Rising daptomycin resistance in<i>Enterococcus faecium</i>across a hospital system occurred via rampant recurrent evolution and occasional transmission between patients

Woods, Robert J.; Read, Andrew F.; Forstchen, Meghan; Kinnear, Clare L.; McKaig, Jordan; Patel, Twisha S; Tracy, Kevin C.; Young, Carol

doi:10.1101/2023.05.09.540070

Cited by 2 publications

(4 citation statements)

References 68 publications

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“…While the experimental environment differs from the clinical environment, we find a similar evolutionary pattern in vivo in patient DN1. A blood culture obtained after daptomycin was stopped showed a second site LiaS E192* nonsense mutation (35), which is consistent with experimental results showing disruptive mutations in LiaF or LiaS in all three replicate in vitro populations.…”

Section: Discussionsupporting

confidence: 89%

“…Notably, the site of parallel evolution varied across founding genotypes and in all of the DNR founded populations. Mutations in these populations were associated with genes or operons previously suggested to be resistant isolates (35), whereas the one case of parallel evolution from a PTR isolate was not.…”

Section: Genetic Evolution In Experimental Populationsmentioning

confidence: 82%

“…For the croRS mutation occurring between DNS2 and DNR2, a structural variant was found using GATK. This mutation was later identified as an inversion using long read sequencing (35). Lollipop plots used to display variants were generated using trackViewer (36).…”

Section: Variant Callingmentioning

confidence: 99%

“…Mutations were considered candidate daptomycin resistance gene mutations if they were in genes previously associated with daptomycin resistance (38). Additionally, variants were removed if present in multiple MLSTs as resistance was not associated with MLST in prior analysis (35). Genes annotated as hypothetical or phage-associated were also removed from the list of considered genes due to the high level of variability and low quality of evidence.…”

Section: Mutations In Candidate Daptomycin Resistance Genesmentioning

confidence: 99%

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Reversion to sensitivity explains limited transmission of resistance in a hospital pathogen

Tracy,

McKaig,

Kinnear

et al. 2024

Preprint

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Bacterial pathogens that are successful in hospital environments must survive times of intense antibiotic exposure and times of no antibiotic exposure. When these organisms are closely associated with human hosts, they must also transmit from one patient to another for the resistance to spread. The resulting evolutionary dynamics have led to rising levels of resistance in hospitals. Here, we focus on an important but understudied aspect of this dynamic: the loss of resistance when resistant organisms evolve in an environment without antibiotic pressure. Based on prior data, we hypothesize that resistance arising in the context of strong selection may carry a high cost and revert to sensitivity quickly once the selective pressure is removed. Conversely, resistant isolates that persist through times of no antibiotic pressure should carry a lower cost and revert less quickly. To test this hypothesis, we utilize a genetically diverse set of patient-derived, daptomycin-resistantEnterococcus faeciumisolates that include cases of both de novo emergence of resistance within patients and putatively transmitted resistance. Bot these strains have survived periods of antibiotic exposure, but only putatively transmitted resistant strains have survived extended periods without antibiotic exposure. These strains were then allowed to evolve in antibiotic free laboratory conditions. We find that putatively transmitted resistant strains tended to have lower level resistance and that evolution in antibiotic-free conditions resulted in minimal loss of resistance. In contrast, resistance that arose de novo within patients was higher level but exhibited greater declines in resistance in vitro. Sequencing of the experimentally evolved isolates revealed that reversal of high level resistance resulted from evolutionary pathways that were frequently genetically associated with the unique resistance mutations of that strain. Further, these results suggest the rapid reversal of high-level resistance was associated with accessible evolutionary pathways where an increase in fitness is associated with decreased resistance. We describe how this rapid loss of resistance may limit the spread of resistance within the hospital and shape the diversity of resistance phenotypes across patients.

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Section: Discussionsupporting

confidence: 89%

Section: Genetic Evolution In Experimental Populationsmentioning

confidence: 82%

Section: Variant Callingmentioning

confidence: 99%

Section: Mutations In Candidate Daptomycin Resistance Genesmentioning

confidence: 99%

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Reversion to sensitivity explains limited transmission of resistance in a hospital pathogen

Tracy,

McKaig,

Kinnear

et al. 2024

Preprint

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Heterogeneous collateral effects in daptomycin-resistantE. faecalis

Huynh,

Maltas,

Wood

2023

Preprint

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Daptomycin, a cyclic lipopeptide antibiotic that targets the cell membrane, is an important therapeutic option for treating multi-drug-resistant infections, including vancomycin-resistant enterococci (VRE). Recent work has uncovered an array of daptomycin resistance mechanisms in enterococci, but relatively little is known about how these molecular defenses contribute to collateral effects–that is, to increased resistance or sensitivity to other drugs. In this work, we investigate collateral effects that arise during daptomycin adaptation ofE. faecalisin four independent laboratory-evolved populations. Using a combination of growth assays and both single isolate and population sequencing, we identified DAP-resistant lineages with mutations in one or more genes previously associated with DAP resistance, and these isolates are characterized by divergent phenotypic properties–including different levels of DAP resistance and different growth rates (i.e. fitness costs) in drug-free media. Interestingly, we also observed strongly divergent collateral responses to different antibiotics, particularly CRO, with collateral resistance arising in mutants harboring DAP-resistance mutations in cardiolipin synthetase (cls) or in genes linked to the two-component signaling system YxdJK (bceRor a regulated transporterycvR). By contrast, mutations inliaX, a component of a LiaFSR two-component signaling system, arose in two of the four populations, with point mutations associated with CRO-sensitivity and a large structural integration of plasmid pTEF3 associated with extreme CRO-sensitivity and a dramatically reduced growth rate. Our results reveal considerable phenotypic differences in mutations targeting the LiaSFR system and highlight trade-offs between resistance to daptomycin, collateral profiles (most notably to CRO), and drug-free growth rates in evolving lineages. As a whole, these results underscore how rich–and remarkably diverse–evolutionary dynamics can emerge even in parallel populations adapting to simple daptomycin escalation protocols.

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Rising daptomycin resistance inEnterococcus faeciumacross a hospital system occurred via rampant recurrent evolution and occasional transmission between patients

Cited by 2 publications

References 68 publications

Reversion to sensitivity explains limited transmission of resistance in a hospital pathogen

Reversion to sensitivity explains limited transmission of resistance in a hospital pathogen

Heterogeneous collateral effects in daptomycin-resistantE. faecalis

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