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PubMed2004

Investigation of negative cross-resistance as a resistance-management tool for insecticide-treated nets.

Resistance management for insecticide-treated nets (ITNs) remains a challenge. Options are limited, because a safe and highly active insecticide with a persistence of several months is required. These criteria have only been met by pyrethroids, although organophosphates (OPs) and carbamates have been considered as alternatives for impregnation of eave curtains. It has been observed that some pyrethroid-resistant mosquito strains show increased OP susceptibility over pyrethroid-susceptible strains (i.e., negative cross-resistance). The current study investigated whether this phenomenon applies to a range of mosquito species and strains, because a mixture or rotation strategy for resistance management could then be envisaged. Adult female mosquitoes from laboratory strains of Anopheles stephensi Liston, Anopheles gambiae Giles, and Culex quinquefasciatus Say were tested in World Health Organization susceptibility test kits. For An. stephensi, the highly pyrethroid-resistant DUB 234 strain showed the same level of resistance to malathion as the pyrethroid-susceptible DUB S. The malathion-resistant ST MAL strain was as susceptible to pyrethroids as the insecticide-susceptible BEECH. For An. gambiae, the malathion tolerance of the previously pyrethroid-resistant RSP strain was significantly higher than that of the insecticide-susceptible KWA. For Cx. quinquefasciatus, selection of the QUINQ strain with permethrin abolished preexisting resistance to the OP malathion as pyrethroid resistance increased, rendering the strain more susceptible to malathion than PEL SS. Some indication of negative cross-resistance to malathion was found for the permethrin-resistant MUHEZA strain. The occurrence of negative cross-resistance seems dependent on the history of insecticide selection and is not generally applicable. Resistance management for ITNs will need to use mechanisms other than negative cross-resistance to be effective.

Animals↗
PubMed2004

Determination of antibiotic resistance and resistance plasmids of clinical Enterococcus species.

To determine the antibiotic resistance pattern and resistance plasmids, we studied 23 antibiotic-resistant clinical isolates of Enterococcus spp. which caused infection in Bayindir-Ankara Hospital, Turkey. Biochemical and physiological identification tests were applied by the Vitek system and compared with the results of protein profiles by SDS-PAGE. From 23 isolates, 20 were identified as E. faecalis, 2 as E. faecium and 1 as E. gallinarum. Twenty four antibiotics belong to 10 different groups were used in susceptibility tests. Multiple antibiotic resistance was determined in 10 of 23 Enterococcus spp. Overall resistance to the used antibiotics was 47.3% and low level resistance was 16.6%. Among the isolates tested, 8.7% demonstrated high level gentamicin resistance, 17.4% demonstrated high level streptomycin resistance, and 43.5% demonstrated penicillin resistance. High level vancomycin resistant Enterococcus spp. rate was 34.8%, and 60.9% exhibited low level resistance to vancomycin and teicoplanin. They contain plasmids which varied in numbers between 1 and 11 and the plasmid sizes ranged from 2.08 to 56.15 kb. In curing experiments with acriflavine, two different plasmids were shown in different molecular sizes of 33.49 and 13.6 kb while the first determined glycopeptide and penicillin resistance, the second one determined either glycopeptide or penicillin resistance in two different E. faecalis strains. On the other hand, a 22.58 kb plasmid, determining kanamycin resistance, was detected in an E. faecium strain. After the curing experiments, an elimination of 37.17 and 44.47 kDa protein bands was shown in E. faecium EFA1 and E. faecalis EFA13 in SDS-PAGE, respectively. This survey indicates the increase of antibiotic-resistant enterococci, especially to vancomycin in our hospital isolates.

Anti-Bacterial Agents↗
PubMed1999

Discovery of differentially expressed genes associated with paclitaxel resistance using cDNA array technology: analysis of interleukin (IL) 6, IL-8, and monocyte chemotactic protein 1 in the paclitaxel-resistant phenotype.

In an attempt to define the molecular changes associated with the paclitaxel-resistant phenotype in human cancer, a paclitaxel-resistant ovarian cancer cell line, SKOV-3TR, was established through stepwise selection in increasing paclitaxel concentrations. SKOV-3TR was cross- resistant to doxorubicin and vincristine and overexpressed multidrug resistance gene 1 but not multidrug resistance associated protein. SKOV-3TR and the paclitaxel-sensitive SKOV-3 parent line were characterized using human cDNA array technology that examined expression of a wide variety of genes involved in cell growth, signal transduction, cell death, and immune function. cDNA probes from reverse transcribed mRNAs of both paclitaxel-resistant and parent cells were compared to identify genes differentially expressed in the paclitaxel-resistant cells. Of 588 different human cDNA transcripts compared, 6 genes were found to be markedly decreased, and 12 genes increased in the resistant subline. Northern analysis and/or reverse transcription-PCR confirmed that 12 of these 18 genes were over- or underexpressed in SKOV-3TR. In addition, at least eight of the genes were found differentially expressed in several other paclitaxel- and/or doxorubicin-resistant cell lines, both those with increased multidrug resistance expression and those without. Included in the set of overexpressed genes were the cytokines/chemokines interleukin 6, interleukin 8, and monocyte chemotactic protein 1. ELISA assays confirm that mRNA overexpression of these cytokine/chemokines was associated with the increased secretion of these molecules in the tissue culture supernatant. Evaluation of supernatants from an expanded collection of paclitaxel- and Adriamycin-resistant cell lines demonstrated that all of the resistant lines had significant overexpression of at least one cytokine/chemokine as compared with their drug-sensitive parent line. The overexpression of these cytokines seemed to be stable and associated with a drug-resistant phenotype with only a modest induction of cytokine expression in the parent line with short-term paclitaxel exposure. These findings suggest that the development of paclitaxel resistance is accompanied by multiple changes in gene expression including stable alterations in selective chemokine and cytokine expression. The role these associated genetic changes have in the drug-resistant phenotype is discussed.

Breast Neoplasms↗
PubMed2004

[Establishment of 5 resistant ovarian cancer cell strains and expression of resistance-related genes].

OBJECTIVE: To investigate expression difference of several drug resistance related genes between sensitive and resistant ovarian carcinoma cells. METHODS: Cell lines resistant to cisplatin, carboplatin and taxol were established from ovarian carcinoma cell lines of SKOV3 and A2780, and their biological features were detected. The expressions of several genes related to drug resistance were measured by RT-PCR method. RESULTS: (1) The values of resistance index (RI) of resistant cells to relevant drugs were elevated 3 times or more, with different degrees of cross-resistance to several other drugs (RI 2 approximately 20). They grew more slowly than primary cells (Td elongated 1.4 approximately 2.4 times, P < 0.01) without obvious changes in G(1), G(2), and S ratios (P > 0.05). Intracellular concentrations of relevant drugs were reduced 2.0 approximately 8.5 times in resistant cells (P < 0.05). (2) p53, lung resistance protein-1 (LRP-1), multiple drug resistance related protein-1 (MRP-1) genes were expressed at lower levels in resistant cells than in sensitive cells; while protein kinase C (PKC), topoisomerase (topo) I, and topo II beta were expressed higher, no obvious alterations were found concerning glutathione S transferase-pi (GST-pi), and topo II alpha. Expression of multiple drug resistance-1 (MDR-1) gene was either elevated or reduced in different cells. CONCLUSIONS: The expressions of resistance related genes were widely different in different kinds of resistant cells, suggesting more than one pathway leading to resistance transformation. This adds more difficulties for clinical management.

Carboplatin↗
PubMed1985

[Antitumor drug resistance and therapeutic approaches to reverse resistance].

Acquired multidrug resistance as well as innate drug resistance are directly related to ineffectiveness and failure of the cancer chemotherapy. The mechanisms of such resistance, especially those of innate resistance, have not been fully elucidated. Drug resistant tumor cells, however, usually bear biochemical changes which are related to resistance mechanisms. New modalities with high selectivity against resistant cells could, therefore, be possible if we could target these biochemical changes. Vincristine (VCR)-and adriamycin (ADM)-resistant tumor cells (pleiotropic drug resistant cells) usually show an enhanced outward transport of these antitumor agents, and they express unique glycoproteins in the plasma membrane. By targeting for these biochemical changes characteristic to the resistant tumor cells, we establish new modality which shows high selectivity against drug resistant tumor cells. In this review, I will describe genetic origin of drug resistance, biochemical mechanisms of drug resistance and reversal of drug resistance in tumor cells. The modality to utilize calcium channel blockers which inhibit the enhanced outward transport of VCR and ADM from resistant tumor cells will be reviewed.

Antineoplastic Agents↗
PubMed1996

Physicochemical properties correlated with drug resistance and the reversal of drug resistance in Plasmodium falciparum.

At high molar excess, verapamil can selectively increase the accumulation and cytotoxicity of structurally dissimilar natural product drugs in many multidrug-resistant tumor cell lines. Such concentrations of verapamil are also capable of increasing the accumulation and activity of chloroquine in chloroquine-resistant strains of the human malaria parasite Plasmodium falciparum. Despite such similarities, it is not clear why chloroquine-resistant P. falciparum is often susceptible to closely related compounds such as amodiaquine, whereas cancer cells are cross-resistant to many structurally unrelated drugs. For 13 aminoquinoline and aminoacridine compounds, relative drug resistance was negatively correlated with lipid solubility at physiological pH (r2 = 0.90, p < 0.0001). The ability of verapamil (5 microM) to reverse drug resistance was also negatively correlated with lipid solubility (r2 = 0.88, p < 0.0001). Furthermore, molar refractivity was weakly correlated with relative drug resistance (r2 = 0.46, p < 0.05) and reversal of drug resistance (r2 = 0.52, p < 0.005). Verapamil increases chloroquine accumulation by resistant parasites, a mechanism suggested to account for its selective chemosensitization effect. We show that the initial rate of chloroquine accumulation by resistant parasites is increased by verapamil. This effect of verapamil is abolished when deoxy-glucose is substituted for glucose. Therefore, verapamil produces an energy-dependent increase in the permeability of resistant parasites to chloroquine. For a panel of four chloroquine-resistant and two chloroquine-susceptible isolates, the effect of verapamil on the accumulation of chloroquine and monodesethyl amodiaquine was found to be correlated (r2 = 0.96, p < 0.001). Verapamil chemosensitization was also correlated for the two drugs (r2 = 0.92, p < 0.005), suggesting a common mechanism. In summary, the degree of drug resistance and the extent of verapamil chemosensitization for a particular drug seem to be dependent on general physical features such as lipid solubility and molar refractivity rather than on closely defined structural parameters. These studies provide insight into this important resistance mechanism of malaria parasites and may provide direction for the development of new drugs that are effective against resistant parasites.

Animals↗
PubMed2001

Genetic analysis of methicillin-resistant Staphylococcus aureus expressing high- and low-level mupirocin resistance.

Clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) expressing high- and low-level mupirocin resistance were studied to determine the genetic location of mupirocin and other resistance determinants. Mupirocin resistance was confirmed by MIC determination with E-test strips. Curing and transfer experiments were used to establish the genetic location of the resistance determinants and the PCR with mupA-specific primers was used to detect the presence of mupA genes. High-level mupirocin-resistant isolates had MICs >1024 mg/L, whereas the low-level resistant isolates had MICs of 32-128 mg/L. The isolates carried plasmids ranging from 2.8 to 38 kb in size. All of them carried 26- and 3.0-kb plasmids, but only the high-level mupirocin-resistant isolates carried a 38-kb plasmid. Curing and transfer experiments revealed that the 26-kb plasmid encoded resistance to cadmium, mercuric chloride, propamidine isethionate and ethidium bromide and the 38-kb plasmid was a conjugative plasmid encoding high-level mupirocin resistance. One isolate, IBN287, carried both plasmid-borne high-level and chromosomal low-level mupirocin resistance. The mupA gene was detected on the 38-kb plasmid DNA but not in the genomic DNA of the low-level mupirocin-resistant isolates. The genomic DNA of strain IBN287 cured of the 38-kb mupirocin resistance plasmid did not contain mupA. The results suggest that different genes encoded low- and high-level mupirocin resistance in these isolates.

Anti-Bacterial Agents↗
PubMed2003

Dissection of resistance to soil-borne yellow-mosaic-inducing viruses of barley (BaMMV, BaYMV, BaYMV-2) in a complex breeders' cross by means of SSRs and simultaneous mapping of BaYMV/BaYMV-2 resistance of var. 'Chikurin Ibaraki 1'.

Ninety-three F(1)-derived doubled haploid (DH) lines from a complex breeders' cross involving the Japanese genotype 'Chikurin Ibaraki 1', which is resistant to barley mild mosaic virus (BaMMV) and two strains of barley yellow mosaic virus (BaYMV and BaYMV-2), three susceptible varieties ('Hamu', 'Julia' and a breeding line) and cv. 'Carola', which carries rym4 conferring resistance to BaMMV and BaYMV, were analysed for resistance to BaMMV, BaYMV and BaYMV-2. The DH lines fell into four phenotypic classes. In addition to completely resistant and susceptible genotypes, DHs were observed which were either resistant to BaMMV and BaYMV or to BaYMV and BaYMV-2. For BaMMV and BaYMV-2 resistance, segregation ratios approaching 1r:1s were observed, suggesting the presence of single resistance genes. In contrast, the segregation ratio for BaYMV fits a 3r:1s segregation ratio, suggesting the presence of two independently inherited genes. From the genetic analysis, we conclude that a resistance locus effective against BaYMV and BaYMV-2 originates from Chikurin Ibaraki 1 and segregates independently from the Carola-derived rym4 resistance that is effective against BaYMV and BaMMV. The BaMMV resistance in Chikurin Ibaraki 1 has probably been lost during population development. This hypothesis was tested using a simple-sequence repeat (SSR) marker (Bmac29) linked to rym4. All BaMMV-resistant DH lines supported amplification of the rym4-resistance diagnostic allele. To identify the genetic location of the Chikurin Ibaraki 1-derived resistance against BaYMV/BaYMV-2, bulked DNA samples were constructed from the four resistance classes, and bulked segregant analysis was performed using a genome-wide collection of SSRs. Differentiating alleles were observed at two linked SSRs on chromosome 5H. The location of this BaYMV/BaYMV-2 resistance locus was confirmed and further resolved by linkage analysis on the whole population using a total of five linked SSRs.

Genes, Plant↗
PubMed2005

Costly resistance to parasitism: evidence from simultaneous quantitative trait loci mapping for resistance and fitness in Tribolium castaneum.

Information on the molecular basis of resistance and the evolution of resistance is crucial to an understanding of the appearance, spread, and distribution of resistance genes and of the mechanisms of host adaptation in natural populations. One potential important genetic constraint for the evolution of resistance is fitness cost associated with resistance. To determine whether host resistance to parasite infection is associated with fitness costs, we conducted simultaneous quantitative trait loci (QTL) mapping of resistance to parasite infection and fitness traits using the red flour beetle (Tribolium castaneum) and the tapeworm parasite (Hymenolepis diminuta) system in two independent segregating populations. A genome-wide QTL scan using amplified fragment length polymorphism (AFLP) markers revealed three QTL for beetle resistance to tapeworm infection. These three QTL account for 44-58% variance in beetle infection intensity. We identified five QTL for fecundity and five QTL for egg-to-adult viability, which accounted for 36-57% and 36-49%, respectively, of the phenotypic variance in fecundity and egg-to-adult viability. The three QTL conferring resistance were colocalized with the QTL affecting beetle fitness. The genome regions that contain the QTL for parasite resistance explained the majority of the variance in fecundity and egg-to-adult viability in the mapping populations. Colocalization of QTL conferring resistance to parasite infection and beetle fitness may result from the pleiotropic effects of the resistance genes on host fitness or from tight linkages between resistance genes and adverse deleterious mutations. Therefore, our results provide evidence that the genome regions conferring resistance to tapeworm infection are partially responsible for fitness costs in the resistant beetle populations.

Animals↗
PubMed1997

Emergence of different mechanisms of resistance in the evolution of multidrug resistance in murine erythroleukemia cell lines.

We examined the genetic and biochemical bases for drug resistance and the order of appearance of different mechanisms underlying the increasingly more resistant murine erythroleukemia cell lines established in Adriamycin (ADR). In the first-step low-level resistant cell line PC4-A5 (able to grow in 5 ng/mL ADR), there was a 2-fold reduction in topoisomerase IIalpha and topoisomerase IIbeta mRNA levels, as well as topoisomerase IIalpha protein and activity levels as compared with the parental cell line. The topoisomerase IIalpha activity levels remained reduced as the cells became increasingly more resistant. In contrast, the topoisomerase II mRNA and protein levels returned to approximately the parental levels in resistant cells growing in higher drug concentrations (40-160 ng/mL). Parental cells expressed the multidrug resistance protein (MRP), but beginning with PC4-A5 MRP expression decreased and remained reduced in increasingly resistant cell lines. At high levels of ADR resistance, the cells expressed the mdr3 gene concomitant with the appearance of vincristine resistance and energy-dependent daunomycin and vincristine efflux. Glutathione levels, internal pH, and expression of the major vault protein (MVP) remained unchanged in all cell lines. Fluorescence microscopy revealed no alterations in daunomycin distribution or vesicle numbers between the parental and resistant cell lines. Different resistance mechanisms emerge sequentially as cells become more resistant to ADR; the mechanisms are retained during the development of multidrug resistance (MDR). In intermediate-level MDR cell lines (PC4-A10 and PC4-A20), resistance involves an as yet undetermined mechanism(s).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Heterogeneous expression of fusidic acid resistance in Staphylococcus aureus with plasmid or chromosomally encoded fusidic acid resistance genes.

Fusidic acid resistance expression in a methicillin susceptible Staphylococcus aureus strain (WBG1576), which carries fusidic acid resistance on plasmid pUB101, and a prevalent Western Australian methicillin-fusidic acid resistant strain (WBG8287) were compared. WBG8287 carries fusidic acid resistance on the chromosome and its plasmid content has no effect on the levels of this resistance. WBG1576 and WBG8287 exhibited similar heterogeneous populations in respect to fusidic acid resistance levels in population analyses. A high-level fusidic acid resistant mutant of WBG1576 (BE8) had alterations in Smal chromosomal profiles, but not in plasmid size or resistance expression. Mutations causing increased fusidic acid resistance in WBG1576 are chromosomally located. A high-level fusidic acid resistant mutant of WBG8287 (BE3) had no alterations in Smal chromosomal profiles, or plasmid content and resistances. Comparison of resistance levels to kanamycin and spectinomycin, between high-level resistant colonies of WBG8287 and WBG8287, indicate that mutations in the chromosomal gene fusA, which encodes elongation factor-G, are probably the cause of the increased resistance levels observed in these mutant strains.

Anti-Bacterial Agents↗
PubMedDate not supplied

Multiple antibiotic resistance in South African strains of Streptococcus pneumoniae: mechanism of resistance to beta-lactam antibiotics.

Multiply antibiotic-resistant strains of Streptococcus pneumoniae appeared in South Africa in 1977. In these organisms resistance to chloramphenicol is caused by an inducible, drug-inactivating enzyme; however, the basis for resistance to other antibiotics is unknown. Pneumococci with increased resistance to beta-lactam antibiotics do not produce beta-lactamases, a finding indicating the presence of intrinsic resistance to these drugs. One approach to the understanding of the mechanism of this resistance was to study the pattern of penicillin-binding proteins (PBPs) in the South African pneumococci. With the use of highly radioactive penicillin to label PBPs in vivo, it was found that the South African pneumococci have a PBP pattern that differs from that of the sensitive laboratory strain R6 in several respects. Differences include (1) a lack of PBPs la and lb; (2) the presence of a new, faster moving protein (lower molecular weight), named PBP lc; (3) an apparent decrease in the affinity of PBP 2a for [3H]penicillin; and (4) a lack of PBP 2b. Taking advantage of the fact that penicillin resistance is a property acquired in a stepwise process, a series of isogenic and progressively more resistant transformants was constructed. DNA from the resistant South African strain 8249 of S. pneumoniae was used as the donor in a series of transformations for which the recipients were either strain R6 or transformants of organisms with lower levels of resistance. In vivo labeling of the PBPs of these transformants revealed a gradual shift from a pattern similar to that of the sensitive strain (in the transformants of lower resistance) to a pattern resembling that of the highly resistant donor strain (in the transformants of higher resistance) as the level of penicillin resistance increased.

Anti-Bacterial Agents↗
PubMed2000

Expression of resistance to tetracyclines in strains of methicillin-resistant Staphylococcus aureus.

A diverse collection of methicillin-resistant Staphylococcus aureus (MRSA) isolates resistant to tetracycline was screened by PCR for the presence of the resistance determinants tetK, tetL, tetM or tetO. Twenty-four of 66 isolates had tetM alone, 21 had tetK alone and 21 had both tetK and tetM (tetKM). All isolates were tetL- and tetO-negative. MICs of tetracycline, doxycycline and minocycline were evaluated for all isolates with or without preincubation in the presence of subinhibitory concentrations of tetracycline or minocycline. All isolates with one or more tetracycline resistance determinants were resistant to tetracycline 8 mg/L without induction of resistance. Some MRSA isolates of each of these three genotypes showed an unexpected lack of resistance to tetracyclines when the disc diffusion or agar dilution method was applied to uninduced cells. Resistance to tetracycline and doxycycline was greater (two- to four-fold) in tetK cells preincubated with tetracycline (tetK MRSA isolates were susceptible to minocycline </=0.25 mg/L under all conditions tested). For isolates with tetM alone, preincubation with tetracycline or minocycline gave up to a four-fold increase in the level of resistance to doxycycline and minocycline. Induction of doxycycline and minocycline resistance was clearly observed for tetKM isolates when cells were preincubated with minocycline. This study suggests that, despite the results of susceptibility testing, all tetracycline-resistant S. aureus isolates should be treated as resistant to doxycycline, and all tetM-positive isolates should be treated as resistant to all tetracyclines. A double disc diffusion method has been developed to identify inducible resistance to minocycline and to distinguish between tetK, tetM and tetKM isolates.

Genes, Bacterial↗
PubMed2002

New trends in Staphylococcus aureus infections: glycopeptide resistance in hospital and methicillin resistance in the community.

PURPOSE OF REVIEW: Methicillin-resistant Staphylococcus aureus is prevalent in hospitals throughout the world, and we have got used to its presence in daily clinical practice. However, methicillin-resistant S. aureus has not remained static over the past four decades, but seems to be evolving in unfamiliar directions. This review focuses on recent findings on two directions of methicillin-resistant S. aureus evolution: the acquisition of multiple antibiotic resistance in the hospital and the trend towards methicillin-resistant S. aureus as a community pathogen. RECENT FINDINGS: We looked at reports on glycopeptide resistance in S. aureus and those on community-acquired methicillin-resistant S. aureus strains, with some references of historical value to explain the entire picture of this 'new field' of the methicillin-resistant S. aureus problem. SUMMARY: The references given here (excluding some of low credibility) attest the increasing awareness of the two conspicuous problems concerning methicillin-resistant S. aureus infection. One is the increasing trend of glycopeptide-resistance, making difficult the successful treatment of multi-drug-resistant methicillin-resistant S. aureus infection in the hospital. On the other hand, non-multi-drug-resistant methicillin-resistant S. aureus strains are emerging as novel threats in the community, the genetic analysis of which indicates that they are independent clones from those found in hospitals.

Anti-Bacterial Agents↗
PubMed1998

Patterns of resistance and cross-resistance to human immunodeficiency virus type 1 reverse transcriptase inhibitors in patients treated with the nonnucleoside reverse transcriptase inhibitor loviride.

Human immunodeficiency virus type 1 (HIV-1) strains resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) may easily be selected for in vitro and in vivo under a suboptimal therapy regimen. Although cross-resistance is extensive within this class of compounds, newer NNRTIs were reported to retain activity against laboratory strains containing defined resistance-associated mutations. We have characterized HIV-1 resistance to loviride and the extent of cross-resistance to nevirapine, delavirdine, efavirenz, HBY-097, and tivirapine in a set of 24 clinical samples from patients treated with long-term loviride monotherapy by using a recombinant virus assay. Genotypic changes associated with resistance were analyzed by population sequencing. Overall, phenotypic resistance to loviride ranged from 0.04 to 3.47 log10-fold. Resistance was observed in samples from patients who had discontinued loviride for up to 27 months. Cross-resistance to the other compounds was extensive; however, fold resistance to efavirenz was significantly lower than fold resistance to nevirapine. No genotypic changes were detected in three samples; these were sensitive to all of the NNRTIs tested. The most common genotypic change was the K103N substitution. The range of phenotypic resistance in samples containing the K103N substitution could not be predicted from a genotypic analysis of known NNRTI resistance-associated mutations. The Y181C substitution was detected in one isolate which was resistant to loviride and delavirdine but sensitive to efavirenz, HBY-097, and tivirapine. Our data indicate that the available newer NNRTIs which retain activity against some HIV-1 strains selected by other compounds of this class in vitro may have compromised clinical efficacy in some patients pretreated with NNRTI.

Acetamides↗
PubMed1999

Phenotypes and genotypes of erythromycin-resistant Streptococcus pyogenes strains in Italy and heterogeneity of inducibly resistant strains.

A total of 387 clinical strains of erythromycin-resistant (MIC, >/=1 microg/ml) Streptococcus pyogenes, all isolated in Italian laboratories from 1995 to 1998, were examined. By the erythromycin-clindamycin double-disk test, 203 (52.5%) strains were assigned to the recently described M phenotype, 120 (31.0%) were assigned to the inducible macrolide, lincosamide, and streptogramin B resistance (iMLS) phenotype, and 64 (16.5%) were assigned to the constitutive MLS resistance (cMLS) phenotype. The inducible character of the resistance of the iMLS strains was confirmed by comparing the clindamycin MICs determined under normal testing conditions and those determined after induction by pregrowth in 0.05 microg of erythromycin per ml. The MICs of erythromycin, clarithromycin, azithromycin, josamycin, spiramycin, and the ketolide HMR3004 were then determined and compared. Homogeneous susceptibility patterns were observed for the isolates of the cMLS phenotype (for all but one of the strains, HMR3004 MICs were 0.5 to 8 microg/ml and the MICs of the other drugs were >128 microg/ml) and those of the M phenotype (resistance only to the 14- and 15-membered macrolides was recorded, with MICs of 2 to 32 microg/ml). Conversely, heterogeneous susceptibility patterns were observed in the isolates of the iMLS phenotype, which were subdivided into three distinct subtypes designated iMLS-A, iMLS-B, and iMLS-C. The iMLS-A strains (n = 84) were highly resistant to the 14-, 15-, and 16-membered macrolides and demonstrated reduced susceptibility to low-level resistance to HMR3004. The iMLS-B strains (n = 12) were highly resistant to the 14- and 15-membered macrolides, susceptible to the 16-membered macrolides (but highly resistant to josamycin after induction), and susceptible to HMR3004 (but intermediate or resistant after induction). The iMLS-C strains (n = 24) had lower levels of resistance to the 14- and 15-membered macrolides (with erythromycin MICs increasing two to four times after induction), were susceptible to the 16-membered macrolides (but resistant to josamycin after induction), and remained susceptible to HMR3004, also after induction. The erythromycin resistance genes in 100 isolates of the different groups were investigated by PCR. All cMLS and iMLS-A isolates tested had the ermAM (ermB) gene, whereas all iMLS-B and iMLS-C isolates had the ermTR gene (neither methylase gene was found in isolates of other groups). The M isolates had only the macrolide efflux (mefA) gene, which was also found in variable proportions of cMLS, iMLS-A, iMLS-B, and iMLS-C isolates. The three iMLS subtypes were easily differentiated by a triple-disk test set up by adding a josamycin disk to the erythromycin and clindamycin disks of the conventional double-disk test. Tetracycline resistance was not detected in any isolate of the iMLS-A subtype, whereas it was observed in over 90% of both iMLS-B and iMLS-C isolates.

Anti-Bacterial Agents↗
PubMed2005

Herbicide-resistant crops and weed resistance to herbicides.

The adoption of genetically modified (GM) crops has increased dramatically during the last 3 years, and currently over 52 million hectares of GM crops are planted world-wide. Approximately 41 million hectares of GM crops planted are herbicide-resistant crops, which includes an estimated 33.3 million hectares of herbicide-resistant soybean. Herbicide-resistant maize, canola, cotton and soybean accounted for 77% of the GM crop hectares in 2001. However, sugarbeet, wheat, and as many as 14 other crops have transgenic herbicide-resistant cultivars that may be commercially available in the near future. There are many risks associated with the production of GM and herbicide-resistant crops, including problems with grain contamination, segregation and introgression of herbicide-resistant traits, marketplace acceptance and an increased reliance on herbicides for weed control. The latter issue is represented in the occurrence of weed population shifts, the evolution of herbicide-resistant weed populations and herbicide-resistant crops becoming volunteer weeds. Another issue is the ecological impact that simple weed management programs based on herbicide-resistant crops have on weed communities. Asiatic dayflower (Commelina cumminus L) common lambsquarters (Chenopodium album L) and wild buckwheat (Polygonum convolvulus L) are reported to be increasing in prominence in some agroecosystems due to the simple and significant selection pressure brought to bear by herbicide-resistant crops and the concomitant use of the herbicide. Finally, evolution of herbicide-resistant weed populations attributable to the herbicide-resistant crop/herbicide program has been observed. Examples of herbicide-resistant weeds include populations of horseweed (Conyza canadensis (L) Cronq) resistant to N-(phosphonomethyl)glycine (glyphosate). An important question is whether or not these problems represent significant economic issues for future agriculture.

Adaptation, Physiological↗
PubMed2005

Human multidrug resistance associated protein 4 confers resistance to camptothecins.

PURPOSE: The multidrug resistance associated protein (MRP) 4 is a member of the adenosine triphosphate (ATP)-binding cassette transporter family. Camptothecins (CPTs) have shown substantial anticancer activity against a broad spectrum of tumors by inhibiting DNA topoisomerase I, but tumor resistance is one of the major reasons for therapeutic failure. P-glycoprotein, breast cancer resistance protein, MRP1, and MRP2 have been implicated in resistance to various CPTs including CPT-11 (irinotecan), SN-38 (the active metabolite of CPT-11), and topotecan. In this study, we explored the resistance profiles and intracellular accumulation of a panel of CPTs including CPT, CPT-11, SN-38, rubitecan, and 10-hydroxy-CPT (10-OH-CPT) in HepG2 cells with stably overexpressed human MRP4. Other anticancer agents such as paclitaxel, cyclophosphamide, and carboplatin were also included. METHODS: HepG2 cells were transfected with an empty vehicle plasmid (V/HepG2) or human MRP4 (MRP4/HepG2). The resistance profiles of test drugs in exponentially growing V/HepG2 and MRP4/HepG2 cells were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay with 4 or 48 h exposure time of the test drug in the absence or presence of various MRP4 inhibitors. The accumulation of CPT-11, SN-38, and paclitaxel by V/HepG2 and MRP4/HepG2 cells was determined by validated high-performance liquid chromatography methods. RESULTS: Based on the resistance folds from the MTT assay with 48 h exposure time of the test drug, MRP4 conferred resistance to CPTs tested in the order 10-OH-CPT (14.21) > SN-38 carboxylate (9.70) > rubitecan (9.06) > SN-38 lactone (8.91) > CPT lactone (7.33) > CPT-11 lactone (5.64) > CPT carboxylate (4.30) > CPT-11 carboxylate (2.68). Overall, overexpression of MRP4 increased the IC50 values 1.78- to 14.21-fold for various CPTs in lactone or carboxylate form. The resistance of MRP4 to various CPTs tested was significantly reversed in the presence of dl-buthionine-(S,R)-sulfoximine (BSO, a gamma-glutamylcysteine synthetase inhibitor), MK571, celecoxib, or diclofenac (all MRP4 inhibitors). In addition, the accumulation of CPT-11 and SN-38 over 120 min in MRP4/HepG2 cells was significantly reduced compared to V/HepG2 cells, whereas the addition of celecoxib, MK571, or BSO significantly increased their accumulation in MRP4/HepG2 cells. There was no significant difference in the intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells, indicating that P-glycoprotein was not involved in the observed resistance to CPTs in this study. MRP4 also conferred resistance to cyclophosphamide and this was partially reversed by BSO. However, MRP4 did not increase resistance to paclitaxel, carboplatin, etoposide (VP-16), 5-fluorouracil, and cyclosporine. CONCLUSIONS: Human MRP4 rendered significant resistance to cyclophosphamide, CPT, CPT-11, SN-38, rubitecan, and 10-OH-CPT. CPT-11 and SN-38 are substrates for MRP4. Further studies are needed to explore the role of MRP4 in resistance, toxicity, and pharmacokinetics of CPTs and cyclophosphamide.

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