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PubMed2005

Emergence and evolution of enfuvirtide resistance following long-term therapy involves heptad repeat 2 mutations within gp41.

The objective of this study was to track the evolution of sequence changes in both the heptad region 1 (HR1) and HR2 domains of gp41 associated with resistance to enfuvirtide (ENF) in a patient cohort receiving long-term ENF treatment. We studied 17 highly antiretroviral agent-experienced patients receiving long-term ENF treatment with virological rebound or a lack of suppression. Sixty-two samples obtained after between 5 and 107 weeks of ENF therapy were analyzed. Baseline samples from 15 of these 17 patients were available for analysis. Viruses from five samples from four patients were also sequenced after the cessation of ENF therapy. Drug susceptibilities were assessed by a pseudotype virus reporter assay. We identified HR1 and HR2 sequence changes over time in relation to the baseline sequences. Mutations in HR1 (amino acids 36 to 45) were noted in all cases, including previously unreported changes N42Q/H and N43Q. In addition to a range of HR2 sequence changes at polymorphic sites, isolates from 6 of 17 (35%) patients developed an S138A substitution in the HR2 domain at least 8 weeks after the start of ENF treatment and also subsequent to the first emergence of HR1 mutations. In most, but not all, cases the S138A mutation accompanied HR1 mutations at position 43. Molecular modeling demonstrates the close proximity of S138A with amino acids 40 and 45 in HR1. Of note, isolates in samples available from four patients demonstrated the loss of both the HR1 and the S138A HR2 mutations following the cessation of therapy. We show that the S138A HR2 mutation increased the level of resistance by approximately threefold over that conferred by the HR1 mutation N43D. Continual evolution of HR1 in the domain from amino acids 36 to 45 was observed during long-term ENF therapy. We have identified, for the first time, an ENF resistance-associated HR2 mutation, S138A, which appeared in isolates from 6 of 17 patients with virological failure and demonstrated its potential to contribute to drug resistance. We propose that this represents a possible secondary and/or compensatory mutation, particularly when it coexists with mutations at position 43 in HR-1.

Amino Acid Sequence↗
PubMed2005

High survival frequencies at low herbicide use rates in populations of Lolium rigidum result in rapid evolution of herbicide resistance.

The frequency of phenotypic resistance to herbicides in previously untreated weed populations and the herbicide dose applied to these populations are key determinants of the dynamics of selection for resistance. In total, 31 Lolium rigidum populations were collected from sites with no previous history of exposure to herbicides and where there was little probability of gene flow from adjacent resistant populations. The mean survival frequency across all 31 populations following two applications of commercial rates (375 g ha(-1)) of the acetyl-coenzyme A carboxylase (ACCase) inhibiting herbicide, diclofop-methyl was 0.43%. Survivors from five of these populations were grown to maturity and seed was collected. Dose-response experiments compared population level resistance to diclofop-methyl in these selected lines with their original parent populations. A single cycle of herbicide selection significantly increased resistance in all populations (LD(50) R:S ratios ranged from 2.8 to 23.2), confirming the inheritance and genetic basis of phenotypic resistance. In vitro assays of ACCase inhibition by diclofop acid indicated that resistance was due to a non-target-site mechanism. Following selection with diclofop-methyl, the five L. rigidum populations exhibited diverse patterns of cross-resistance to ACCase and ALS-inhibiting herbicides, suggesting that different genes or gene combinations were responsible for resistance. The relevance of these results to the management of herbicide resistance are discussed.

Biological Evolution↗
PubMed2005

A molecular target for suppression of the evolution of antibiotic resistance: inhibition of the Escherichia coli RecA protein by N(6)-(1-naphthyl)-ADP.

We report that N(6)-(1-naphthyl)-ADP inhibits the Escherichia coli RecA protein in vitro. A novel rapid screen identified it as a potent inhibitor of RecA nucleoprotein filament formation, and further characterization established it as an ATP-competitive inhibitor of RecA-catalyzed ATP hydrolysis. This and other inhibitors of RecA activities represent a new approach for understanding the molecular targets and pathways involved in the evolution of antibiotic resistance in bacteria.

1-Naphthylamine↗
PubMed2006

Ageing and the evolution of female resistance to remating in seed beetles.

Female remating behaviour is a key mating system parameter that is predicted to evolve according to the net effect of remating on female fitness. In many taxa, females commonly resist male remating attempts because of the costs of mating. Here, we use replicated populations of the seed beetle Acanthoscelides obtectus selected for either early or late life reproduction and show that 'Early' and 'Late' females evolved different age-specific rates of remating. Early females were more likely to remate with control males as they aged, while Late females were more resistant to remating later in life. Thus, female remating rate decreases with age when direct selection on late-life fitness is operating and increases when such selection is relaxed. Our findings not only demonstrate that female resistance to remating can evolve rapidly, but also that such evolution is in accordance with the genetic interests of females.

Aging↗
PubMed2000

Evolution of lamivudine resistance in human immunodeficiency virus type 1-infected individuals: the relative roles of drift and selection.

Human immunodeficiency virus type 1 (HIV-1) rapidly develops resistance to lamivudine during monotherapy, typically resulting in the appearance at position 184 in reverse transcriptase (RT) of isoleucine instead of the wild-type methionine (M184I) early in therapy, which is later replaced by valine (M184V). M184V reduces viral susceptibility to drug in vitro by approximately 100-fold, but also results in a lower processivity of RT. We show that a drop in absolute viral fitness associated with the outgrowth of M184V results in a drop in viral load only in individuals with high CD4(+) counts, from whom we estimate the relative fitness of M184V in the presence of drug to be approximately 10% of that of the wild type prior to therapy. The timing of emergence of the M184V mutant varies widely between infected individuals. From analysis of the frequency of M184I and M184V mutants determined at multiple time points in seven individuals during lamivudine therapy, we estimated the fitness advantage of M184V over M184I during therapy to be approximately 23% on average. We have also estimated the average ratio of the frequencies of the two mutants prior to therapy to be 0. 2:1, with a range from 0.12:1 to 0.33:1. We have found that the differences between individuals in the rate of evolution of lamivudine resistance arise due to genetic drift affecting the relative frequency of M184I and M184V prior to therapy. These results show that stochastic effects can be significant in HIV evolution, even when there is large fitness difference between mutant and wild-type variants.

Anti-HIV Agents↗
PubMed2001

Divergence in fitness and evolution of drug resistance in experimental populations of Candida albicans.

The dissemination and persistence of drug-resistant organisms in nature depends on the relative fitness of sensitive and resistant genotypes. While resistant genotypes are expected to be at an advantage compared to less resistant genotypes in the presence of drug, resistance may incur a cost; resistant genotypes may be at a disadvantage in the absence of drug. We measured the fitness of replicate experimental populations of the pathogenic yeast Candida albicans founded from a single progenitor cell in a previous study (L. E. Cowen, D. Sanglard, D. Calabrese, C. Sirjusingh, J. B. Anderson, and L. M. Kohn, J. Bacteriol. 182:1515-1522, 2000) and evolved in the presence, and in the absence, of the antifungal agent fluconazole. Fitness was measured both in the presence and in the absence of fluconazole by placing each evolved population in direct competition with the drug-sensitive ancestor and measuring the reproductive output of each competitor in the mixture. Populations evolved in the presence of drug diverged in fitness. Any significant cost of resistance, indicated by reduced fitness in the absence of drug, was eliminated with further evolution. Populations evolved in the absence of drug showed more uniform increases in fitness under both conditions. Fitness in the competition assays was not predicted by measurements of the MICs, doubling times, or stationary-phase cell densities of the competitors in isolation, suggesting the importance of interactions between mixed genotypes in competitions.

Antifungal Agents↗
PubMed1996

Evolution of drug resistance in Salmonella panama isolates in Chile.

In a search for Salmonella isolates in the environment in Chile in 1975, drug-susceptible strains of Salmonella panama were recovered for the first time from river water and vegetables in the vicinity of Santiago. Two to 3 years later, antibiotic-resistant S. panama began to appear in a variety of sources (meat, animals, vegetables, etc.), giving rise to a human epidemic that involved the entire nation. Of 139 clinical isolates studied, 7 were drug susceptible, 11 were resistant only to nitrofurans, and 3 were streptomycin, spectinomycin, and nitrofuran resistant; none of these 21 isolates harbored plasmid DNA. Most isolates (n = 107) were resistant to nitrofurans (chromosomal) and to streptomycin, spectinomycin, sulfonamides, tetracycline, and mercuric and tellurite salts; this multidrug resistance was encoded on a 218-kb plasmid classified in a number of strains as being in the IncHI2 group. From 1982 to 1993, 11 isolates acquired an additional self-transferable plasmid coding for resistance to any one of ampicillin (61 kb), ampicillin and trimethoprim (65 kb), ampicillin, trimethoprim, streptomycin, and sulfonamides (71 kb), ampicillin, gentamicin, kanamycin, and tetracycline (120 kb), or a nontransferable plasmid of approximately 6 kb encoding resistance to ampicillin or kanamycin. With the exception of ampicillin or ampicillin and trimethoprim resistance, S. panama isolates from foodstuffs, mainly pork meat products, and animals had resistance patterns that were the same as those found in clinical specimens. Remarkably, strains from goats and goat cheese and from shellfish isolated in particular rural regions were either drug susceptible or resistant only to streptomycin-spectinomycin encoded on a mobile genetic element and to nitrofurans. The report describes the arrival of a susceptible S. panama strain, its spread all over the country, and the evolution of progressively complex resistance patterns.

Chile↗
PubMed1988

[Evolution of bacterial resistance to five aminoglycosides. A study of 3,354 strains isolated in a hospital milieu].

The authors studied the susceptibility to 5 aminoglycosides (amikacin, dibekacin, gentamicin, netilmicin and tobramycin) of 3,354 strains isolated at the Centre Hospitalier Sud in Bordeaux during 1987. The results are compared to those obtained in 1984 on 2,818 strains. Amikacin remains the most active aminoside against the Enterobacteriaceae and Acinetobacter; against Pseudomonas, tobramycin has become the best one at that time, as well as netilmicin against Staphylococcus aureus. Evolution: no significative increase of Enterobacteriaceae resistance to aminoglycosides was observed during the last 3 years except for Providencia and Serratia. For Acinetobacter and Pseudomonas, percentage of resistant strains is respectively two-fold and three-fold higher. Although resistance increased in that species, netilmicin and amikacin showed a still good activity against Staphylococcus aureus.

Acinetobacter↗
PubMed2003

Progressive reversion of human immunodeficiency virus type 1 resistance mutations in vivo after transmission of a multiply drug-resistant virus.

Evolution and transmission of multiply drug-resistant human immunodeficiency virus type 1 (HIV-1) may limit therapeutic options as global treatment efforts expand. However, the stability of these mutants in the absence of drug selection pressure is not known. We performed a longitudinal analysis of plasma virus from a person who acquired HIV-1 that contained multiple reverse transcriptase (RT) and protease (PR) mutations. In the absence of therapy, 5 of 12 drug resistance mutations reverted in a stepwise fashion to wild type over the course of 52 weeks. Reversion of the M184V mutation alone did not change viral replicative capacity (RC), but it led to enhanced resistance to zidovudine and tenofovir. However, reversions of a second RT mutation and 3 PR mutations were associated with an increase in viral RC, and this was temporally correlated with a marked decrease in CD4 cell number. This study demonstrates the gradual stepwise back-mutation of certain drug resistance mutations in vivo in the absence of ongoing drug selection pressure. Moreover, it suggests that, despite initially impaired viral fitness, a transmitted HIV-1 isolate with multiple drug resistance mutations can evolve to develop increased RC and significant pathogenicity.

Adult↗
PubMed1981

Evolution of antimicrobial resistance and nosocomial infection. Lessons from the Vanderbilt experience.

The development of antimicrobial resistance by bacteria has had profound effects of the clinical use of antibiotics, especially in hospital-acquired infections. In 1973, a large outbreak of nosocomial infections due to Serratia marcescens began at the Vanderbilt University medical complex, a major characteristic of which was high-level resistance to gentamicin and carbenicillin. Investigation of the outbreak and subsequent in vitro studies have shown that the evolution and epidemiology of this high-level resistance operated at three levels of organizations: (1) dissemination of individual strains, (2) dissemination of a plasmid among different strains and (3) movement of a discrete genetic element, or transposon, between plasmids. The investigations of this outbreak and other studies reviewed support the concept that resistant strains can evoke as a result of R-plasmid exchange within the hospital environment, providing an opportunity for control of this exchange can be interrupted.

Carbenicillin↗
PubMed1986

New observations regarding evolution of trimethoprim resistance.

A clinically isolated strain of Escherichia coli, resistant to more than 1000 mg/l of trimethoprim, expressed chromosomal dihydrofolate reductase to a level 200-fold higher than that of drug sensitive E. coli K-12 strains, and this high cellular enzyme activity was found to increase further when the cells were cultured in the presence of trimethoprim. The induced increase in enzyme activity was dependent on the drug concentration. The increase was six-fold at 100 mg/l of trimethoprim. The aberrantly regulated dihydrofolate reductase gene mediating trimethoprim resistance could be transduced into E. coli K-12 or moved by recombination into an F' factor and then transferred into trans position in relation to the corresponding chromosomal gene. In either of these positions, the synthesis of dihydrofolate reductase could be induced to increase by adding trimethoprim to the culture medium. The observed induction was dependent on protein synthesis, since it could be abolished by chloramphenicol. No other folic acid analogue was found to induce increased expression of the dihydrofolate reductase gene. Also thymine starvation had no effect. Two further clinical isolates of E. coli, highly resistant to trimethoprim, were shown to produce drug resistant, plasmid-mediated dihydrofolate reductases, which were distinct from the earlier known enzyme types I and II.

Bacteria↗
PubMed2004

[Regional surveillance of the evolution of methicillin resistant Staphylococcus aureus (MRSA): what results for what teaching?].

OBJECTIVE: The aim of this study was to describe the evolution of MRSA within hospitals located in Franche-Comté from 1999 to 2003 and to establish the MRSA risk according to the type of hospitalization. METHODS: Surveillance of multidrug resistant bacteria was carried out according to the French national guidelines for the prevention of nosocomial infections. RESULTS: The global incidence of MRSA colonized/infected patients (screened by clinical samples) per 1000 patient-days had decreased from 0.73 in 1999 to 0.58 in 2003 (P < 0.004). However, analyzing the results according to each type of hospitalization revealed great heterogeneity. In 2003, the increase of MRSA incidence in short-term public hospitalization was indeed alarming whereas MRSA risk had regularly decreased in the other hospitalization types (rehabilitation and long-term care-facilities) since 1999. The number of potentially serious colonizations/infections caused by MRSA (bacteremia, deep infections, and pulmonary infections) accounted for 12.8% of all colonizations/infections. CONCLUSION: MRSA, in spite of improved prevention in our region, remains responsible for numerous infections.

Cross Infection↗
PubMed2000

Evolution of chloramphenicol resistance, with emergence of cross-resistance to florfenicol, in bovine Salmonella Typhimurium strains implicates definitive phage type (DT) 104.

The prevalence of resistance to florfenicol, a phenicol drug newly introduced in veterinary therapy, was determined in 86 chloramphenicol-resistant Salmonella Typhimurium isolates from cattle collected during 1985-1995. All were highly resistant to chloramphenicol (MICs > or = 128 mg/L) and 38 were simultaneously resistant to florfenicol (MICs >16 mg/L) and to beta-lactam agents, spectinomycin, streptomycin, sulphonamides and tetracyclines. The isolates susceptible to florfenicol harboured the chloramphenicol acetyl transferase gene, cat of type I. All the florfenicol-resistant isolates harboured the floR resistance gene and the characteristic multiple resistance genetic locus, previously characterised in a S. Typhimurium DT104 strain and identified by a multiplex PCR. Plasmid profiles and ribotype patterns were determined for all the isolates. The florfenicol-resistant isolates were grouped into the same ribotyping pattern and presented similar plasmid profiles, whereas the florfenicol-susceptible isolates showed a wider genetic diversity that is usual for S. Typhimurium. Thus, the florfenicol-resistant isolates could represent a clonal cluster, closely related to, if not of DT104 phage type, which appeared in 1989 and is now predominant within chloramphenicol-resistant S. Typhimurium. The multiplex PCR provided a useful tool to survey further evolution of multiresistant S. Typhimurium strains.

Animals↗
PubMed2000

Evolution of antibiotic resistance in gram-positive pathogens.

Staphylococcus aureus is a common cause of soft tissue infection, e.g. impetigo, cellulitis, or wound infection, and causes osteomyelitis, arthritis, bacteremia with metastatic infection, and scalded skin and toxic shock syndromes. Coagulase-negative staphylococci have become increasingly important causes of nosocomial bacteremia associated with invasive monitoring, intravascular catheters and prosthetic heart valves or joints. Most staphylococci produce b-lactamase and are resistant to penicillin. An increasing proportion of S. aureus have intrinsic resistance to methicillin (MRSA) and present major problems in hospitals for the control of cross infection. The glycopeptides, teicoplanin and vancomycin, are the antibiotics of first choice for treatment of these infections. After the first report describing a Japanese clinical isolate of vancomycin-resistant S. aureus (VRSA), several papers have documented the emergence of these microorganisms. Since the development and spreading of this phenomenon which is perceived as a fearsome threat to the already difficult therapy of nosocomial infections due to the prevalence of heterogeneous vancomycin resistance, we found the incidence of MRSA exceeds 35% in our hospital. Out of 179 methicillin-resistant S. aureus isolated during 1997-1998, two strains (1.1%) gave subclones with vancomycin MICs of 8 mg/L. PFGE showed identical restriction patterns for both isolates, suggesting transfer of a single clone between two different patients.

Anti-Bacterial Agents↗
PubMed2004

Good vs complementary genes for parasite resistance and the evolution of mate choice.

BACKGROUND: Female mate choice may be adaptive when males exhibit heritable genetic variation at loci encoding resistance to infectious disease. The Hamilton-Zuk hypothesis predicts that females should assess the genetic quality of males by monitoring traits that indicate health and vigor (condition-dependent choice, or CD). Alternatively, some females may employ a more direct method of screening and select mates based on the dissimilarity of alleles at the major histocompatibility loci (we refer to this as opposites-attract, or OA). Empirical studies suggest that both forms of mate choice exist, but little is known about the potential for natural selection to shape the two strategies in nature. RESULTS: We used computer simulation models to examine the evolutionary fates of the two forms of mate choice in populations at risk for infection by debilitating parasites. We found that populations exhibiting random mating (no mate choice) can be invaded and replaced completely by individuals practicing CD type mate choice. We also found that an allele encoding OA choice can increase when rare in randomly mating populations, but that it does not go to fixation under selection. A similar result was obtained when the OA strategy was introduced into populations practicing CD mate choice. As before, we found that the OA choice allele will increase when rare, and that it will not go to fixation under selection. The converse however was not true, as CD individuals gain no rare advantage when introduced into an OA population. CONCLUSIONS: Taken together, the results suggest that, when rare, OA is the best strategy for parasite evasion (of those considered here). The consequence of OA increasing in the population, however, is to reduce the parasite driven genotype oscillations and facilitate the breakdown of linkage disequilibrium at the disease-resistance loci. This leads to a neutrally stable situation in which different strategies have equal fitness, and suggests that multiple forms of mate choice may be expected to occur in populations at risk from infectious disease.

Alleles↗
PubMed1990

Implications of gene amplification for evolution and management of insecticide resistance.

Simulations were used to compare evolution of insecticide resistance predicted by a conventional two-allele model with predictions from three- and four-allele models that assume resistance is based on gene amplification. Results were similar between models when insecticide concentration was low or moderate. In contrast, when 10% of the population was not exposed to insecticide each generation, high insecticide concentrations slowed resistance development in the two-allele model, but caused rapid development of high levels of resistance in the three- and four-allele models. The presence of a third allele at an initial frequency as low as 10-7 doubled or tripled the rate of resistance development in some cases. Attempts to slow evolution of resistance by overwhelming it with high concentrations of insecticides are not likely to succeed if gene amplification or other mechanisms generate alleles that confer high levels of resistance.

Alleles↗
PubMed1999

Evolution of insulin resistance in coronary artery disease patients on four different pharmacological therapies.

The objective of the study was to examine the evolution of insulin sensitivity in a group of patients with stable coronary artery disease receiving one of four different pharmacological therapies. Insulin sensitivity was evaluated using an insulin suppression test in 40 newly diagnosed patients with coronary artery disease and no previous history of metabolic disorders, who were not taking any medication which might affect insulin sensitivity. The insulin suppression test consisted of a constant infusion of glucose, insulin and somatostatin for 150 min; insulin resistance was estimated by determining the steady-state plasma glucose concentrations during the last 60 minutes of the test. The insulin sensitivity index was calculated by the formula: insulin sensitivity index = (glucose infusion rate/steady state plasma glucose concentrations) x 10(3). A second insulin suppression test was performed after 6 months' therapy with either isosorbide mononitrate, atenolol, diltiazem or captopril in 30 of the 40 patients. There were no differences between any of the groups before therapy was initiated. After 6 months, patients treated with captopril and, to a lesser extent, those treated with diltiazem showed statistically significantly decreased steady state plasma glucose concentrations and increased insulin sensitivity index compared to basal values. No statistically significant differences were found in the other two groups. We conclude that captopril and, to a lesser extent, diltiazem improve insulin sensitivity in patients with stable coronary artery disease.

Adrenergic beta-Antagonists↗