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Results for “resistance evolution”

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PubMed2007

Virological characterization of an infection with a dual-tropic, multidrug-resistant HIV-1 and further evolution on antiretroviral therapy.

We studied a case of recent infection with multidrug-resistant (MDR) HIV-1. Over 16 months off-therapy, the CD4 cell count decreased from 419 to 184 cells/mul. Antiretroviral therapy (ART) then led to an incomplete virological response but to an immunological benefit, concurrently with a shift to CCR5-only tropism and a reduction in replication capacity. ART, even if suboptimal, can be of interest in the case of MDR virus infection.

Adult↗

PubMed1999

Antibiotic use in humans and bacterial resistance.

As with any public health problem, the evolution of antibacterial resistance must be viewed from a perspective of risk, and analysed in terms of probabilities within the populations. It is necessary to be able to predict the risk of antibacterial resistance, in the future, and two main strategies have recently been developed in mathematical models that may help to evaluate these risks. It is also important to understand how antibiotics are used and how their use affects the evolution of antibacterial resistance. Understanding the epidemiology of antibacterial resistance will enable us to develop preventive strategies to limit existing resistance and to avoid the emergence of new strains of resistant bacteria.

Anti-Bacterial Agents↗

PubMed1997

A model for the origins and spread of drug-resistant malaria.

A general method of investigating parasite population genetics is presented and used to investigate the evolution of drug resistance in Plasmodium. The most important biological factor is the nature of the control, presumably through host immunity, of the malarial infection. Two models are examined: a 'generalized immunity' (GI) model in which immunity regulates the overall level of infection, and a 'specific immunity' (SI) model in which each clone within the infection is regulated independently. These models are used to investigate 3 critical factors in the evolution of resistance: (i) the frequency of resistant alleles in the population prior to drug use, (ii) the dynamics of resistance following drug application and (iii) the magnitude of threshold frequencies below which resistance will not evolve. These analyses also identify the implicit assumptions made in several previous models, reconcile their differing conclusions and allow a more informed debate about the practical application of drugs.

Alleles↗

PubMed2026

Multidimensional prophage profiling of carbapenem-resistant Enterobacteriaceae in Thailand: a nationwide, multicentre, genomic study.

BACKGROUND: Prophages influence bacterial fitness, resistance, and evolution, yet their epidemiology remains poorly understood in carbapenem-resistant Enterobacteriaceae (CRE). In this nationwide study in Thailand, we aimed to describe prophage repertoires in clinical CRE isolates and to explore their potential relevance for molecular epidemiology. METHODS: We performed a nationwide, retrospective, genomic analysis of all CRE clinical isolates collected through our previous national surveillance study involving 11 hospitals in 11 provinces in Thailand between March 25, 2012, and Jul 21, 2017. Whole-genome sequencing data from 747 CRE isolates were analysed. Intact prophages were identified using PHAge Search Tool Enhanced Release (PHASTER) and clustered by nucleotide sequence similarity. Prophage profiles were compared across multilocus sequence types, carbapenemase genotypes, specimens, geography, and patient demographics (age and sex). FINDINGS: Of the included 747 CRE isolates, 170 (23%) were Escherichia coli and 577 (77%) were Klebsiella pneumoniae. 220 (29%) of 747 strains had been isolated from female patients and 264 (35%) from male patients; metadata on patient sex were missing for 263 (35%) isolates. The median patient age was 63 years (IQR 50-72). 71 (10%) of isolates were from blood, 283 (38%) from sputum, 284 (38%) from urine, and 109 (15%) from other specimens. 374 distinct prophage clusters were identified, with significantly more prophages per genome in K pneumoniae (mean 3·01 [SD 1·55]) than in E coli (1·64 [1·46]; p<0·0001). Prophage repertoires largely mirrored bacterial multilocus sequence types. However, even within the highly clonal K pneumoniae sequence type 16 lineage, discrete prophage variation was identified, with common profiles observed in geographically dispersed patients. Respiratory K pneumoniae frequently carried a mosaic prophage with environmental signatures and a type VI secretion system, whereas blood-derived E coli harboured a prophage with immune-modulating genes. Distinct prophage clusters were observed across clinical specimens, age groups, carbapenemase genotype, and geographical region. Strains coharbouring blaNDM-1 plus blaOXA-232 (114 [15%] of 747) had the highest prophage loads. INTERPRETATION: The prophage content was shaped by the bacterial lineage, ecological niche, and temporal dynamics, providing an additional layer of epidemiological resolution beyond conventional genome typing. Integrating prophage profiling into molecular surveillance frameworks could help to identify transmission events, improve infectious source attribution, and enhance infection control strategies. FUNDING: Japan Agency for Medical Research and Development.

Female↗

PubMed2003

Inheritance of resistance to flumethrin in the Mexican Aldama strain of the cattle tick Boophilus microplus (Acari: Ixodidae).

The objective of this study was to evaluate the inheritance mode of resistance to flumethrin in the Mexican Aldama Boophilus microplus strain. Two Mexican strains were used, the Chiapas susceptible (SS), and the Aldama flumethrin-resistant from Tamaulipas. Six steers weighing ca. 250 kg were randomly assigned for each of six crosses: the susceptible (SS), resistant (RR), and the F1 (RS, SR) reciprocal crosses and F2 (RS x RS and SR x SR). The reciprocal crosses were made to evaluate maternal and sex linkage effects. Bioassays tested resistant and susceptible larvae along with their hybrid F1 and F2 progeny against a series of concentrations of flumethrin (0, 0.0075, 0.00150, 0.00300, 0.00600 and 0.01200 microg/g). To test the single-gene hypothesis of resistance, a nonparametric line-cross test proposed by Collins was used. The bioassay data were subjected to probit analysis and the resistance factor and effective dominance obtained. Results of this study indicated that inheritance for flumethrin resistance in the Aldama strain was autosomal and controlled for more than one gene. The F1 and F2 larvae had similar lower resistant factor (RF 2.8-4.5) while the resistant Aldama strain was 21-fold higher (RF 81.8) than the mean of the F1 and F2. The extent of flumethrin resistance in the Aldama B. microplus strain depended upon the concentration of the pesticide used. Resistance was almost dominant at the lowest dose while almost completely recessive at the highest dose. Maternal effects were shown for egg-mass. These results shown here indicate more than one gene basis of flumethrin resistance in B. microplus ticks are present. Therefore it is necessary to locate and understand the major loci for elucidate the mechanism of resistance and improve the ability to track and delay the evolution of resistance.

Animals↗

PubMed1999

Comparison of Erysiphe cichoracearum and E. cruciferarum and a survey of 360 Arabidopsis thaliana accessions for resistance to these two powdery mildew pathogens.

In previous work, UEA1 and UCSC1, two geographically distinct, powdery mildew isolates, were recognized for their ability to infect Arabidopsis thaliana. We have clarified the identity of these isolates by determining their host ranges, reexamining their morphology, and comparing their DNA sequences for the 5.8S ribosomal RNA and two flanking internal transcribed spacer sequences. These experiments confirm that UEA1 is a member of Erysiphe cruciferarum and that UCSC1 belongs to E. cichoracearum. Interactions of the two Erysiphe isolates with 360 A. thaliana accessions were examined to provide a comprehensive profile of naturally occurring powdery mildew resistance in this weedy species. The majority of A. thaliana accessions (213) were susceptible to both isolates. Among the accessions exhibiting some degree of resistance, most (84) responded differentially to UEA1 and UCSC1 and the remainder were resistant to both isolates. Notably, resistance to UCSC1 cosegregated with RPW7, a locus previously demonstrated to confer resistance to UEA1 in Ms-0 x Landsberg (erecta) crosses. With this large collection of resistant accessions, questions about species specificity, genetic diversity and the evolution of resistance to powdery mildews can be addressed.

Arabidopsis↗

PubMed2000

Imipenem resistance of enterobacter aerogenes mediated by outer membrane permeability.

Multidrug-resistant Enterobacter aerogenes strains are increasingly isolated in Europe and especially in France. Treatment leads to imipenem resistance, because of a lack of porin. We studied the evolution of resistance in 29 strains isolated from four patients during their clinical course. These strains belonged to the prevalent epidemiological type observed in France in previous studies (C. Bosi, et al., J. Clin. Microbiol. 37:2165-2169, 1999; A. Davin-Regli et al., J. Clin. Microbiol. 34:1474-1480, 1996). They also harbored a TEM-24 extended-spectrum beta-lactamase-coding gene. Thirteen strains were susceptible to gentamicin and resistant to imipenem and cefepime. All of the patients showed E. aerogenes strains with this resistance after an imipenem treatment. One patient showed resistance to imipenem after a treatment with cefpirome. Twelve of these 13 strains showed a lack of porin. Cessation of treatment with imipenem for three patients was followed by reversion of susceptibility to this antibiotic and the reappearance of porins, except in one case. For one patient, we observed three times in the same day the coexistence of resistant strains lacking porin and susceptible strains possessing porin. The emergence of multidrug-resistant E. aerogenes strains is very disquieting. In our study, infection by E. aerogenes increased the severity of the patients' illnesses, causing a 100% fatality rate.

Bacterial Typing Techniques↗

PubMed1996

In vitro selection of Plasmodium falciparum lines resistant to dihydrofolate-reductase inhibitors and cross resistance studies.

A cloned Plasmodium falciparum line was subjected to in vitro drug pressure, by employing a relapse protocol, to select progressively resistant falciparum lines to pyrimethamine and cycloguanil, the two dihydrofolate-reductase (DHFR) inhibitor antimalarial drugs. The falciparum lines resistant to pyrimethamine were selected much faster than those resistant to cycloguanil. In 348 days of selection/cultivation, there was 2,400-fold increase in IC50 value to pyrimethamine, whereas only about 75-fold decrease in sensitivity to cycloguanil was registered in 351 days. Pyrimethamine-resistant parasites acquired a degree of cross resistance to cycloguanil and methotrexate, another DHFR inhibitor, but did not show any cross resistance to some other groups of antimalarial drugs. The highly pyrimethamine-resistant line was not predisposed for faster selection to cycloguanil resistance. Resistance acquired to pyrimethamine was stable. The series of resistant lines obtained form a good material to study the 'evolution' of resistance more meaningfully at molecular level.

Animals↗

PubMed2006

Multitrait evolution in lines of Drosophila melanogaster selected for increased starvation resistance: the role of metabolic rate and implications for the evolution of longevity.

Starvation resistance is a trait often associated with longevity. Animals with increased longevity frequently show elevated starvation resistance and vice versa. Consequently, both life-history traits are thought to share genetic and physiological mechanisms, such as increased fat content and lowered metabolic rate. Here, we present results from 20 generations of selection on Drosophila melanogaster for increased starvation resistance at the time of adult eclosion. We observe that starvation resistance can be the result of more than one mechanism, all associated with an increase in fat resources. In general, metabolic rate is lowered under starved conditions relative to fed conditions. Metabolic rate in the starvation resistant lines is generally higher than in control lines under starved conditions. Starvation resistant flies are able to sustain a higher metabolic rate for a longer period of time when food is unavailable. This implies depletion of the increased fat reserves. However, longevity was not consistently affected by selection for increased starvation resistance. Similarly, paraquat resistance differed between selection lines and did not associate with starvation resistance, but rather with longevity. The results are discussed in relation to previous reported results on starvation resistance and its relation with mechanisms of aging and longevity.

Animals↗

PubMed1987

Origin, evolution and dissemination of antibiotic resistance genes.

Comparison of resistance genes from different sources support the hypothesis that the antibiotic-producing microorganisms are the source of resistant determinants present in clinical isolates. There is also evidence that Gram-positive cocci (staphylococci and streptococci) can serve as a reservoir of resistance genes for Gram-negative bacteria.

Amino Acid Sequence↗

PubMed1998

Emergence of Streptococcus pyogenes strains resistant to erythromycin in Gipuzkoa, Spain.

The aim of this study was to determine the evolution of resistance to macrolides and other antibiotics in strains of Streptococcus pyogenes isolated in the province of Gipuzkoa, Spain. During the period 1984-1996, all 2561 strains of Streptococcus pyogenes studied showed full susceptibility to penicillin. Until 1990, only 1.2% of Streptococcus pyogenes isolates were resistant to erythromycin. Since then, resistance to erythromycin increased every year until 1995, when 34.8% (87/250) of Streptococcus pyogenes strains were found to be resistant. In 1996 the rate of resistance to erythromycin was 17.8% (75/422). During the study period, 96.1% (246/256) of the Streptococcus pyogenes isolates resistant to erythromycin were susceptible to clindamycin. Of the remaining erythromycin-resistant Streptococcus pyogenes strains, resistance to clindamycin was constitutive in seven strains and inducible in three. When investigated by the polymerase chain reaction (PCR), all Streptococcus pyogenes strains resistant to erythromycin and susceptible to clindamycin showed the 1.4 kb fragment of the mefA gene, recently described as the novel macrolide-efflux-resistance determinant. The most frequent T-agglutination patterns among Streptococcus pyogenes resistant to erythromycin were T4 and T8,25. The emergence and rapid spread of erythromycin-resistant Streptococcus pyogenes in Gipuzkoa and its relationship to the presence of the mefA gene are described.

Agglutination↗

PubMed2002

Models for the spread of resistant pathogens.

I consider three mathematical models of the epidemiology of antibiotic treatment and the evolution of resistance. All of these models explore the relationship between the volume of antibiotic use and the frequency and rate of ascent (or descent) of resistance. The first model is in the population genetics tradition and assumes that in the absence of treatment the frequency of resistance wanes at a rate proportional to the fitness costs associated with resistance, but precipitously ascends to high frequencies in treated patients. The second two models are in the compartment, or SIR, model tradition of infectious disease epidemiology. The first of these considers the relationship between resistance and rates of antibiotic treatment in open communities. The second explores the factors contributing to the frequency of resistance in the closed settings of hospitals and nursing homes. While I give some consideration to the epidemiological and medical implications of the results of the analysis of the properties of these models, for the most part the models are the message. I end with a harangue about the utility of simple mathematics for these considerations and a plea to obtain realistic estimates of the parameters of these models and test the validity of the predictions generated from the analysis of these models.

Antibiotic Prophylaxis↗

PubMed2006

Defining the Pseudomonas aeruginosa SOS response and its role in the global response to the antibiotic ciprofloxacin.

Pseudomonas aeruginosa infections can be virtually impossible to eradicate, and the evolution of resistance during antibiotic therapy is a significant concern. In this study, we use DNA microarrays to characterize the global transcriptional response of P. aeruginosa to clinical-like doses of the antibiotic ciprofloxacin and also to determine the component that is regulated by LexA cleavage and the SOS response. We find that genes involved in virtually every facet of metabolism are down-regulated in response to ciprofloxacin. The LexA-controlled SOS regulon identified by microarray analysis includes only 15 genes but does include several genes that encode proteins involved in recombination and replication, including two inducible polymerases known to play a role in mutation and the evolution of antibiotic resistance in other organisms. The data suggest that the inhibition of LexA cleavage during therapy might help combat this pathogen by decreasing its ability to adapt and evolve resistance.

Anti-Bacterial Agents↗

PubMed1993

Antimicrobial resistance spread in aquatic environments.

The increased use of antimicrobials in farming, together with the practice of raw sewage discharge into receiving waters, has resulted in a significant increase in the numbers of antibiotic resistant bacteria present in aquatic environments. The role of this environment to act, not only as a reservoir of clinical resistance genes, but also as a medium for the spread and evolution of resistance genes and their vectors, is discussed.

Anti-Bacterial Agents↗

PubMed1997

Esterase gene amplification in Culex pipiens.

In the mosquito Culex pipiens one of the major resistance mechanisms to organophosphorous pesticides (OPs) is increased detoxification of insecticide. This resistance is the consequence of overproduction of two types of esterases, esterases A and B, coded at two loci, Est-3 (A esterase) and Est-2 (B esterase). We have analysed the genomic structure of these genes in different strains resistant to OPs and have attempted to characterize the different types of mutations leading to the resistant phenotypes. It is shown that, concerning the more frequent resistant phenotypes, mutations leading to resistance are of two main types. First, overproduction of one A esterase present in Southern France results from a regulatory mechanism. The second type of mutation is gene amplification which involves events that have initially generated the duplication of both the A and B esterase or only the B esterase locus. We report the point that the most frequent esterase overproductions are the results of eight different mutations and that, given the range of distribution of these genotypes, mutation leading to an efficient resistance gene is one of the most limiting factors for the evolution toward resistance in Culex pipiens.

Animals↗

PubMed2026

Outer membrane changes enable evolutionary escape from bacterial predation.

Antimicrobial resistance (AMR) is a threat to modern medicine. To combat AMR pathogens, natural predators like bacteriophages and predatory bacteria have gained interest recently. Predatory bacterium Bdellovibrio bacteriovorus is ubiquitous and has a broad prey range. It is particularly potent at killing many AMR Gram-negative bacterial pathogens featured on the WHO priority list. However, it is currently unclear whether prey bacteria can evolve genetically-determined resistance against predation by B. bacteriovorus. Here, we show that the model bacterium Escherichia coli K-12 consistently evolves resistance against B. bacteriovorus during experimental evolution. Selection for resistance scaled positively with predation pressure and was widespread after two cycles of predator exposure. Similar to antibiotics, predation resistance was costly, manifesting in a trade-off between predation resistance and fitness in the absence of predators. Genetic analysis combined with proteomics identified mutations that lead to the down-regulation of the outer membrane porin OmpF as a common resistance mechanism. In addition, a rarer mutation in cell envelope lipopolysaccharide-modifying enzyme WaaF also conferred predation resistance, likely by a pleiotropic effect, which included OmpF down regulation. While our study uncovers evolutionary and mechanistic aspects of prey escape from predation, it also highlights that the high cost of resistance reflects a handicap for the pathogen and can thus be exploited to increase treatment sustainability. Altogether, our work generates essential knowledge in ecologically important predator-prey interactions and can advance predatory bacteria as "living antibiotics" to combat AMR.

Bdellovibrio bacteriovorus↗

PubMed1987

Stress, competence, and development: continuities in the study of schizophrenic adults, children vulnerable to psychopathology, and the search for stress-resistant children.

The evolution of an ongoing research study into stress-resistant factors in children is traced from the early work on adult schizophrenia through the identification of risk factors in children vulnerable to stress. Future directions for the research are explored, including the necessity for defenses against possible politicization of the findings.

Child↗

PubMed2026

Nonantibiotic-driven evolution reveals rare but predictable routes to broad antibiotic resistance.

Many medications not prescribed to treat infectious diseases have antibacterial activity at physiologically relevant concentrations, raising the risk that chronic administration of such nonantibiotics may inadvertently select for resistance in the host microbiome. However, how frequently such exposures select for adaptations that impact broad drug resistance, including to antibiotics, remains unclear. Here, we systematically evolved Escherichia coli under exposure to 40 antibiotics and nonantibiotics and profiled the cross-resistance of the drug-adapted strains to 21 antibiotics representing all major classes. Our measurements revealed that most drug-adapted strains did not become multidrug resistant. However, five nonantibiotics and three antibiotics emerged as exceptions and were repeatedly selected for broad antibiotic resistance. Whole-genome sequencing of all 168 evolved strains revealed that changes in the regulation of efflux pumps repeatedly underlay broad drug resistance and converged into two key regulatory genes, acrR and lon. Our work suggests that although inadvertent antibiotic cross-resistance is rare, specific nonantibiotics can still potentially pose a risk for the emergence of multidrug resistance.IMPORTANCEMany medications not typically prescribed to treat infectious diseases have potent antimicrobial activity at physiological concentrations. This anti-bacterial activity raises concern that long-term administration of such nonantibiotics might unintentionally select for multidrug resistance, including resistance to antibiotics. Using Escherichia coli, we show that in most cases, these nonantibiotics do not broadly select for resistance to antibiotics in vitro. However, we identified five nonantibiotics that repeatedly selected for resistance to multiple antibiotics through a shared mechanism of action-upregulation of the multidrug efflux pump AcrAB-TolC. These findings highlight that while the overall risk is low, certain nonantibiotics may still contribute to the emergence of multidrug resistance. Identifying these high-risk drugs can help guide safer prescribing practices and inform strategies to limit the spread of antibiotic resistance.

Escherichia coli↗