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PubMed2005

Intermediate mutation frequencies favor evolution of multidrug resistance in Escherichia coli.

In studying the interplay between mutation frequencies and antibiotic resistance among Escherichia coli natural isolates, we observed that modest modifications of mutation frequency may significantly influence the evolution of antibiotic resistance. The strains having intermediate mutation frequencies have significantly more antibiotic resistances than strains having low and high mutation frequencies.

Anti-Bacterial Agents↗
PubMed2006

Comparative studies on mucosal and intravenous transmission of simian immunodeficiency virus (SIVsm): the kinetics of evolution to neutralization resistance are related to progression rate of disease.

The kinetics of appearance of autologous neutralizing antibodies were studied in cynomolgus macaques infected with simian immunodeficiency virus (SIVsm) by the intravenous (IV) route (six monkeys) or the intrarectal (IR) route (ten monkeys). The SIVsm inoculum virus and reisolates obtained at 2 weeks, 3 or 4 months and later than 1 year were tested in a GHOST(3) cell line-based plaque-reduction assay with autologous sera collected at the same sampling times. All monkeys developed a neutralizing-antibody response to the inoculum virus, those infected by the IV route earlier than monkeys infected by the IR route. Animals were divided into progressor (P), slow-progressor (SP) and long-term non-progressor (LTNP) monkeys, based on progression rate. In P monkeys, neutralization escape could be demonstrated by 3 months post-infection. Neutralization-resistant variants also emerged in SP and LTNP monkeys, but were much delayed compared with P monkeys. Evolution of neutralization resistance was also demonstrated by a positive-control serum in the heterologous reaction. Pooled sera from four LTNP monkeys showed a broad neutralizing capacity, including neutralization of escape variants. These results from a large group of infected monkeys showed that SIV evolves to neutralization resistance in the infected host and that the kinetics of this evolution are related to the route of transmission and the progression rate of SIV disease. The results suggest an important role for neutralizing antibodies in controlling viraemia. Although this control is transient in the infected host, neutralization resistance is relative and variant viruses may be neutralized by a broadly cross-neutralizing serum pool.

Animals↗
PubMed2006

Six years after the commercial introduction of Bt maize in Spain: field evaluation, impact and future prospects.

We carried out a 6-year-field evaluation to assess potential hazards of growing Compa, a transgenic Bt maize variety based on the transformation event CG 00256-176. Two categories of hazards were investigated: the potential of the target corn borer Sesamia nonagrioides to evolve resistance to Bt maize and effects on non-target organisms. In order to address the first hazard, dispersal capacity of the corn borer was measured and our results indicated that larvae move to plants other than those onto which the female oviposited - even to plants in adjacent rows - in remarkable numbers and they do so mostly at a mature age, suggesting that mixing Bt and non-Bt seeds in the same field would not be a very useful deployment strategy to delay/prevent resistance. In addition, adults move among fields to mate and males may do so for up to 400 m. Three different aspects of potential non-target effects were investigated: sub-lethal effects on the target S. nonagrioides, effects on non-target maize pests, and effects on maize-dwelling predators. Larvae collected in Bt fields at later growth stages, in which event 176 Bt maize expresses Bt toxin at sub-lethal concentrations, had longer diapause and post-diapause development than larvae collected in non-Bt fields, a feature that might lead to a certain isolation between populations in both type of fields and accelerate Bt resistance evolution. Transgenic maize did not have a negative impact on non-target pests in the field; more aphids and leafhoppers but similar numbers of cutworms and wireworms were counted in Bt versus non-Bt fields; in any case differences in damage or yield were recorded. We observed no difference in the numbers of the most relevant predators in fields containing transgenic or no transgenic maize.

Bacillus thuringiensis↗
PubMed2004

Predicting differential responses to structured treatment interruptions during HAART.

Highly active antiretroviral therapy (HAART) has been used clinically in various administration schemes for several years. However, due to the development of drug resistance, evolution of viral strains, serious side effects, and poor patient compliance, the combination of drugs used in HAART fails to effectively contain virus long term in a high proportion of patients. Our group and others have suggested a change to the usual regimen of continuous HAART through structured treatment interruptions (STIs). STIs may provide similar clinical benefits as continuous treatment such as reduced viral loads and reestablishment of CD4(+)T cells while allowing patients drug holidays. We explore the use of STIs using a previously published model that accurately represents CD4(+)T-cell counts and viral loads during both untreated HIV-1 infection and HAART therapy. We simulate the effects of different STI regimens including weekly and monthly interruptions together with variations in treatment initiation time. We predict that differential responses to STIs as observed in conflicting clinical trial data are impacted by the duration of the interruption, stage of infection at initiation of treatment, strength of the immune system in suppressing virus, or pre-therapy CD4(+)T-cell count or virus load. Our results indicate that dynamics occurring below the limit of detection (LOD) are influenced by these factors, and contribute to reemergence or suppression of virus during interruptions. Simulations predict that short-term viral suppression with varying interruption strategies does not guarantee long-term clinical benefit.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Effect of electrical potential on the electro-demulsification of oily sludge.

Oily sludge, produced mostly in petroleum refineries and petrochemical industries, is one of the major industrial wastes that require treatment. Typically, these sludge wastes are water-in-oil emulsions that are stabilized by fine solids. These fine particles adsorb at the droplet surface and by lowering the demulsification rate constant, act as a barrier to prevent droplet coalescence. In this investigation, the effects of different electrical potential gradients and amphoteric surfactant on effectiveness of phase separation were investigated. It was concluded that lower electrical potential (0.5 V/cm) produced a higher demulsification rate. The solid phase remaining after the experiment was of a more compact and stable consistency. It was concluded that application of the amphoteric surfactant does not improve the total efficiency of the process. The role of oil constituents in stabilizing water-in-oil emulsions, and their effect on the dynamics of the process, were considered in every step of the experiment. Analysis of pH changes, resistance evolution, and hydrocarbon polarity analysis confirmed that the application of lower electrical gradient results in better phase separation.

Journal Article↗
PubMed2006

Genetic variation in Drosophila melanogaster pathogen susceptibility.

Genetic variation in susceptibility to pathogens is a central concern both to evolutionary and medical biologists, and for the implementation of biological control programmes. We have investigated the extent of such variation in Drosophila melanogaster, a major model organism for immunological research. We found that within populations, different Drosophila genotypes show wide-ranging variation in their ability to survive infection with the entomopathogenic fungus Beauveria bassiana. Furthermore, striking divergence in susceptibility has occurred between genotypes from temperate and tropical African locations. We hypothesize that this may have been driven by adaptation to local differences in pathogen exposure or host ecology. Genetic variation within populations may be maintained by temporal or spatial variation in the costs and benefits of pathogen defence. Insect pathogens are employed widely as biological control agents and entomopathogenic fungi are currently being developed for reducing malaria transmission by mosquitoes. Our data highlight the need for concern about resistance evolution to these novel biopesticides in vector populations.

Animals↗
PubMedDate not supplied

The limits of specificity: an experimental analysis with RNA aptamers to MS2 coat protein variants.

It has been hypothesized that selections for aptamers with high affinity for a given target molecule will of necessity identify aptamers that have high specificity for that target. We have attempted to assess this hypothesis by selecting aptamers that can bind to MS2 coat protein or to single- or double-substitution variants of the coat protein. Some aptamers selected to bind MS2 coat protein or its variants were mildly specific for their cognate targets, discriminating by two- to fourfold against closely related proteins. Specificity determinants on both the coat proteins and the aptamers could be identified. However, many aptamers could readily bind to each of the different coat proteins. The identification of such aptamer 'generalists' belies the proposed relationship between the affinities and specificities of selected RNA ligands. These results imply that, while aptamers may not finely discriminate between closely related targets, neither will their binding be negated by mutations in targets. Aptamer pharmaceuticals may therefore better resist the evolution of resistance.

Allolevivirus↗
PubMed2005

Evolution of erythromycin resistance in Streptococcus pneumoniae in Italy.

OBJECTIVES: To evaluate erythromycin resistance in recent invasive isolates of Streptococcus pneumoniae in Italy, to study the phenotypic and genotypic characteristics of the isolates, and to compare data with those obtained in a previous survey. METHODS: Invasive pneumococcal isolates were obtained from 56 laboratories throughout the country, in 2001-2003. Isolates were serotyped and antimicrobial susceptibilities determined by Sensititre panels and Etest. A new PCR was performed to detect erythromycin resistance genes. Typing methods for selected erythromycin-resistant isolates included PFGE and multilocus sequence typing (MLST). RESULTS: One hundred and fifty-five isolates out of 444 (34.9%) were resistant to erythromycin: 95 isolates (21.4%) carried erm(B), 56 (12.6%) carried mef(A) and three carried both genes. One isolate, carrying neither erm(B) nor mef(A), showed a point mutation in domain V of the 23S rRNA genes. The mef(A)-positive isolates carried subtype mef(A) (47 isolates), subtype mef(E) (nine isolates), and both subtype mef(E) and erm(B) (three isolates). All subtype mef(A) strains, except two, belonged to serotype 14, appeared to be clonally related by PFGE and related to the England14-9 clone by MLST. The two isolates belonging to other serotypes showed different genetic backgrounds. CONCLUSIONS: Erythromycin resistance in S. pneumoniae has increased in the last few years in Italy. erm(B) is still the predominant resistance determinant; however, the increase in erythromycin resistance (34.9% versus 28.8% of the previous years) is mainly due to an increase in the proportion of isolates carrying the efflux pump mef(A), whereas the proportion of isolates carrying erm(B) has not changed.

Drug Resistance, Bacterial↗
PubMed2003

Low potential for climatic stress adaptation in a rainforest Drosophila species.

The ability of sensitive rainforest species to evolve in response to climate change is largely unknown. We show that the Australian tropical rainforest fly Drosophila birchii exhibits clinal variation in desiccation resistance, but the most resistant population lacks the ability to evolve further resistance even after intense selection for over 30 generations. Parent-offspring comparisons indicate low heritable variation for this trait but high levels of genetic variation for morphology. D. birchii also exhibits abundant genetic variation at microsatellite loci. The low potential for resistance evolution highlights the importance of assessing evolutionary potential in targeted ecological traits and species from threatened habitats.

Adaptation, Physiological↗
PubMed1997

Oral isotretinoin treatment policy. Do we all agree?

A consensus meeting was held in Brussels in 1995 to review current oral isotretinoin (Roaccutane/Accutane) treatment policies among internationally renowned experts and to improve service to needy patients by proposing treatment guidelines based upon a review of 1,000 acne patients who received this therapy. The group agreed that acne conditions warranting oral isotretinoin treatment include severe acne and poorly responsive acne which improves less than 50% after 6 months of therapy with combined oral and topical antibiotics. Furthermore, acne which relapses, scars or induces consequential psychological distress should be treated with oral isotretinoin. Other indications are gram-negative folliculitis, inflammatory rosacea such as rhinophyma, pyoderma faciale, acne fulminans and hidradenitis suppurativa. Treatment was usually initiated at a daily dose of 0.5 mg/kg (but may be higher) and increased to 1.0 mg/kg. Aiming at a total does of 120-150 mg/kg per treatment course treatment lasted 4-7 months depending upon daily doses. The same dosage guidelines were applied to repeated courses of oral isotretinoin therapy with no evidence of increased risk. Mucocutaneous side-effects were predictable; dose-dependent and systemic side-effects were rarely problematic. Acne patients gain immeasurable physical and emotional relief from isotretinoin treatment and society benefits from limiting bacterial resistance evolution and reducing health care costs.

Acne Vulgaris↗
PubMed1990

[Corneal complications of climatic keratopathy].

The "keratopathie de Bietti" or climatic droplet keratopathy or keratopathie climatique (KC) is a degenerative disease of the cornea which is probably due to the exposure to ultraviolet rays. Usually the evolution is a progressive invasion of cornea by amber nodules which lift up the corneal epithelium. We observed that numerous patients suffered from severe corneal ulcerations which appeared to be spontaneous and which evolution was frequently disastrous. The aim of this work was to pick up epidemiologic data on KC in order to check the following hypothesis: the corneal opaquenesses, due to non traumatic perforations, would be more frequent among patients suffering from KC than among the rest of population. The study, carried out in Republic of Djibouti, dealed with two groups of people: an hospitable group of 217 patients suffering from a KC and a random sample of 2,446 persons among Djibouti people, from which a study ill-healthy was carried out among people from 40 years old. The mistakes were controled by adjustment on age and climatic conditions. The result is that corneal blindnesses which seemed to be spontaneous were more frequent in a significative way among people suffering from KC than among healthy people as old as ill people and living in the same conditions (12% against 0.7%; p = 0.003; Odds ratio adjusted on age: 31.8 IC: 8.8-115.20). On the etiopathogenic point of view the bacterial, fungal and deficiency causes could scarcely be accepted. The unfavourable evolution, resisting to all the treatments, drove to several hypothesis among them is responsibility of free amoebas as acanthamoeba.

Blindness↗
PubMed2002

HIV mutagenesis and the evolution of antiretroviral drug resistance.

The development of antiretroviral drug resistance is a major threat to the effective treatment of human immunodeficiency virus type 1 (HIV-1) infection. Drug treatment failure is associated with accumulation of drug resistance mutations and the evolution of drug resistance. Studies from microbial systems provide evidence for a correlation between drug resistance development and increased pathogen mutation rates. Recent studies with HIV-1 have shown that drugs targeted against reverse transcriptase (RT) as well as drug-resistant RT can increase HIV-1 mutation frequencies. Furthermore, combinations of drug and drug-resistant RT have been found to increase virus mutation frequencies in a multiplicative manner. The correlation of increased HIV-1 mutation rates with the evolution of antiretroviral drug resistance indicates that drug failure could increase the likelihood of further resistance evolving from subsequent drug regimens.

Anti-HIV Agents↗
PubMedDate not supplied

Molecular characterization, spread and evolution of multidrug resistance in Salmonella enterica typhimurium DT104.

Multidrug-resistant Salmonella enterica serovar Typhimurium phage type DT104 has emerged during the last decade as a global health problem because of its involvement in diseases in animals and humans. Multidrug-resistant DT104 strains are mostly resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides and tetracyclines (ACSSuT resistance type). The genes coding for such resistances are clustered on the chromosome. This paper reviews new developments in the characterization of S. enterica Typhimurium DT104, its chromosomal antibiotic resistance genes and their spread among other S. enterica Typhimurium phage types and other S. enterica serovars, the development of specific detection methods, virulence characteristics, and the evolution of multidrug-resistance with regard to the emergence of quinolone resistance.

Animals↗
PubMed1998

Population dynamics of tuberculosis treatment: mathematical models of the roles of non-compliance and bacterial heterogeneity in the evolution of drug resistance.

SETTING: Patient non-compliance and/or spatial heterogeneity in drug concentration or effectiveness may contribute to the emergence of drug resistance during multiple-drug chemotherapy of tuberculosis. OBJECTIVE: Using mathematical models of mycobacterial population dynamics under antimicrobial treatment, to assess the effects of non-compliance, heterogeneity and other factors on the success of treatment. DESIGN: A mathematical model is used to generate predictions about the ascent of drug resistance in treated hosts with non-compliance and/or a 'protected compartment' of bacteria where only one drug is active; simulations of a more realistic version of this model take into account random mutation, and different assumptions about the size of, and growth rate of bacteria in, the protected compartment. RESULTS: The existence of a protected compartment can increase the likelihood of resistance to the single drug active in that compartment, but only if bacteria resistant to that drug can grow in the protected compartment or if the host is non-adherent to the treatment regimen. However, the protected compartment may also slow the ascent of bacteria resistant to drugs not active in it (e.g. isoniazid) by providing a reservoir of non-selected mycobacteria. The model predicts that relative rates of killing are more important than mutation rates in determining the order in which resistant mutants ascend. Model predictions, in combination with data about drug resistance patterns, suggest that non-compliance, but not heterogeneity, is an important cause of treatment failure. CONCLUSION: Patterns of acquired drug resistance may be used to infer processes of selection during treatment; mathematical models can aid in generating predictions about the relative impacts of treatment parameters in the evolution of resistance, and eventually in suggesting improved treatment protocols.

Antitubercular Agents↗
PubMed2001

Predicting the emergence of antibiotic resistance by directed evolution and structural analysis.

Directed evolution can be a powerful tool to predict antibiotic resistance. Resistance involves the accumulation of mutations beneficial to the pathogen while maintaining residue interactions and core packing that are critical for preserving function. The constraint of maintaining stability, while increasing activity, drastically reduces the number of possible mutational combination pathways. To test this theory, TEM-1 beta-lactamase was evolved using a hypermutator E. coli-based directed evolution technique with cefotaxime selection. The selected mutants were compared to two previous directed evolution studies and a database of clinical isolates. In all cases, evolution resulted in the generation of the E104K/M182T/G238S combination of mutations ( approximately 500-fold increased resistance), which is equivalent to clinical isolate TEM-52. The structure of TEM-52 was determined to 2.4 A. G238S widens access to the active site by 2.8 A whereas E104K stabilizes the reorganized topology. The M182T mutation is located 17 A from the active site and appears to be a global suppressor mutation that acts to stabilize the new enzyme structure. Our results demonstrate that directed evolution coupled with structural analysis can be used to predict future mutations that lead to increased antibiotic resistance.

Amino Acid Sequence↗
PubMed1999

Parallel evolution of drug resistance in HIV: failure of nonsynonymous/synonymous substitution rate ratio to detect selection.

Parallel or convergent evolution at the molecular level has been difficult to demonstrate especially when rigorous statistical criteria are applied. We present sequence data from the protease gene from eight patients infected with the human immunodeficiency virus (HIV-1). These patients have been on multiple drug therapies for at least 2 years. We present sequence data from two timepoints: time zero--the initiation of drug therapy--and a subsequent timepoint between 59 and 104 weeks after the initiation of drug therapy. In addition to the sequence data, we present viral load data from both initial and final timepoints. Our phylogenetic analyses indicate significant evolution of virus from initial to final time points, even in three of eight patients who show low viral loads. Of the five patients who escaped drug therapy, identical amino acid replacements were seen in all five patients at two different codon positions, an indication of parallel evolution. We also measured genetic diversity for these patients and found no correlation between genetic diversity and viral load. Finally, we calculated the nonsynonymous and synonymous substitution rates and showed that the ratio of nonsynonymous to synonymous substitution compared to the value of one may be a poor indicator of natural selection.

Anti-HIV Agents↗
PubMed1998

[Methicillin-resistant Staphylococcus aureus: evolution and epidemiology, clinical impact, and prevention].

Methicillin-resistant Staphylococcus aureus (MRSA) strains have become endemic in hospitals in many countries. In most cases, epidemic clones emerge occasionally on the endemic background. Early institution of simple measures aimed at preventing hand-borne cross-contamination has resulted in low rates of MRSAs in a few countries of northern Europe. Although environmental contamination plays a role in some cases, colonized or infected patients are the main reservoir. Three significant problems have been identified in countries with high levels of endemicity, namely identification of the reservoir in the hospital, including detection of healthy carriers who are readmitted; notification of departments that receive healthy carriers transferred from another department in the same hospital or from another hospital; and the increasing and hard-to-control reservoir of resistant bacteria in extended-care facilities. These three problems are related to the current level of endemicity and to the risk of dissemination of resistant strains during hospital-to-hospital patient transfers. The technical responses to these problems vary with the environment and available means. They include detection of carriers in high-risk units, use of standardized reporting forms for patient transfers, and recording of the presence of MRSA in computerized medical records. Decontamination of carriers can help to prevent cross-contamination in some situations. It is of the utmost importance that all the facets of MRSA endemicity be taken into account at the level of the hospital as a whole and that all decision makers and health care providers make a commitment to reducing MRSA endemicity.

Cross Infection↗