Compensatory mutations modulate the competitiveness and dynamics of plasmid-mediated colistin resistance in <i>Escherichia coli</i> clones

Qin, Yang; MacLean, R. Craig; Papkou, Andrei; Pritchard, M. C.; Powell, Lydia C.; Thomas, David W.; Andrey, Diego O.; Li, Mei; Spiller, O. Brad; Wang, Yang; Walsh, Timothy R.

doi:10.1038/s41396-019-0578-6

Cited by 46 publications

(55 citation statements)

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“…The mcr - 3.1 gene was identified predominantly in the IncHI2 plasmid, which is associated with the spread of MDR, including β-lactams and quinolones [ 14 , 21 ]. Agreeing with Li et al [ 16 ], the mcr - 3.5 genes belonged to IncP plasmid. The less frequent plasmid replicon types in our study, such as IncI1-α, IncM, IncN, and IncP, were reported to co-harbor genes resistant to aminoglycosides, β-lactams, quinolones, and tetracyclines in Enterobacteriaceae [ 17 , 21 , 22 ].…”

Section: Resultssupporting

confidence: 64%

“…In addition, Fukuda et al [ 13 ] identified the mcr-3 gene in 8% of E. coli isolated from diseased pigs in Japan. mcr-3- carrying plasmids can stably persist by lowering fitness cost [ 16 ], suggesting careful monitoring of the mcr-3 gene in Korean livestock.…”

Section: Resultsmentioning

confidence: 99%

“…The mcr - 3.5 variant in pK18EC025 differed from the mcr - 3.1 gene variant found in this study (pK18EC051 and pK15EC053) as well as the original mcr - 3 variant from China (pWJ1) by three amino acid substitutions (M23V, A457E, and T488I). Although the MIC of colistin was not altered by these substitutions, Yang et al [ 16 ] demonstrated that mcr-3.5 has higher fitness than mcr-3.1 .…”

Section: Resultsmentioning

confidence: 99%

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Emergence of mcr-3 carrying Escherichia coli in Diseased Pigs in South Korea

et al. 2020

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We examined the prevalence and molecular characteristics of mcr-3 carrying colistin-resistant Escherichia coli among cattle, pig, and chicken isolates in South Korea. Among a total of 185 colistin-resistant E. coli isolates determined in this study (47 from cattle, 90 from pigs, and 48 from chicken), PCR amplification detected mcr-3 genes in 17 isolates predominantly from diseased pigs. The mcr-3 genes were characterized as mcr-3.1 in 15 isolates and mcr-3.5 in 2 isolates. The mcr-3 gene was transferred to the E. coli J53 recipient strain from more than 50% of the mcr-3-carrying isolates. The mcr-3.1 and mcr-3.5 genes were identified predominantly in IncHI2 and IncP plasmids, respectively. Multi-locus sequence typing analysis revealed eight previously reported sequence types (ST), including ST1, ST10, and ST42. We identified isolates with similar pulsed-field gel electrophoresis patterns from diseased pigs in three farms. Besides, the isolates carried various virulence factors and demonstrated resistance to multiple antimicrobials, including β-lactams and quinolones. Further, the mcr-3.5 encodes three amino acid substitutions compared with mcr-3.1. To the best of our knowledge, this is the first report of pathogenic E. coli carrying mcr-3.5 in South Korea, which implies that mcr-3 variants may have already been widely spread in the pig industry.

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Section: Resultssupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Emergence of mcr-3 carrying Escherichia coli in Diseased Pigs in South Korea

et al. 2020

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“…Figure 8, left column (experiment with fixed mutation frequency for plasmid fitness cost compensation of 10 −5 ) shows that the number of plasmid cost-compensated E. coli is lower when the cost of carrying the plasmid increases (given that bacteria replicate more slowly); however, cost-compensated bacteria (green line) outpace the non-compensated bacteria (red line) much earlier. Thus, the expected benefit of mutational compensation is proportional to the fitness cost imposed by the plasmid (37). By increasing the plasmid fitness cost, the replication of bacteria is impaired, thus possibly reducing the population size and the possibility of obtaining compensatory mutations.…”

Section: Resultsmentioning

confidence: 99%

“…In fact, this might explain why E. coli isolates harboring plasmids with extended-spectrum β-lactamases have increased mutation frequencies (57). As proof of this concept, the benefit for cost-compensated strains (and for K. pneumoniae ) becomes clear in a hypothetical scenario containing strains with a 10 −3 mutation frequency (37).…”

Section: Discussionmentioning

confidence: 98%

Simulating the Influence of Conjugative Plasmids Kinetic Values on the Multilevel Dynamics of Antimicrobial Resistance in a Membrane Computing Model

Campos

San-Milán

Sempere

et al. 2020

Preprint

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20Plasmids harboring antibiotic resistance genes differ in their kinetic values as plasmid 21 conjugation rate, segregation rate by incompatibility with related plasmids, rate of 22 stochastic loss during replication, cost reducing the host-cell fitness, and frequency of 23 compensatory mutations to reduce plasmid cost, depending on the cell mutation 24 frequency. How variation in these values influence the success of a plasmid and their 25 resistance genes in complex ecosystems, as the microbiota? Genes are located in 26 plasmids, plasmids in cells, cells in populations. These populations are embedded in 27 ensembles of species in different human hosts, are able to exchange between them 28 bacterial ensembles during cross-infection and are located in the hospital or the 29 community setting, under various levels of antibiotic exposure. Simulations using new 30 membrane computing methods help predict the influence of plasmid kinetic values on 31 such multilevel complex system. In our simulation, conjugation frequency needed to be 32 at least 10 -3 to clearly influence the dominance of a strain with a resistant plasmid. Host 33 strains able to stably maintain two copies of similar plasmids harboring different 34 resistances, coexistence of these resistances can occur in the population. Plasmid loss 35 rates of 10 -4 or 10 -5 or plasmid fitness costs ≥0.06 favor the plasmids located in the most 36 abundant species. The beneficial effect of compensatory mutations for plasmid fitness 37 cost is proportional to this cost, only at high mutation frequencies (10 -3 -10 -5 ). 38Membrane computing helps set a multilevel landscape to study the effect of changes in 39 plasmid kinetic values on the success of resistant organisms in complex ecosystems. 40 41 42 43 44 Plasmid kinetics are widely assumed to necessarily influence the spread of antibiotic 45 resistance genes in bacterial populations and ecosystems (1-10). The main parameters 46 that affect plasmid kinetics are: a) the rate of plasmid conjugation/transfer (the rate at 47 which a bacterial cell harboring a conjugative plasmid [donor] transfers this plasmid to 48 a recipient cell; b) the segregation rate due to plasmid incompatibility (considering the 49 number of plasmid genome copies that are stably maintained in a bacterial cell); c) the 50 rate of plasmid cost (the reduction imposed by the presence [and transfer] of a plasmid 51 in the growth rate of the host bacterial cell); d) the rate of plasmid cost compensation 52 (measuring the effect of mutations reducing plasmid cost); e) the frequency of 53 mutational events in the plasmid or bacterial genome; and f) the rate of plasmid loss (the 54 rate at which plasmids are lost during the bacterial replication process). 55 However, the effects of these changes on the kinetics of plasmid resistance genes among 56 bacterial populations are necessarily influenced by numerous other factors acting in 57 actual biological ecosystems, such as the intestinal microbiota. Of these factors, our 58 previously published studies...

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Comprehensive Genomic Investigation of Coevolution of mcr genes in Escherichia coli Strains via Nanopore Sequencing

Zhang

et al. 2021

Global Challenges

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ance genes among pathogens, although some resistance genes already existed in the pre-antibiotic era. [3] There are still contrasting opinions concerning the role of clinical antibiotics in the evolution of antibiotic resistance genes, all of which are supported by different facts. [4-6] The actual correlation between these two factors may depend on the specific resistance mechanisms under investigation, and both ancient origin and post-antibiotic evolution in different environments may account for the current severe problem of antibiotic resistance in human pathogens. Horizontal gene transfer conferred by plasmids or other mobile elements plays a key role in the transmission of antibiotic resistance among different pathogens. [7] Furthermore, the persistence of resistance genes is critical for bacteria to constitute a real ongoing threat. The fitness cost endowed by the acquired resistance genes or plasmids can determine differences in the persistence of resistance genes among bacteria. [8,9] However, the role of mobile elements and antibiotics in the persistence and evolution of multiple acquired resistance genes, such as different mcr genes, in the same bacterial population has not been extensively investigated. The emergence of novel plasmid-associated mcr genes (mcr-1 to mcr-10) conferring resistance to colistin, a last-resort antibiotic used to treat severe bacterial infections caused by different Horizontal gene transfer facilitates the spread of antibiotic resistance genes, which constitutes a global challenge. However, the evolutionary trajectory of the mobile colistin resistome in bacteria is largely unknown. To investigate the coevolution and fitness cost of the colistin resistance genes in wild strains, different assays to uncover the genomic dynamics of mcr-1 and mcr-3 in bacterial populations are utilized. Escherichia coli strains harboring both mcr-1 and mcr-3.1/3.5 are isolated and mcr genes are associated with diverse mobile elements. Under exposure to colistin, the mcr-1-bearing resistome is stably inherited during bacterial replication, but mcr-3 is prone to be eliminated in populations of certain strains. In the absence of colistin, the persistence rates of the mcr-1 and mcr-3-bearing subclones varies depending on the genomic background. The decay of the mcr-bearing bacterial populations can be mediated by the elimination of mcr-containing segments, large genomic deletions, and plasmid loss. Mobile elements, including plasmids and transposons, are double-edged swords in the evolution of the resistome. The findings support the idea that antibiotic overuse accounts for global spread of multidrug-resistant (MDR) bacteria. Therefore, stringent regulation of antibiotic prescription for humans and animals should be performed systematically to alleviate the threat of MDR bacteria.

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Compensatory mutations modulate the competitiveness and dynamics of plasmid-mediated colistin resistance in Escherichia coli clones

Cited by 46 publications

References 13 publications

Emergence of mcr-3 carrying Escherichia coli in Diseased Pigs in South Korea

Emergence of mcr-3 carrying Escherichia coli in Diseased Pigs in South Korea

Simulating the Influence of Conjugative Plasmids Kinetic Values on the Multilevel Dynamics of Antimicrobial Resistance in a Membrane Computing Model

Comprehensive Genomic Investigation of Coevolution of mcr genes in Escherichia coli Strains via Nanopore Sequencing

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