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PubMed1997

Cellular adaptation to drug exposure: evolution of the drug-resistant phenotype.

The efficacy of all chemotherapeutic agents is limited by the occurrence of drug resistance. For etoposide (VP-16), increased expression of MDR-1 or MRP and alterations in topoisomerase IIalpha have been shown to confer tolerance. To further understand resistance to VP-16, three sublines, designated MCF-7-VP17, ZR-75B-VP13, and MDA-MB-231-VP7, were initially isolated as single clones from parental cells by exposure to VP-16. Subsequently, a population of cells from each subline was exposed to 3-fold higher drug concentrations, allowing stable sublines to be established at higher extracellular drug concentrations. Characterization of the resistant sublines demonstrates the adaptation that occurs with advancing drug concentrations during in vitro selections. Reduced topoisomerase II mRNA and protein levels were observed in the initial isolates. This reduction was accompanied by a decrease in topoisomerase II activity and cellular growth rate and was associated with 6-314-fold resistance to topoisomerase II poisons. With advancing resistance, MRP expression increased and VP-16 accumulation decreased. This adaptation allowed for partial restoration of topoisomerase II activity as a result of increased expression (MCF-7-VP17 and ZR-75B-VP13) or hyperphosphorylation (MDA-MB-231-VP7), with a resultant increase in growth rate. In MDA-MB-231-VP7 cells, hyperphosphorylation coincided with increased casein kinase II mRNA and protein levels, suggesting a role for this kinase in the acquired hyperphosphorylation. In this cell line, hyperphosphorylation mediated the increased activity despite a fall in topoisomerase IIalpha protein levels secondary to an acquired 600-bp deletion in one topoisomerase IIalpha allele, which resulted in reduced protein levels. In all three sublines, high levels of resistance were attained as a result of synergism between the reduced topoisomerase IIalpha levels and MRP overexpression. These studies demonstrate how cellular adaptation to increasing drug pressure occurs and how more than one mechanism can contribute to the resistant phenotype when increasing selecting pressure is applied. Reduced expression of topoisomerase II is sufficient to confer substantial resistance early in the selection process, with synergy from MRP overexpression helping to confer high levels of resistance.

Antineoplastic Agents, Phytogenic↗

PubMed2002

Mode of amplification and reorganization of resistance genes during recent Arabidopsis thaliana evolution.

The NBS-LRR (nucleotide-binding site plus leucine-rich repeat) genes represent the major class of disease resistance genes in flowering plants and comprise 166 genes in the ecotype Col-0 of Arabidopsis thaliana. NBS-LRR genes are organized in single-gene loci, clusters, and superclusters. Phylogenetic analysis reveals nine monophyletic clades and a few phylogenetic orphans. Most clusters contain only genes from the same phylogenetic lineage, reflecting their origin from the exchange of sequence blocks as a result of intralocus recombination. Multiple duplications increased the number of NBS-LRR genes in the progenitors of Arabidopsis, suggesting that the present complexity in Col-0 may derive from as few as 17 progenitors. The combination of physical and phylogenetic analyses of the NBS-LRR genes makes it possible to detect relatively recent gene rearrangements, which increased the number of NBS-LRR genes by about 50, but which are almost never associated with large segmental duplications. The identification of 10 heterogeneous clusters containing members from different clades demonstrates that sequence sampling between different resistance gene loci and clades has occurred. Such events may have taken place early during flowering plant evolution, but they generated modules that have been duplicated and remobilized also more recently.

Arabidopsis↗

PubMed1990

Evolution of dexamethasone-induced insulin resistance in rats.

Glucocorticoids are known to cause insulin resistance and glucose intolerance. Although there have been many studies investigating the mechanism of this effect, several aspects remain to be clarified. The aim of this study was to investigate the evolution and sites of insulin resistance in dexamethasone-treated rats. To achieve this, chronically catheterized nonstressed rats had glucose kinetics measured during an oral glucose tolerance test by means of a double isotope technique. Studies were performed after 6, 48, or 96 h of dexamethasone administration (10 micrograms.rat-1.day-1) and were compared with control rats not treated with the steroid. Total hepatic glucose production (HGP) was increased in the 6-h (166 +/- 8.3, P less than 0.05) and 48-h (198 +/- 21, P less than 0.03) treated groups but not in the 96-h treated rats (140 +/- 8, P = 0.99) compared with the controls (141 +/- 8 mg/55 min). This increased HGP was despite the presence of higher insulin levels in the steroid-treated rats (1,220 +/- 115, P less than 0.09; 1,732 +/- 197, P less than 0.005; 1,567 +/- 107, P less than 0.001 in 6-, 48-, and 96-h treated rats, respectively, compared with 937 +/- 99 mU.l-1 x 55 min-1 in control rats). The metabolic clearance rate of glucose was higher in the dexamethasone-treated rats (200 +/- 14, P less than 0.07; 227 +/- 18, P less than 0.01; 227 +/- 17, P less than 0.01 in 6-, 48-, and 96-h groups, respectively, compared with 165 +/- 10 ml/55 min in control rats).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2002

Methods for data mining from large multinational surveillance studies.

Traditionally, large surveillance studies have been analyzed by the use of the MICs at which 90% of isolates tested are inhibited (MIC(90)s), MIC(50)s, frequency distributions, and percent susceptibility. In the past, these approaches have proved satisfactory for the monitoring of resistance. From these traditional uses, one can readily detect an increase in MICs for organism and drug combinations. Now that large surveillance studies have been conducted for a number of years and databases have grown to include a large number of datum points, new approaches to the extraction of useful information from these studies are needed. The present study proposes approaches, including the use of antibiotypes, principal components analysis, phylogenetics, and population genetic analysis, to the evaluation of data from large multinational surveillance studies. Application of these types of analyses can be used to describe genetic diversity, analyze changes in susceptibility patterns over time, and possibly, shed light on the origins and evolution of antimicrobial resistance. As global surveillance studies become more common and new questions concerning the evolution of resistance are raised, innovative approaches to analysis of the data will increase in importance.

Algorithms↗

PubMed1998

Bacterial evolution and the cost of antibiotic resistance.

Bacteria clearly benefit from the possession of an antibiotic resistance gene when the corresponding antibiotic is present. But do resistant bacteria suffer a cost of resistance (i.e., a reduction in fitness) when the antibiotic is absent? If so, then one strategy to control the spread of resistance would be to suspend the use of a particular antibiotic until resistant genotypes declined to low frequency. Numerous studies have indeed shown that resistant genotypes are less fit than their sensitive counterparts in the absence of antibiotic, indicating a cost of resistance. But there is an important caveat: these studies have put resistance genes into naive bacteria, which have no evolutionary history of association with the resistance genes. An important question, therefore, is whether bacteria can overcome the cost of resistance by evolving adaptations that counteract the harmful side-effects of resistance genes. In fact, several experiments (in vitro and in vivo) show that the cost of antibiotic resistance can be substantially diminished, even eliminated, by evolutionary changes in bacteria over rather short periods of time. As a consequence, it becomes increasingly difficult to eliminate resistant genotypes simply by suspending the use of antibiotics.

Bacteria↗

PubMed1996

Molecular evolution of bacterial beta-lactam resistance.

BACKGROUND: Two groups of penicillin-destroying enzymes, the class A and class C beta-lactamases, may have evolved from bacterial transpeptidases that transfer X-D-Ala-D-Ala peptides to the growing peptidoglycan during cell wall synthesis. Both the transpeptidases and the beta-lactamases are acylated by beta-lactam antibiotics such as penicillin, which mimic the peptide, but breakdown and removal of the antibiotic is much faster in the beta-lactamases, which lack the ability to process D-Ala-D-Ala peptides. Stereochemical factors driving this evolution in specificity are examined. RESULTS: We have compared the crystal structures of two classes of beta-lactamases and a beta-lactam-sensitive D-alanyl-D-alanine carboxy-peptidase/transpeptidase (DD-peptidase). The class C beta-lactamase is more similar to the DD-peptidase than to another beta-lactamase of class A. CONCLUSIONS: The two classes of beta-lactamases appear to have developed from an ancestral protein along separate evolutionary paths. Structural differentiation of the beta-lactamases from the DD-peptidases appears to follow differences in substrate shapes. The structure of the class A beta-lactamase has been further optimized to exclude D-alanyl peptides and process penicillin substrates with near catalytic perfection.

Anti-Bacterial Agents↗

PubMed2005

Drug resistance models for malaria.

The main factors affecting the evolution of drug resistance in malaria according to theoretical models are reviewed here. The overwhelming influence on the emergence and rate of spread of drug resistance is the proportion of infected hosts that are treated with drugs. A second important effect is drug efficacy in killing parasites. Factors such as average transmission rate, recombination, the biological cost of resistance, and the mode of gene action also influence the rate of spread but have relatively minor impacts. A simple population dynamics model that captures the epidemiological effects of drug treatment and resistance, as opposed to a population genetics model that does not, is presented in order to illustrate the main conclusions.

Animals↗

PubMed1996

Carbapenem resistance in Pseudomonas aeruginosa from cystic fibrosis patients.

The evolution of imipenem resistance was evaluated in Pseudomonas aeruginosa sequentially isolated from 42 patients with cystic fibrosis. Susceptibility was determined using a commercial microdilution system and imipenem resistance was confirmed by the agar dilution technique. Resistance to imipenem increased during the years from 1988 to 1992. A total of 12 patients (28.5%) carried resistant strains (11.6% of the total P. aeruginosa isolates) but only two of them were treated with the carbapenem. The other patient under imipenem treatment did not harbour resistant isolates. Sixty-four per cent of the imipenem resistant isolates were also meropenem resistant and showed low susceptibility to the other beta-lactams and tobramycin and amikacin. Twenty-one strains were selected for biochemical study. Imipenem susceptible strains showed normal OprD in two strains and diminished OprD in two more. Five strains with MIC of imipenem of 4-8 mg/L lacked OprD while another two had a band with decreased density. All strains with MIC higher than 8 completely lacked this band in western-blot analysis. Imipenem MICs of 0.5-2 mg/L only slightly increased to 1-4 mg/L when a pattern of beta-lactamase derepression was observed. While those with imipenem MICs between 8-16 mg/L increased the imipenem MIC to 16-64 mg/L in the population with a beta-lactamase derepression phenotype.

Adolescent↗

PubMed1992

On the Mechanism of Resistance to Paraquat in Hordeum glaucum and H. leporinum: Delayed Inhibition of Photosynthetic O(2) Evolution after Paraquat Application.

The mechanism of resistance to paraquat was investigated in biotypes of Hordeum glaucum Steud. and H. leporinum Link. with high levels of resistance. Inhibition of photosynthetic O(2) evolution after herbicide application was used to monitor the presence of paraquat at the active site. Inhibition of photosynthetic O(2) evolution after paraquat application was delayed in both resistant biotypes compared with the susceptible biotypes; however, this differential was more pronounced in the case of H. glaucum than in H. leporinum. Similar results could be obtained with the related herbicide diquat. Examination of the concentration dependence of paraquat-induced inhibition of O(2) evolution showed that the resistant H. glaucum biotype was less affected by herbicide compared with the susceptible biotype 3 h after treatment at most rates. The resistant H. leporinum biotype, in contrast, was as inhibited as the susceptible biotype except at the higher rates. In all cases photosynthetic O(2) evolution was dramatically inhibited 24 h after treatment. Measurement of the amount of paraquat transported to the young tissue of these plants 24 h after treatment showed 57% and 53% reductions in the amount of herbicide transported in the case of the resistant H. glaucum and H. leporinum biotypes, respectively, compared with the susceptible biotypes. This was associated with 62% and 66% decreases in photosynthetic O(2) evolution of young leaves in the susceptible H. glaucum and H. leporinum biotypes, respectively, a 39% decrease in activity for the resistant H. leporinum biotype, but no change in the resistant H. glaucum biotype. Photosynthetic O(2) evolution of leaf slices from resistant H. glaucum was not as inhibited by paraquat compared with the susceptible biotype; however, those of resistant and susceptible biotypes of H. leporinum were equally inhibited by paraquat. Paraquat resistance in these two biotypes appears to be a consequence of reduced movement of the herbicide in the resistant plants; however, the mechanism involved is not the same in H. glaucum as in H. leporinum.

Journal Article↗

PubMed2006

Complex dynamics and stability of resistance to antimalarial drugs.

A succession of antimalarial drugs has been deployed to treat human falciparum malaria but each has, in turn, been nullified by the spread of drug resistance. The consensus view has always been that, once present, resistance will inevitably rapidly increase to 100%. However, recent field evidence has shown this is not inevitable, and that drug resistance may initially spread and then stabilize at relatively low frequencies. It is proposed that intense competition between separate malaria clones co-infecting the same human can generate complex dynamics capable of explaining this observation. Standard population genetic analysis confirms this assertion. The dynamics underlying the evolution of antimalarial resistance may therefore be much more complex than previously realized, and can resolve the apparent paradox between field data and the underlying theory of the evolution of resistance. This explanation is novel and the results are equally applicable to other parasitic species where multiple infections of the same host are common.

Animals↗

PubMed2001

The acetylcholinesterase gene and organophosphorus resistance in the Australian sheep blowfly, Lucilia cuprina.

Acetylcholinesterase (AChE), encoded by the Ace gene, is the primary target of organophosphorous (OP) and carbamate insecticides. Ace mutations have been identified in OP resistants strains of Drosophila melanogaster. However, in the Australian sheep blowfly, Lucilia cuprina, resistance in field and laboratory generated strains is determined by point mutations in the Rop-1 gene, which encodes a carboxylesterase, E3. To investigate the apparent bias for the Rop-1/E3 mechanism in the evolution of OP resistance in L. cuprina, we have cloned the Ace gene from this species and characterized its product. Southern hybridization indicates the existence of a single Ace gene in L. cuprina. The amino acid sequence of L. cuprina AChE shares 85.3% identity with D. melanogaster and 92.4% with Musca domestica AChE. Five point mutations in Ace associated with reduced sensitivity to OP insecticides have been previously detected in resistant strains of D. melanogaster. These residues are identical in susceptible strains of D. melanogaster and L. cuprina, although different codons are used. Each of the amino acid substitutions that confer OP resistance in D. melanogaster could also occur in L. cuprina by a single non-synonymous substitution. These data suggest that the resistance mechanism used in L. cuprina is determined by factors other than codon bias. The same point mutations, singly and in combination, were introduced into the Ace gene of L. cuprina by site-directed mutagenesis and the resulting AChE enzymes expressed using a baculovirus system to characterise their kinetic properties and interactions with OP insecticides. The K(m) of wild type AChE for acetylthiocholine (ASCh) is 23.13 microM and the point mutations change the affinity to the substrate. The turnover number of Lucilia AChE for ASCh was estimated to be 1.27x10(3) min(-1), similar to Drosophila or housefly AChE. The single amino acid replacements reduce the affinities of the AChE for OPs and give up to 8.7-fold OP insensitivity, while combined mutations give up to 35-fold insensitivity. However, other published studies indicate these same mutations yield higher levels of OP insensitivity in D. melanogaster and A. aegypti. The inhibition data indicate that the wild type form of AChE of L. cuprina is 12.4-fold less sensitive to OP inhibition than the susceptible form of E3, suggesting that the carboxylesterases may have a role in the protection of AChE via a sequestration mechanism. This provides a possible explanation for the bias towards the evolution of resistance via the Rop-1/E3 mechanism in L. cuprina.

Acetylcholinesterase↗

PubMed2001

Better control of antibiotic resistance.

This text summarizes the conclusions of the French Working Party to Promote Research to Control Bacterial Resistance, initiated by the French Institute for Public Health Surveillance. The goal was to identify and prioritize the research areas most pertinent to the evolution of antibiotic resistance. The working group was part of a nationwide consultation of experts in the field of bacterial resistance and was coordinated with 2 other groups addressing (1) the use and surveillance of resistance to antibiotics and (2) the control and prevention of resistance to antibiotics. The proposals were discussed at a meeting held on 13 January 1999 by a large group of French microbiologists and clinicians who specialize in infectious diseases. The expert panel stressed that the determinants of evolution of antimicrobial resistance and the possibility of reversing this evolution are not completely known or understood. It emphasized the need for efforts to anticipate emergence of new resistances, to analyze the consequences of bacterial resistance, to develop rapid tests for determination of susceptibility to antibiotics, and to develop new antibiotics.

Animals↗

PubMed2006

Evolution of gene families: the multidrug resistance transporter genes in five related yeast species.

The available genomic sequences of five closely related hemiascomycetous yeast species (Kluyveromyces lactis, Kluyveromyces waltii, Candida glabrata, Ashbya (Eremothecium) gossypii with Saccharomyces cerevisiae as a reference) were analysed to identify multidrug resistance (MDR) transport proteins belonging to the ATP-binding cassette (ABC) and major facilitator superfamilies (MFS), respectively. The phylogenetic trees clearly demonstrate that a similar set of gene (sub)families already existed in the common ancestor of all five fungal species studied. However, striking differences exist between the two superfamilies with respect to the evolution of the various subfamilies. Within the ABC superfamily all six half-size transporters with six transmembrane-spanning domains (TMs) and most full-size transporters with 12 TMs have one and only one gene per genome. An exception is the PDR family, in which gene duplications and deletions have occurred independently in individual genomes. Among the MFS transporters, the DHA2 family (TC 2.A.1.3) is more variable between species than the DHA1 family (TC 2.A.1.2). Conserved gene order relationships allow to trace the evolution of most (sub)families, for which the Kluyveromyces lactis genome can serve as an optimal scaffold. Cross-species sequence alignment of orthologous upstream gene sequences led to the identification of conserved sequence motifs ("phylogenetic footprints"). Almost half of them match known sequence motifs for the MDR regulators described in S. cerevisiae. The biological significance of those and of the novel predicted motifs awaits to be confirmed experimentally.

ATP-Binding Cassette Transporters↗

PubMed2004

Independent evolution of human immunodeficiency virus (HIV) drug resistance mutations in diverse areas of the brain in HIV-infected patients, with and without dementia, on antiretroviral treatment.

AIDS dementia complex (ADC) in human immunodeficiency virus (HIV)-infected patients continues to be a problem in the era of highly active antiretroviral therapy (HAART). A better understanding of the drug resistance mutation patterns that emerge in the central nervous system (CNS) during HAART is of paramount importance as these differences in drug resistance mutations may explain underlying reasons for poor penetration of antiretroviral drugs into the CNS and suboptimal concentrations of the drugs that may reside in the brains of HIV-infected individuals during therapy. Thus, we provide a detailed analysis of HIV type 1 (HIV-1) protease and reverse transcriptase (RT) genes derived from different regions of the brains of 20 HIV-1-infected patients (5 without ADC, 2 with probable ADC, and 13 with various stages of ADC) on antiretroviral therapy. We show the compartmentalization and independent evolution of both primary and secondary drug resistance mutations to both RT and protease inhibitors in diverse regions of the CNS of HIV-infected patients, with and without dementia, on antiretroviral therapy. Our results suggest that the independent evolution of drug resistance mutations in diverse areas of the CNS may emerge as a consequence of incomplete suppression of HIV, probably related to suboptimal drug levels in the CNS and drug selection pressure. The emergence of resistant virus in the CNS may have considerable influence on the outcome of neurologic disease and also the reseeding of HIV in the systemic circulation upon failure of therapy.

AIDS Dementia Complex↗

PubMed1992

Current status of bacterial resistance to third-generation cephalosporins.

A review of the evolution of bacterial resistance to third-generation cephalosporins is presented, focusing mainly on the prototypical member of this group-cefotaxime. Third-generation cephalosporins generally remain highly active against most Enterobacteriaceae, staphylococci, streptococci, Haemophilus, and Neisseriaceae. Only enterobacteria with a high frequency of mutant derepressed strains that hyperproduce chromosomally mediated beta-lactamase, Pseudomonas spp., and some glucose nonfermenter Gram-negative bacilli have demonstrated increased levels of resistance. The significance of derepressed strains and of the recently described extended-spectrum, plasmid-mediated beta-lactamases to the usefulness of the third-generation cephalosporins is discussed.

Cefotaxime↗

PubMed1995

Malathion resistance levels in sympatric populations of Drosophila simulans (Diptera: Drosophilidae) and D. melanogaster differ by two orders of magnitude.

Malathion resistance levels were determined in populations of the sympatric species Drosophila melanogaster (Meigen) and Drosophila simulans (Sturtevant) from a collection site in Tampa Bay, FL, with a 20+ yr history of intensive malathion exposure. Bioassays of insecticide resistance were done by using a desiccation technique that reduces both the effects of avoidance behavior on the results and the total time of the assay. Resistance levels in isofemale lines of D. simulans are as much as 2 orders of magnitude higher than those in the D. melanogaster lines and are significantly higher than any previously reported resistance levels for organophosphate exposure in Drosophila sp. Comparison with specimens from additional collection sites in the region indicates that the normal ratio of these sympatric species has been altered at our study site. The use of Drosophila sp. as a model system to study resistance management strategies and differences in the evolution of insecticide resistance among sympatric species is discussed.

Animals↗

PubMed1999

Golgi complex is brefeldin A resistant in multidrug resistant cells.

The multidrug resistance (MDR) is one of the main reasons for chemotherapeutic failures in cancer patients. The overexpression of mdr1 gene product, P-glycoprotein (Pgp), leads to the appearance of resistant tumor cells. In the previous paper (Erokhina, 1997) we have demonstrated that the first stages of Pgp-mediated MDR are accompanied by the reorganization of cytoskeleton elements and the vacuolar system. These data were true for two independently isolated sublines of Syrian hamster embryo fibroblasts transformed by Raus sarcoma virus. In this study, we continued the investigation of the properties of the vacuolar system in Pgp-expressing cells. Brefeldin A (BFA), which is not a Pgp substrate, affects different elements of the vacuolar system and blocks vesicular transport. Our data demonstrate that BFA has different effects on parental and resistant cells. In parental cells, the Golgi apparatus and vesicular transport are sensitive to BFA, while in resistant sublines, BFA affects the vesicular transport but not the Golgi apparatus structure. We discuss the existence of similar and different BFA targets in parental and resistant cells and their role in the evolution of multidrug resistance mechanisms.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Multiple genetic processes result in heterogeneous rates of evolution within the major cluster disease resistance genes in lettuce.

Resistance Gene Candidate2 (RGC2) genes belong to a large, highly duplicated family of nucleotide binding site-leucine rich repeat (NBS-LRR) encoding disease resistance genes located at a single locus in lettuce (Lactuca sativa). To investigate the genetic events occurring during the evolution of this locus, approximately 1.5- to 2-kb 3' fragments of 126 RGC2 genes from seven genotypes were sequenced from three species of Lactuca, and 107 additional RGC2 sequences were obtained from 40 wild accessions of Lactuca spp. The copy number of RGC2 genes varied from 12 to 32 per genome in the seven genotypes studied extensively. LRR number varied from 40 to 47; most of this variation had resulted from 13 events duplicating two to five LRRs because of unequal crossing-over within or between RGC2 genes at one of two recombination hot spots. Two types of RGC2 genes (Type I and Type II) were initially distinguished based on the pattern of sequence identities between their 3' regions. The existence of two types of RGC2 genes was further supported by intron similarities, the frequency of sequence exchange, and their prevalence in natural populations. Type I genes are extensive chimeras caused by frequent sequence exchanges. Frequent sequence exchanges between Type I genes homogenized intron sequences, but not coding sequences, and obscured allelic/orthologous relationships. Sequencing of Type I genes from additional wild accessions confirmed the high frequency of sequence exchange and the presence of numerous chimeric RGC2 genes in nature. Unlike Type I genes, Type II genes exhibited infrequent sequence exchange between paralogous sequences. Type II genes from different genotype/species within the genus Lactuca showed obvious allelic/orthologous relationships. Trans-specific polymorphism was observed for different groups of orthologs, suggesting balancing selection. Unequal crossover, insertion/deletion, and point mutation events were distributed unequally through the gene. Different evolutionary forces have impacted different parts of the LRR.

Alleles↗