Emergence and Within-Host Genetic Evolution of Methicillin-Resistant
            <i>Staphylococcus aureus</i>
            Resistant to Linezolid in a Cystic Fibrosis Patient

Rouard, Caroline; Garnier, Fabien; Leraut, J.; Lepainteur, M.; Rahajamananav, Lalaina; Languepin, Jeanne; Ploy, Marie-Cécile; Bourgeois-Nicolaos, Nadège; Doucet‐Populaire, Florence

doi:10.1128/aac.00720-18

Cited by 26 publications

(29 citation statements)

References 56 publications

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“…Even though establishing relationships between mutations and the related phenotypic change in resistance was not the aim of this study, differences in AMR profiles among isolates have been associated with previously reported point mutations in the target genes of the antimicrobials and the acquisition of Tn4001 and Tn4001-like elements [43]. In agreement with the findings of Rouard et al [53], the level of resistance to linezolid in isolates recovered from patient 3 showed a possible correlation with the percentage of reads harbouring the G2576T mutation in the 23S rRNA gene, and thus with the number of 23S rRNA gene copies carrying this mutation. In addition to the differences in AMR profiles, we also detected decreases in the growth rates of sequential isolates in three out of four patients, when compared to the first isolate (Fig.…”

Section: Discussionsupporting

confidence: 90%

“…High phenotypic and/or genotypic diversity, including antimicrobial susceptibility, among S. aureus sequential isolates recovered from patients with CF as well as among variants from the same sputum sample have been described previously [ 5,6,48,52,53]. Even though establishing relationships between mutations and the related phenotypic change in resistance was not the aim of this study, differences in AMR profiles among isolates have been associated with previously reported point mutations in the target genes of the antimicrobials and the acquisition of Tn4001 and Tn4001-like elements [43].…”

Section: Discussionmentioning

confidence: 99%

“…Two limitations of our study are the small sample size and the analysis of only one colony from each clinical specimen at each different time point. Even though several studies that analyse intra-host evolution of MRSA in the setting of CF have used the one-colony-per-sample method [5,53,59], it underestimates the heterogeneity of S. aureus in the CF airways at each sampling moment, as we now know that host-adapted bacterial populations are not homogeneous.…”

Section: Discussionmentioning

confidence: 99%

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Comparative genomics of ST5 and ST30 methicillin-resistant Staphylococcus aureus sequential isolates recovered from paediatric patients with cystic fibrosis

et al. 2021

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Staphylococcus aureus chronic airway infection in patients with cystic fibrosis (CF) allows this pathogen to adapt over time in response to different selection pressures. We have previously shown that the main sequence types related to community-acquired methicillin-resistant S. aureus (MRSA) infections in Argentina – ST5 and ST30 – are also frequently isolated from the sputum of patients with CF, but in these patients they usually display multi-drug antimicrobial resistance. In this study, we sequenced the genomes of MRSA from four paediatric CF patients with the goal of identifying mutations among sequential isolates, especially those possibly related to antimicrobial resistance and virulence, which might contribute to the adaptation of the pathogen in the airways of patients with CF. Our results revealed genetic differences in sequential MRSA strains isolated from patients with CF in both their core and accessory genomes. Although the genetic adaptation of S. aureus was distinct in different hosts, we detected independent mutations in thyA, htrA, rpsJ and gyrA – which are known to have crucial roles in S. aureus virulence and antimicrobial resistance – in isolates recovered from multiple patients. Moreover, we identified allelic variants that were detected in all of the isolates recovered after a certain time point; these non-synonymous mutations were in genes associated with antimicrobial resistance, virulence, iron scavenging and oxidative stress resistance. In conclusion, our results provide evidence of genetic variability among sequential MRSA isolates that could be implicated in the adaptation of these strains during chronic CF airway infection.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Comparative genomics of ST5 and ST30 methicillin-resistant Staphylococcus aureus sequential isolates recovered from paediatric patients with cystic fibrosis

et al. 2021

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“…Prior studies tried to assess the number of SNPs accumulating over time, but mostly under selective conditions. Rouard et al (2018) calculated that during selection for linezolid resistance an expected 17–93 mutations should accumulate per genome per year. A more global calculation using a significantly larger strain collection resulted in average number of less than 10 SNPs per genome per year (Harris et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Genomic Evolution of Staphylococcus aureus During Artificial and Natural Colonization of the Human Nose

et al. 2019

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Staphylococcus aureus can colonize the human vestibulum nasi for many years. It is unknown whether and, how S. aureus adapts to this ecological niche during colonization. We determined the short (1 and 3 months) and mid-term (36 months) genomic evolution of S. aureus in natural carriers and artificially colonized volunteers. Eighty-five S. aureus strains were collected from 6 natural carriers during 3 years and 6 artificially colonized volunteers during 1 month. Multi-locus sequence typing (MLST) and single nucleotide polymorphism (SNP) analysis based on whole-genome sequencing (WGS) were carried out. Mutation frequencies within resident bacterial populations over time were quantified using core genome SNP counts (comparing groups of genomes) and pairwise SNP divergence assessment (comparing two genomes from strains originating from one host and sharing identical MLST). SNP counts (within 1–3 months) in all naturally colonizing strains varied from 0 to 757 (median 4). These strains showed random and independent patterns of pairwise SNP divergence (0 to 44 SNPs, median 7). When the different core genome SNP counts over a period of 3 years were considered, the median SNP count was 4 (range 0–26). Host-specific pairwise SNP divergence for the same period ranged from 9 to 57 SNPs (median 20). During short term artificial colonization the mutation frequency was even lower (0–7 SNPs, median 2) and the pairwise SNP distances were 0 to 5 SNPs (median 2). Quantifying mutation frequencies is important for the longitudinal follow-up of epidemics of infections and outbreak management. Random pattern of pairwise SNP divergence between the strains isolated from single carriers suggested that the WGS of multiple colonies is necessary in this context. Over periods up to 3 years, maximum median core genome SNP counts and SNP divergence for the strains studied were 4 and 20 SNPs or lower. During artificial colonization, where median core genome SNP and pairwise SNP distance scores were 2, there is no early stage selection of different genotypes. Therefore, we suggest an epidemiological cut off value of 20 SNPs as a marker of S. aureus strain identity during studies on nasal colonization and also outbreaks of infection.

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“…But those step-specific adaptations may also trade off with each other: the pathogenic strains that are successful and dominant at the initiation of the disease might differ from those that are successful and dominant at a given advanced step of an infection. Within-host evolution has been described in many human bacterial diseases, such as those associated with Helicobacter pylori (4), Staphyloccocus aureus (5), or the causative agent of melioidosis, Burkholderia pseudomallei (6), and the genetic basis behind the adaptations has stimulated a lot of interest. However, the studied adaptations are generally focused on antibiotic resistance and rarely on the adaptation to the environment given by the host, and the potential trade-offs hindering adaptations to each step of the infection, especially within the host, are rarely considered (7).…”

mentioning

confidence: 99%

Step-Specific Adaptation and Trade-Off over the Course of an Infection by GASP Mutation Small Colony Variants

Faucher

Mazana

Kardacz

et al. 2021

mBio

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During an infection, parasites face a succession of challenges, each decisive for disease outcome. The diversity of challenges requires a series of parasite adaptations to successfully multiply and transmit from host to host. Thus, the pathogen genotypes that succeed during one step might be counterselected in later stages of the infection. Using the bacterium Xenorhabdus nematophila and adult Drosophila melanogaster flies as hosts, we showed that such step-specific adaptations, here linked to GASP (i.e., growth advantage in stationary phase) mutations in the X. nematophila master gene regulator lrp, exist and can trade off with each other. We found that nonsense lrp mutations had lowered the ability to resist the host immune response, while all classes of mutations in lrp were associated with a decrease in the ability to proliferate during early infection. We demonstrate that reduced proliferation of X. nematophila best explains diminished virulence in this infection model. Finally, decreased proliferation during the first step of infection is accompanied by improved proliferation during late infection, suggesting a trade-off between the adaptations to each step. Step-specific adaptations could play a crucial role in the chronic phase of infections in any disease organisms that show similar small colony variants (SCVs) to X. nematophila. IMPORTANCE Within-host evolution has been described in many bacterial diseases, and the genetic basis behind the adaptations has stimulated a lot of interest. Yet, the studied adaptations are generally focused on antibiotic resistance and rarely on the adaptation to the environment given by the host, and the potential trade-offs hindering adaptations to each step of the infection are rarely considered. Those trade-offs are key to understanding intrahost evolution and thus the dynamics of the infection. However, understanding these trade-offs supposes a detailed study of host-pathogen interactions at each step of the infection process, with an adapted methodology for each step. Using Drosophila melanogaster as the host and the bacterium Xenorhabdus nematophila, we investigated the bacterial adaptations resulting from GASP mutations known to induce the small colony variant (SCV) phenotype positively selected within the host over the course of an infection, as well as the trade-off between step-specific adaptations.

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Emergence and Within-Host Genetic Evolution of Methicillin-Resistant Staphylococcus aureus Resistant to Linezolid in a Cystic Fibrosis Patient

Cited by 26 publications

References 56 publications

Comparative genomics of ST5 and ST30 methicillin-resistant Staphylococcus aureus sequential isolates recovered from paediatric patients with cystic fibrosis

Comparative genomics of ST5 and ST30 methicillin-resistant Staphylococcus aureus sequential isolates recovered from paediatric patients with cystic fibrosis

Genomic Evolution of Staphylococcus aureus During Artificial and Natural Colonization of the Human Nose

Step-Specific Adaptation and Trade-Off over the Course of an Infection by GASP Mutation Small Colony Variants

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