different chromosomes of HSRs in the chromosome 4 and to subsequent breakages of the resulting dicentrics within HSRs. A great number of different chromosomal rearrangements was also found in the cells containing HSRs. Possibly, formation of HSR leads to destabilization of the karyotype and to the variability of the genome. The length of HSRs varied in different cells of each subline. The levels of colchicine-resistance in different sublines did not correlate with the average length of HSRs in their cells. The lack of connection between the lengths of HSRs and the levels of drug resistance as well as the existence of highly resistant sublines with gene amplification, but without HSRs, suggest that amplified genes are localized in Djungarian hamster colchicine-resistant cells both in chromosomes and extrachromosomally.

Animals↗
PubMed1983

[Amplification of portions of the genome in the somatic cells of mammals resistant to colchicine. IV. Genetic transformation using amplified genes from Djungarian hamster cells highly resistant to colchicine].

DNA-mediated transfer of colchicine-resistance from Djungarian hamster DM5/7 cell line, 750-fold resistant to the drug, was studied. The resistance to colchicine of DM5/7 cells is due to amplification of the genes, possibly coding for the polypeptide p22. Both high-molecular weight DNA (presumably, chromosomal DNA) and low-molecular weight DNA (presumably, extrachromosomal DNA) effectively transferred the colchicine-resistance to Djungarian hamster and mouse cells. DNA of sensitive to colchicine but resistant to ouabain mouse cells CAK-143OuaR was not capable to transfer colchicine-resistance, but effectively transferred ouabain-resistance connected with a mutation in Na+/K+-dependent ATP-ase locus. The differences in genetic transformation with amplified p22 genes and mutant Na+/K+-dependent ATP-ase genes were revealed. All cells of 3 colchicine-resistant transformants of DM-15 cells and all 10 spontaneously derived resistant clones contain the additional chromosome 4. The role of trisomy 4 in the development of colchicine-resistance in DM-15 cells is discussed.

Animals↗
PubMed1982

Isolation of recombinants doubly and triply drug-resistant to streptomycin, tetracycline and chloramphenicol by PEG-induced cell fusion of singly resistant staphylococcus aureus L-forms.

Various combinations of four substrains of Staphylococcus aureus L-form (strain STA-EMT-1), each of which was resistant to one of the following four drugs, streptomycin (SM), tetracycline (TC), chloramphenicol (CP) and erythromycin (EM), were submitted to polyethylene glycol (PEG)-induced cell fusion. PEG-induced cell fusion followed by enrichment culture in the liquid basal medium supplemented with penicillin G resulted in development of recombinants that were doubly drug-resistant to SM and TC, SM and CP, and TC and CP, but no recombinant doubly resistant to EM and TC, was obtained by treatment of a EM-resistant and TC-resistant substrains with PEG. No recombinants resistant to SM, CP and TC could be obtained by treatment of substrains resistant to SM, CP and TC, respectively, with PEG. But recombinants triply resistant to these three drugs were produced by two-step cell fusion; that is by fusion of a recombinant doubly resistant to two of the three drugs with a substrain resistant to the third drug.

Chloramphenicol↗
PubMed1995

Expression of multidrug resistance-associated protein in NIH/3T3 cells confers multidrug resistance associated with increased drug efflux and altered intracellular drug distribution.

Multidrug resistance is a major obstacle to cancer treatment. Using an expression cDNA library transfer approach to elucidating the molecular basis of non-P-glycoprotein-mediated multidrug resistance, we previously established that expression of multidrug resistance protein (MRP), an ATP-binding cassette superfamily transporter, confers multidrug resistance (G. D. Kruh et al., Cancer Res., 54: 1649-1652, 1994). In the present study, we generated NIH/3T3 MRP transfectants without using chemotherapeutic drugs to facilitate the pharmacological analysis of the MRP phenotype. MRP transfectants displayed increased resistance to several lipophilic drugs, including doxorubicin, daunorubicin, etoposide, actinomycin D, vincristine, and vinblastine. However, increased resistance was not observed for Taxol, a drug for which transfection of MDR1 confers high levels of resistance. Verapamil increased the sensitivity of MRP transfectants relative to control transfectants, but reversal was incomplete for doxorubicin and etoposide, the drugs for which MRP conferred the highest resistance levels. For the latter two drugs, MRP transfectants, which were approximately 8- and approximately 10-fold more sensitive than control cells in the absence of verapamil, exhibited 3.8- and 3.3-fold relative sensitization with 10 microM verapamil, respectively, but remained approximately 2 and approximately 3-fold more resistant than control cells. Analysis of drug kinetics using radiolabeled daunorubicin revealed decreased accumulation and increased efflux in MRP transfectants. Confocal microscopic analysis of intracellular daunorubicin in MRP transfectants was consistent with reduced intracellular drug concentrations, and also revealed an altered pattern of intracellular drug distribution characterized by the initial accumulation of drug in a perinuclear location, followed by the development of a punctate pattern of drug scattered throughout the cytoplasm. This pattern was suggestive of a process of drug sequestration, possibly followed by vesicle transport. Both increased drug efflux and perinuclear drug accumulation are consistent with the reported localization of MRP in plasma and cytosolic membranes (N. Krishnamachary and M. S. Center, Cancer Res., 53: 3658-3663, 1993; M. J. Flens et al., Cancer Res., 54: 4557-4563, 1994). These results thus indicate that the drug specificity of MRP is quite similar to that of MDR1, but also suggest potential differences in Taxol specificity and the level of verapamil sensitivity. In addition, these results indicate that MRP functions to extrude drug from the cell, but additionally suggest the intriguing possibility that drug sequestration contributes to drug resistance by protecting cellular targets and/or contributing to drug efflux.

3T3 Cells↗
PubMed1994

Overexpression of the multidrug resistance-associated protein (MRP) gene in vincristine but not doxorubicin-selected multidrug-resistant murine erythroleukemia cells.

Multidrug-resistant sublines of the murine erythroleukemia cell line PC4 were sequentially selected in increasing vincristine concentrations (5-160 ng/ml). The low- and intermediate-level resistant cell lines, selected in < or = 40 ng/ml of vincristine, demonstrated resistance to Vinca alkaloids and to an epipodophyllotoxin but little or none to an anthracycline. The expression of murine mdr genes, as analyzed by Northern blotting, revealed a baseline expression of murine mdr2 in parental cells that was unchanged in the drug-resistant cell lines. Overexpression of mdr3 was observed only in the highest-level resistant cell line, PC-V160, whereas mdr1 mRNA was not detected in any of the cell lines. The polymerase chain reaction, using mdr3-specific primers, excluded the possibility that low levels of P-glycoprotein expression contributed to the resistance phenotype in the low and intermediate-level resistant cell lines. Northern blot analysis using a human complementary DNA probe for the multidrug resistance-associated protein (MRP) demonstrated overexpression of murine mrp in each of the vincristine-selected sublines. Genomic amplification of the mrp gene was coincident with mrp overexpression. The expression of mrp was also examined in two series of previously characterized doxorubicin-selected cell lines derived from parental PC4 and C7D murine erythroleukemia cells. In contrast to the vincristine-selected cell lines, overexpression of mrp was not detected. These studies demonstrate that, in murine erythroleukemia cells selected for vincristine resistance, overexpression of murine mrp occurred prior to that for murine mdr. In contrast to human MRP, selection for vincristine, but not doxorubicin resistance, resulted in the overexpression of murine mrp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Brefeldin A sensitivity and resistance in Schizosaccharomyces pombe. Isolation of multiple genes conferring resistance.

The fungal metabolite brefeldin A (BFA) causes the inhibition of protein secretion and the disruption of the structure and function of the Golgi complex in mammalian cells. Here we show that BFA has identical effects in the fission yeast Schizosaccharomyces pombe which normally contains a Golgi complex of stacked cisternae similar to the Golgi complexes in animal cells. After treatment with BFA, secretion was inhibited, Golgi complexes disappeared, and there was an accumulation of endoplasmic reticulum. These results indicate that the effects of BFA in fungi are very similar to those in mammalian cells and provide direct evidence for an effect of BFA on Golgi morphology in fungi. Five spontaneous BFA-resistant mutants were isolated. Genetic analysis showed that the mutations conferring BFA resistance were dominant and in two separate linkage groups. One of the BFA-resistant mutations was found to be allelic to crm1, a gene affecting chromatin structure. All BFA-resistant mutants overexpressed a 20-kDa protein, and the corresponding gene obr1 was isolated and sequenced. However, obr1 overexpression was not sufficient to confer BFA resistance. Plasmids capable of conferring BFA resistance to wild type cells were isolated from libraries constructed from the two BFA-resistant mutants. These plasmids contain six different genes capable of conferring resistance when present in high copy. One of these genes encoded the transcription factor pap1, a homolog of the mammalian AP1 protein. The overexpression of pap1 probably confers BFA resistance indirectly by inducing expression of one or more other proteins. The isolation of several genes conferring BFA resistance suggests several mechanisms are involved.

Amino Acid Sequence↗
PubMed1994

[Bacterial resistance to antibiotics in the Czech Republic. The Working Group for Monitoring Resistance in the Czech Republic].

In 1991 the authors made an investigation on the resistance of clinically important bacteria. Seventeen antibiotic centres in the Czech Republic participated in the investigation. The resistance to antibiotics of 32,567 strains of twelve bacterial species isolated from hospitalized patients depends on 1. the type of bacteria and antibiotics, 2. the source (specimen of pathological material) and 3. the locality (hospital). The resistance of Staphylococcus aureus to oxacillin with the exception of one hospital is not more than 6%, in rare instances also resistance to vancomycin was encountered. The frequency of resistance of gram-negative rods to so-called reserve antibiotics (cephalosporins of the third generation, quinolones and amikacin) depends markedly on the type of bacteria, being highest in typical causal agents of hospital infections--Enterobacter cloacae, Serratia marcescens, Providencia rettgeri and Pseudomonas aeruginosa. With the exception of cephalosporins the resistance of gram-negative rods and Pseudomonas aeruginosa isolated from urine is much greater than in strains from other clinical materials. The frequency of resistance in faculty hospitals which concentrate patients with more serious diseases is high, the highest resistance was, however, recorded in the North Bohemian area--in pneumococci against penicillin (13%) and in haemophili against ampicillin (17%). Every hospital is a closed ecological niche with a typical bacterial population and resistance rate. A competent estimate of an adequate and probably effective antibiotic for immediate initiation of treatment of an urgent infection can thus be made only by somebody with close and steady knowledge of the state of resistance in a given hospital.

Bacteria↗
PubMed1996

[Incidence of resistance and risk factors for resistance in Mycobacterium tuberculosis. A retrospective study of 1,055 patients of a specialty hospital 1984 to 1993].

For the past decade, there have been no data on the time course of drug-resistant tuberculosis and on risk factors for drug resistance in former West Germany. We reviewed the medical records of all patients with positive cultures for Mycobacterium tuberculosis from 1984 until 1993 in a hospital near Hamburg. Drug-susceptibility testing was performed for isoniazid, rifampicin, ethambutol, and streptomycin, using the modified proportion method. Of 1,055 patient, 9.6% had isolates resistant to one or more drugs. Of the isolates, 5.8% showed resistance to isoniazid or rifampicin and 1.8% to both isoniazid and rifampicin. There was no significant change of the resistance rate during the study period. Twenty six percent of 89 patients from South America, Africa or Asia had isolates resistant to one or more drugs, compared with 7.6% of 799 patients born in Germany (odds ratio (OR) 4.2; 95% confidence interval (95% CI) 2.5-7.3). Among patients born in Germany, 32% of 101 patients with a history of prior antituberculosis drug therapy had resistant organisms, versus 4.2% of 698 patients without prior therapy (OR 10.7; 95% CI 6.1-18.7). Resistance orates for 35 patients, who had been treated within the last 5 yrs, and for 65 patients, who had been treated more than 5 yrs ago, were 57 and 17%, respectively (OR 6.6; 95% CI 2.9-16.6). Our results suggest that there is no increase in the proportion of drug-resistant tuberculosis in our hospital, and that patients with a recent history of antituberculosis drug therapy and patients from South America, Africa, or Asia are at high risk for drug resistance.

Adult↗
PubMedDate not supplied

Concomitant decrease of resistance and modifications of the cytoskeleton after all-trans retinoic acid and phorbol ester treatments in a navelbine-resistant bladder carcinoma cell line.

The bladder carcinoma cell line J82-NVB was selected for resistance to the new vinca alkaloid Navelbine. These cells possessed a non-MDR phenotype and were cross-resistant to vinca alkaloids and taxoids. Some morphological differences between sensitive (J82) and resistant (J82-NVB) cells were observed J82 cells had a heterogeneous population morphology with both epithelial and spindle shaped cells, while J82-NVB cells were almost all of the epithelial type. Vimentin intermediate filaments were less organized in J82-NVB than in J82 cells. Moreover, desmosomes were present in the membranes of J82NVB cells but not in J82 cells. These findings suggest that J82 cells are poorly differentiated epithelial cells while J82-NVB cells possess some characteristics of a more differentiated epithelial cell line. After a two-week treatment with all-trans retinoic acid, all the cells became spindle shaped, vimentin filaments reappeared in the cytoplasm of J82-NVB cells and desmosomes disappeared from the membranes of these cells. These changes were accompanied by a decrease from 17 to 4.6 of the resistance factor of J82-NVB cells to Navelbine. This decrease in resistance was concomitant with modifications of microtubules assembly regulation mechanisms. After Navelbine treatment, microtubule reassembly occurred in resistant but not in sensitive nor in retinoic acid treated cells. Okadaic acid, a protein phosphatase inhibitor, inhibited microtubule reassembly in resistant cells, and 2-aminopurine, a protein kinase inhibitor, induced microtubule reassembly in sensitive cells after Navelbine treatment. These findings show that microtubule reassembly after depolymerization is regulated by the kinase/phosphatase systems. A treatment with phorbol myristate acetate (PMA), a protein kinase C (PKC) agonist, induced the same morphological modifications and resistance decrease as retinoic acid treatment. A specific PKC inhibitor (Bisindolymaleimide) prevented these PMA-induced morphological modifications and resistance decrease in J82-NVB cells, showing that these effects were mediated by PKC. This study suggests that, in part by acting on some properties of the cytoskeleton, the differentiation modulator, retinoic acid, and the signal transduction modulator, phorbol myristate acetate, can decrease the resistance of J82-NVB cells to microtubule poisons.

2-Aminopurine↗
PubMed1996

PAK-104P, a pyridine analogue, reverses paclitaxel and doxorubicin resistance in cell lines and nude mice bearing xenografts that overexpress the multidrug resistance protein.

Multidrug resistance (MDR) is considered multifactorial and has been associated with overexpression of the multidrug resistance protein (MRP). However, effective compounds for reversal of MRP-related MDR are limited. In the present study, the modulatory activity of the novel pyridine analogue PAK-104P on MRP-mediated resistance to doxorubicin and paclitaxel was investigated in two doxorubicin-selected human tumor cell lines [HT1080/DR4 (sarcoma) and HL60/ADR (leukemia)] and compared with the nonimmunosuppressive cyclosporine analogue PSC-833. In cell lines HT1080/DR4 (MRP/lung resistance-related protein phenotype) and HL60/ADR (MRP phenotype), doxorubicin resistance was significantly higher (250-fold and 180-fold, respectively) than that to paclitaxel (6-fold and 9-fold, respectively). With noncytotoxic concentrations of PAK-104P (1 and 5 microM), the reversal of doxorubicin resistance was significant but partial in HT1080/DR4 and HL60/ADR cells (dose-modifying factor for 5.0 microM PAK-104P, 25.0 and 31.2, respectively), whereas complete reversal of paclitaxel resistance was achieved in HL60/ADR cells. In contrast, PSC-833 modulation of doxorubicin and paclitaxel resistance was modest. Cellular drug uptake and retention studies by flow cytometry analysis demonstrated that PAK-104P was effective in restoring cellular doxorubicin concentrations in resistant cells to levels comparable to those obtained in parental cells. In athymic nude mice, PAK-104P significantly potentiated the therapeutic efficacy of doxorubicin and paclitaxel against resistant HT1080/DR4 xenografts. Of significance is that the maximum tolerated doses of doxorubicin and paclitaxel were administered in combination with PAK-104P, documenting improvement in the therapeutic index of these agents. In addition to reversing P-glycoprotein-mediated MDR, the pyridine analogue PAK-104P provides an example of an effective in vivo modulator of MRP-mediated MDR.

ATP-Binding Cassette Transporters↗
PubMed1990

Detection of borderline oxacillin-resistant Staphylococcus aureus and differentiation from methicillin-resistant strains.

Eighty-eight Staphylococcus aureus clinical isolates meeting criteria for borderline oxacillin resistance (intermediate susceptibility or resistance to oxacillin but susceptibility to amoxicillin/clavulanic acid upon disk diffusion testing) were studied to determine optimal test techniques and conditions for differentiating borderline oxacillin-resistant Staphylococcus aureus (BORSA) from methicillin-resistant Staphylococcus aureus (MRSA). Further testing revealed three distinct resistance patterns: 61 strains (69%) consistently met BORSA criteria and had average beta-lactamase levels five- to six-fold higher than oxacillin-susceptible controls; 11 strains (13%) were markedly heteroresistant MRSA with delayed appearance of resistant colonies leading to spurious susceptibility to amoxicillin/clavulanic acid; 16 strains (18%) appeared to be oxacillin-susceptible on repetitive testing. Under conditions used to elicit intrinsic methicillin resistance in Staphylococcus aureus, a large percentage of BORSA appeared resistant to amoxicillin/clavulanic acid. This clearly shows that BORSA may be misidentified as MRSA while heteroresistant MRSA may appear to be BORSA. It is concluded that amoxicillin/clavulanic acid zone sizes should be measured after a full 24 hours of incubation, that susceptibility testing of Staphylococcus aureus under certain environmental conditions should be interpreted with caution, and that MIC testing is the most reliable technique for differentiating these two resistance patterns in Staphylococcus aureus.

Amoxicillin↗
PubMed1998

Antimicrobial resistance in staphylococci and enterococci in 10 Portuguese hospitals in 1996 and 1997. POSGAR. Portuguese Study Group of Antimicrobial Resistance.

During a 2-year period, 10 Portuguese hospitals located throughout the country studied antimicrobial susceptibilities of clinically relevant staphylococci and enterococci. Of more than 12,000 Staphylococcus aureus isolates tested, two main patterns were found, methicillin-sensitive organisms most of them resistant only to penicillin but a few to other antimicrobials and methicillin-resistant S. aureus (MRSA) strains (prevalence 48.2%) resistant to most of the antimicrobials tested and uniformly susceptible to vancomycin. Among coagulase-negative staphylococci (CNS), 71% of S. epidermidis (approximately 5,000 isolates tested) and 84% S. haemolyticus (approximately 1,000 isolates tested) were also resistant to methicillin as well as most other antimicrobials except vancomycin. Most of the 5,000 Enterococcus faecalis isolates tested were susceptible to ampicillin and vancomycin, in contrast to 650 E. faecium isolates, 70% of which were resistant to ampicillin and 20% to vancomycin and all other antibiotics. A high prevalence of aminoglycoside resistance occurred in both Enterococcus species. This survey showed that resistance profiles of staphylococci and enterococci hospital isolates have not changed in the last 5 years in Portugal, with the exception of the rise in vancomycin resistance in E. faecium. The high prevalence of methicillin resistance in S. aureus and in the CNS remains an issue of medical concern.

Anti-Bacterial Agents↗
PubMed2025

Evolutionary engineering and molecular characterization of an antimycin A-resistant Saccharomyces cerevisiae strain: the key role of pleiotropic drug resistance (PDR1).

Antimycin A, an antifungal agent that inhibits mitochondrial respiration, provides a useful model for studying resistance mechanisms. Antifungal resistance is an escalating clinical concern with limited treatment options available. To understand the molecular mechanisms of antimycin A resistance, a genetically stable, antimycin A-resistant Saccharomyces cerevisiae strain was successfully developed for the first time through an evolutionary engineering strategy, based on long-term systematic application of gradually increasing antimycin A stress in repetitive batch cultures without prior chemical mutagenesis. Comparative whole genome resequencing analysis of the evolved strain ant905-9 revealed two missense mutations in PDR1 and PRP8 genes involved in pleiotropic drug resistance and RNA splicing, respectively. Using CRISPR/Cas9 genome editing tools, the identified mutations were introduced individually and together into the reference strain, and it was confirmed that the Pdr1p.M732R mutation alone confers antimycin A-resistance in S. cerevisiae. Comparative transcriptomic analysis of the reverse-engineered Pdr1p.M732R strain showed alterations in PDR (pleiotropic drug resistance), transmembrane transport, vesicular trafficking, and autophagy pathways. Our results highlight the potential key role of PDR1 in antifungal drug resistance. This study provides new insights into mitochondrial drug resistance and the adaptive potential of yeast under respiratory stress.

Saccharomyces cerevisiae↗
PubMed2000

Molecular evolution in a multidrug-resistant lineage of Streptococcus pneumoniae: emergence of strains belonging to the serotype 6B Icelandic clone that lost antibiotic resistance traits.

Since their first detection in 1988, penicillin-resistant Streptococcus pneumoniae isolates have rapidly spread in Iceland to account for close to 20% of all pneumococcal disease in that country by 1993. The major component (70%) of the resistant pneumococci identified from 1989 to 1992 was the progeny of a single multidrug-resistant clone (Icelandic clone) with a homogeneous chromosomal macrorestriction profile and identical multilocus enzyme type expressing serotype 6B and resistance to penicillin, tetracycline, chloramphenicol, erythromycin, and trimethoprim-sulfamethoxazole. The rest of the non-penicillin-susceptible isolates included bacteria with serotype 6A and serogroups 19 and 23. The unique geographic and epidemiological setting and the availability of a complete collection of all non-penicillin-susceptible isolates of S. pneumoniae in Iceland prompted us to carry out a molecular epidemiological study to monitor the fate of the Icelandic clone between 1989 and 1996; in addition, we wished to extend the characterization to representative groups of all non-penicillin-susceptible serotype 6B pneumococci which showed variations in antibiotype and which were recovered in Iceland between late 1989 and the end of 1996. Also included in the study were non-penicillin-susceptible isolates of serogroup 23. Pulsed-field gel electrophoresis of SmaI-restricted chromosomal DNA and Southern hybridization with the lytA DNA probe and probes specific for antibiotic resistance genes were used to characterize pneumococcal isolates. The results show that (i) the Icelandic clone remained the predominant type among penicillin-resistant S. pneumoniae through 1996; (ii) the emergence of variants of the Icelandic clone which had lost one or more of the antibiotic resistance phenotypes and/or resistant genes, singly or in combination, was documented during the surveillance period; and (iii) isolates belonging to the internationally spread multidrug-resistant serotype 23F clone were present in the Icelandic collection since late 1989 but did not increase in number during the subsequent years.

Adult↗
PubMed1988

Ampicillin, tetracycline, and chloramphenicol resistant Haemophilus influenzae in adults with chronic lung disease. Relationship of resistance to prior antimicrobial therapy.

Antibiotic resistance in 1,003 sputum isolates of Haemophilus influenzae from adults with chronic lung disease was assessed from January 1983 through June 1986. The incidence of resistance was 3.2% for tetracycline, 0.6% for chloramphenicol, and 12.5% for ampicillin. Resistance to ampicillin or tetracycline usually occurred alone, while 100% of chloramphenicol resistant isolates were co-resistant to tetracycline or ampicillin. More than 90% of antibiotic resistant isolates were nontypable and belonged to biotypes II, III, or V. Chart reviews of 331 patients revealed that patients with ampicillin resistant isolates were more likely than control subjects to have received ampicillin in the prior 6 wk (33% versus 6%, p less than 0.0001), whereas patients with isolates resistant to tetracycline or chloramphenicol plus tetracycline were more likely to have received tetracycline than control subjects (24% and 50%, respectively, versus 5%, p less than 0.005). The incidence of ampicillin resistance and the reluctance of physicians caring for adults to use chloramphenicol suggests that a newer cephalosporin such as cefotaxime may be the initial therapy of choice for severe H. influenzae disease in our patient population.

Adult↗