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Brandis, Gerrit
Publications (10 of 22) Show all publications
Brandis, G., Cao, S. & Hughes, D. (2019). Measuring Homologous Recombination Rates between Chromosomal Locations in Salmonella. BIO-PROTOCOL, 9(3), Article ID e3159.
Open this publication in new window or tab >>Measuring Homologous Recombination Rates between Chromosomal Locations in Salmonella
2019 (English)In: BIO-PROTOCOL, ISSN 2331-8325, Vol. 9, no 3, article id e3159Article in journal (Refereed) Published
Abstract [en]

Homologous recombination between two similar DNA molecules, plays an important role in the repair of double-stranded DNA breaks. Recombination can occur between two sister chromosomes, or between two locations of similar sequence identity within the same chromosome. The assay described here is designed to measure the rate of homologous recombination between two locations with sequence similarity within the same bacterial chromosome. For this purpose, a selectable/counter-selectable genetic cassette is inserted into one of the locations and homologous recombination repair rates are measured as a function of recombinational removal of the inserted cassette. This recombinational repair process is called gene conversion, non-reciprocal recombination. We used this method to measure the recombination rates between genes within gene families and to study the stability of mobile genetic elements inserted into members of gene families.

Place, publisher, year, edition, pages
BIO-PROTOCOL, 2019
Keywords
Homologous recombination, Homologous recombination rate(s), DNA repair, Double stranded DNA breaks, Salmonella, Gene families
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-377594 (URN)10.21769/BioProtoc.3159 (DOI)000458033700009 ()
Funder
Swedish Research Council, 2016-04449Swedish Research Council, 2017-03953Carl Tryggers foundation , CTS16: 194Carl Tryggers foundation , CTS17: 204
Available from: 2019-03-01 Created: 2019-03-01 Last updated: 2019-03-07Bibliographically approved
Brandis, G., Cao, S. & Hughes, D. (2019). Operon Concatenation Is an Ancient Feature That Restricts the Potential to Rearrange Bacterial Chromosomes. Molecular biology and evolution, 36(9), 1990-2000
Open this publication in new window or tab >>Operon Concatenation Is an Ancient Feature That Restricts the Potential to Rearrange Bacterial Chromosomes
2019 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 36, no 9, p. 1990-2000Article in journal (Refereed) Published
Abstract [en]

The last common ancestor of the Gammaproteobacteria carried an important 40-kb chromosome section encoding 51 proteins of the transcriptional and translational machinery. These genes were organized into eight contiguous operons (rrnB-tufB-secE-rpoBC-str-S10-spc-alpha). Over 2 Gy of evolution, in different lineages, some of the operons became separated by multigene insertions. Surprisingly, in many Enterobacteriaceae, much of the ancient organization is conserved, indicating a strong selective force on the operons to remain colinear. Here, we show for one operon pair, tufB-secE in Salmonella, that an interruption of contiguity significantly reduces growth rate. Our data show that the tufB-secE operons are concatenated by an interoperon terminator-promoter overlap that plays a significant role regulating gene expression. Interrupting operon contiguity interferes with this regulation, reducing cellular fitness. Six operons of the ancestral chromosome section remain contiguous in Salmonella (tufB-secE-rpoBC and S10-spc-alpha) and, strikingly, each of these operon pairs is also connected by an interoperon terminator-promoter overlap. Accordingly, we propose that operon concatenation is an ancient feature that restricts the potential to rearrange bacterial chromosomes and can select for the maintenance of a colinear operon organization over billions of years.

Keywords
tufA, tufB, inversion, promoter-terminator overlap
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-397120 (URN)10.1093/molbev/msz129 (DOI)000493043800012 ()31132113 (PubMedID)
Funder
Swedish Research Council, 2016-04449Swedish Research Council, 2017-03953Carl Tryggers foundation , CTS16:194Carl Tryggers foundation , CTS17:204
Available from: 2019-11-26 Created: 2019-11-26 Last updated: 2019-11-26Bibliographically approved
Brandis, G., Cao, S. & Hughes, D. (2018). Co-evolution with recombination affects the stability of mobile genetic element insertions within gene families of Salmonella. Molecular Microbiology, 108(6), 697-710
Open this publication in new window or tab >>Co-evolution with recombination affects the stability of mobile genetic element insertions within gene families of Salmonella
2018 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 108, no 6, p. 697-710Article in journal (Refereed) Published
Abstract [en]

Bacteria can have multiple copies of a gene at separate locations on the same chromosome. Some of these gene families, including tuf (translation elongation factor EF-Tu) and rrl (ribosomal RNA), encode functions critically important for bacterial fitness. Genes within these families are known to evolve in concert using homologous recombination to transfer genetic information from one gene to another. This mechanism can counteract the detrimental effects of nucleotide sequence divergence over time. Whether such mechanisms can also protect against the potentially lethal effects of mobile genetic element insertion is not well understood. To address this we constructed two different length insertion cassettes to mimic mobile genetic elements and inserted these into various positions of the tuf and rrl genes. Wemeasured rates of recombinational repair that removed the inserted cassette and studied the underlying mechanism. Our results indicate that homologous recombination can protect the tuf and rrl genes from inactivation by mobile genetic elements, but forinsertions within shorter gene sequences the efficiency of repair is very low. Intriguingly, we found that physical distance separating genes on the chromosome directly affects the rate of recombinational repair suggesting that relative location will influence the ability of homologous recombination to maintain homogeneity.

Place, publisher, year, edition, pages
WILEY, 2018
National Category
Genetics Microbiology Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-358073 (URN)10.1111/mmi.13959 (DOI)000434978300008 ()29603442 (PubMedID)
Funder
Swedish Research Council, 2016-04449Swedish Research Council, 2017-03953Carl Tryggers foundation , CTS16:194Carl Tryggers foundation , CTS17:204
Available from: 2018-08-30 Created: 2018-08-30 Last updated: 2018-08-30Bibliographically approved
Brandis, G. & Hughes, D. (2018). Mechanisms of fitness cost reduction for rifampicin-resistant strains with deletion or duplication mutations in rpoB.. Scientific Reports, 8, Article ID 17488.
Open this publication in new window or tab >>Mechanisms of fitness cost reduction for rifampicin-resistant strains with deletion or duplication mutations in rpoB.
2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 17488Article in journal (Refereed) Published
Abstract [en]

Rifampicin resistance (Rif(R)) is caused by mutations in rpoB, encoding the beta-subunit of RNA polymerase. Rif(R )mutations generally incur a fitness cost and in resistant isolates are frequently accompanied by compensatory mutations in rpoA, rpoB or rpoC. Previous studies of fitness compensation focused on Rif(R) caused by amino acid substitutions within rpoB. Rif(R) is also caused by deletion and duplication mutations in rpoB but it is not known whether or how such mutants can ameliorate their fitness costs. Using experimental evolution of Salmonella carrying Rif(R) deletion or duplication mutations we identified compensatory amino acid substitution mutations within rpoA, rpoB or rpoC in 16 of 21 evolved lineages. Additionally, we found one lineage where a large deletion was compensated by duplication of adjacent amino acids (possibly to fill the gap within the protein structure), two lineages where mutations occurred outside of rpoABC, and two lineages where a duplication mutant reverted to the wild-type sequence. All but the two revertant mutants maintained the Rif(R) phenotype. These data suggest that amino acid substitution mutations are the major compensatory mechanism regardless of the nature of the primary Rif(R) mutation.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-371257 (URN)10.1038/s41598-018-36005-y (DOI)000451748700010 ()30504835 (PubMedID)
Funder
Swedish Research Council, 2016-04449Swedish Research Council, 2017-03953Carl Tryggers foundation , CTS16:194Carl Tryggers foundation , CTS17:204
Available from: 2018-12-20 Created: 2018-12-20 Last updated: 2019-01-07Bibliographically approved
Garmendia, E., Brandis, G. & Hughes, D. (2018). Transcriptional Regulation Buffers Gene Dosage Effects on a Highly Expressed Operon in Salmonella. mBio, 9(5), Article ID e01446-18.
Open this publication in new window or tab >>Transcriptional Regulation Buffers Gene Dosage Effects on a Highly Expressed Operon in Salmonella
2018 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 9, no 5, article id e01446-18Article in journal (Refereed) Published
Abstract [en]

Highly expressed genes are commonly located close to the origin of replication of bacterial chromosomes (OriC). This location skew is thought to reflect selective advantages associated with gene dosage effects during the replication cycle. The expression of constitutively expressed genes can vary up to fivefold based on chromosomal location, but it is not clear what level of variation would occur in naturally regulated operons. We tested the magnitude of the chromosome location effect using EF-Tu (tufA, tufB), an abundant protein whose cellular level correlates with, and limits, the maximum growth rate. We translocated the Salmonella tufB operon to four locations across the chromosome. The distance from OriC had only a small effect on growth rate, consistent with this operon having the natural ability to upregulate expression and compensate for reduced gene dosage. In contrast, when the total EF-Tu concentration was limiting for the growth rate (tufA deleted), we observed a strong gene dosage effect when tufB was located further from OriC. However, only a short period of experimental evolution was required before the bacteria adapted to this EF-Tu starvation situation by acquiring genetic changes that increased expression levels from the translocated tufB gene, restoring growth rates. Our findings demonstrate that, at least for the tufB operon, gene dosage is probably not the dominant force selecting for a chromosomal location close to OriC. We suggest that the colocation of highly expressed genes close to OriC might instead be selected because it enhances their coregulation during various growth states, with gene dosage being a secondary benefit. IMPORTANCE A feature of bacterial chromosomes is that highly expressed essential genes are usually located close to the origin of replication. Because bacteria have overlapping cycles of replication, genes located close to the origin will often be present in multiple copies, and this is thought to be of selective benefit where high levels of expression support high growth rate. However, the magnitude of this selective effect and whether other forces could be at play are poorly understood. To study this, we translocated a highly expressed essential operon, tufB, to different locations and measured growth fitness. We found that transcriptional regulation buffered the effects of translocation and that even under conditions where growth rate was reduced, genetic changes that increased the expression of tufB were easily and rapidly selected. We conclude, at least for tufB, that forces other than gene dosage may be significant in selecting for chromosomal location.

Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY, 2018
Keywords
chromosome organization, EF-Tu, location bias, tufB
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-369516 (URN)10.1128/mBio.01446-18 (DOI)000449472200015 ()30206172 (PubMedID)
Funder
Swedish Research Council, 2016-04449Swedish Research Council, 2017-03953Knut and Alice Wallenberg Foundation, 2009.0251Carl Tryggers foundation , CTS16: 194Carl Tryggers foundation , CTS17: 204
Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2018-12-17Bibliographically approved
Cao, S., Huseby, D. L., Brandis, G. & Hughes, D. (2017). Alternative Evolutionary Pathways for Drug-Resistant Small Colony Variant Mutants in Staphylococcus aureus. mBio, 8(3), Article ID e00358-17.
Open this publication in new window or tab >>Alternative Evolutionary Pathways for Drug-Resistant Small Colony Variant Mutants in Staphylococcus aureus
2017 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 8, no 3, article id e00358-17Article in journal (Refereed) Published
Abstract [en]

Staphylococcus aureus is known to generate small colony variants (SCVs) that are resistant to aminoglycoside antibiotics and can cause persistent and recurrent infections. The SCV phenotype is unstable, and compensatory mutations lead to restored growth, usually with loss of resistance. However, the evolution of improved growth, by mechanisms that avoid loss of antibiotic resistance, is very poorly understood. By selection with serial passaging, we isolated and characterized different classes of extragenic suppressor mutations that compensate for the slow growth of small colony variants. Compensation occurs by two distinct bypass mechanisms: (i) translational suppression of the initial SCV mutation by mutant tRNAs, ribosomal protein S5, or release factor 2 and (ii) mutations that cause the constitutive activation of the SrrAB global transcriptional regulation system. Although compensation by translational suppression increases growth rate, it also reduces antibiotic susceptibility, thus restoring a pseudo-wild-type phenotype. In contrast, an evolutionary pathway that compensates for the SCV phenotype by activation of SrrAB increases growth rate without loss of antibiotic resistance. RNA sequence analysis revealed that mutations activating the SrrAB pathway cause upregulation of genes involved in peptide transport and in the fermentation pathways of pyruvate to generate ATP and NAD(+), thus explaining the increased growth. By increasing the growth rate of SCVs without the loss of aminoglycoside resistance, compensatory evolution via the SrrAB activation pathway represents a threat to effective antibiotic therapy of staphylococcal infections. IMPORTANCE Small colony variants (SCVs) of Staphylococcus aureus are a significant clinical problem, causing persistent and antibiotic-resistant infections. However, SCVs are unstable and can rapidly evolve growth-compensated mutants. Previous data suggested that growth compensation only occurred with the loss of antibiotic resistance. We have used selection with serial passaging to uncover four distinct pathways of growth compensation accessible to SCVs. Three of these paths (reversion, intragenic suppression, and translational suppression) increase growth at the expense of losing antibiotic resistance. The fourth path activates an alternative transcriptional program and allows the bacteria to produce the extra ATP required to support faster growth, without losing antibiotic resistance. The importance of this work is that it shows that drug-resistant SCVs can evolve faster growth without losing antibiotic resistance.

Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY, 2017
Keywords
ATP, experimental evolution, growth compensation, hemin biosynthesis, menaquinone, SrrAB, transcriptional regulation, translational suppression
National Category
Microbiology
Identifiers
urn:nbn:se:uu:diva-330055 (URN)10.1128/mBio.00358-17 (DOI)000404733300009 ()
Available from: 2017-11-16 Created: 2017-11-16 Last updated: 2017-11-16Bibliographically approved
Pietsch, F., Bergman, J. M., Brandis, G., Marcusson, L. L., Zorzet, A., Huseby, D. L. & Hughes, D. (2017). Ciprofloxacin selects for RNA polymerase mutations with pleiotropic antibiotic resistance effects. Journal of Antimicrobial Chemotherapy, 72(1), 75-84
Open this publication in new window or tab >>Ciprofloxacin selects for RNA polymerase mutations with pleiotropic antibiotic resistance effects
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2017 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 72, no 1, p. 75-84Article in journal (Refereed) Published
Abstract [en]

Objectives: Resistance to the fluoroquinolone drug ciprofloxacin is commonly linked to mutations that alter the drug target or increase drug efflux via the major AcrAB-TolC transporter. Very little is known about other mutations that might also reduce susceptibility to ciprofloxacin. We discovered that an Escherichia coli strain experimentally evolved for resistance to ciprofloxacin had acquired a mutation in rpoB, the gene coding for the beta-subunit of RNA polymerase. The aim of this work was to determine whether this mutation, and other mutations in rpoB, contribute to ciprofloxacin resistance and, if so, by which mechanism. Methods: Independent lineages of E. coli were evolved in the presence of ciprofloxacin and clones from endpoint cultures were screened for mutations in rpoB. Ciprofloxacin-selected rpoB mutations were identified and characterized in terms of effects on susceptibility and mode of action. Results: Mutations in rpoB were selected at a high frequency in 3 out of 10 evolved lineages, in each case arising after the occurrence of mutations affecting topoisomerases and drug efflux. All ciprofloxacin-selected rpoB mutations had a high fitness cost in the absence of drug, but conferred a competitive advantage in the presence of ciprofloxacin. RNA sequencing and quantitative RT-PCR analysis showed that expression of mdtK, encoding a multidrug efflux transporter, was significantly increased by the ciprofloxacin-selected rpoB mutations. The susceptibility phenotype was shown to depend on the presence of an active mdtK and a mutant rpoB allele. Conclusions: These data identify mutations in RNA polymerase as novel contributors to the evolution of resistance to ciprofloxacin and show that the phenotype is mediated by increased MdtK-dependent drug efflux.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2017
National Category
Infectious Medicine Microbiology in the medical area Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-319816 (URN)10.1093/jac/dkw364 (DOI)000394038700010 ()27621175 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Knut and Alice Wallenberg Foundation
Available from: 2017-04-10 Created: 2017-04-10 Last updated: 2018-01-13Bibliographically approved
Praski Alzrigat, L., Huseby, D. L., Brandis, G. & Hughes, D. (2017). Fitness cost constrains the spectrum of marR mutations in ciprofloxacin-resistant Escherichia coli: Multiple Antibiotic-Resistance, Gram-Negative Bacteria, Multidrug Efflux Pump, Urinary-Tract-Infections, Fluoroquinolone Resistance, Quinolone Resistance, Mechanisms, Expression, Sequence, Soxs. Journal of Antimicrobial Chemotherapy, 2(11), 3016-3024
Open this publication in new window or tab >>Fitness cost constrains the spectrum of marR mutations in ciprofloxacin-resistant Escherichia coli: Multiple Antibiotic-Resistance, Gram-Negative Bacteria, Multidrug Efflux Pump, Urinary-Tract-Infections, Fluoroquinolone Resistance, Quinolone Resistance, Mechanisms, Expression, Sequence, Soxs
2017 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 2, no 11, p. 3016-3024Article in journal (Refereed) Published
Abstract [en]

Objectives: To determine whether the spectrum of mutations in marR in ciprofloxacin-resistant clinical isolates of Escherichia coli shows evidence of selection bias, either to reduce fitness costs, or to increase drug resistance. MarR is a repressor protein that regulates, via MarA, expression of the Mar regulon, including the multidrug efflux pump AcrAB-TolC. Methods: Isogenic strains carrying 36 different marR alleles identified in resistant clinical isolates, or selected for resistance in vitro, were constructed. Drug susceptibility and relative fitness in growth competition assays were measured for all strains. The expression level of marA, and of various efflux pump components, as a function of specific mutations in marR, was measured by qPCR. Results: The spectrum of genetic alterations in marR in clinical isolates is strongly biased against inactivating mutations. In general, the alleles found in clinical isolates conferred a lower level of resistance and imposed a lower growth fitness cost than mutations selected in vitro. The level of expression of MarA correlated well with the MIC of ciprofloxacin. This supports the functional connection between mutations in marR and reduced susceptibility to ciprofloxacin. Conclusions: Mutations in marR selected in ciprofloxacin-resistant clinical isolates are strongly biased against inactivating mutations. Selection favours mutant alleles that have the lowest fitness costs, even though these cause only modest reductions in drug susceptibility. This suggests that selection for high relative fitness is more important than selection for increased resistance in determining which alleles of marR will be selected in resistant clinical isolates.

National Category
Microbiology in the medical area
Research subject
Microbiology
Identifiers
urn:nbn:se:uu:diva-320003 (URN)10.1093/jac/dkx270 (DOI)000413464200006 ()28962020 (PubMedID)
Funder
Swedish Research Council, 2013-02904Swedish Research Council, 2016-04449
Available from: 2017-04-21 Created: 2017-04-21 Last updated: 2018-02-02Bibliographically approved
Brandis, G., Cao, S., Huseby, D. L. & Hughes, D. (2017). Having your cake and eating it - Staphylococcus aureus small colony variants can evolve faster growth rate without losing their antibiotic resistance. MICROBIAL CELL, 4(8), 275-277
Open this publication in new window or tab >>Having your cake and eating it - Staphylococcus aureus small colony variants can evolve faster growth rate without losing their antibiotic resistance
2017 (English)In: MICROBIAL CELL, ISSN 2311-2638, Vol. 4, no 8, p. 275-277Article in journal (Refereed) Published
Abstract [en]

Staphylococcus aureus can produce small colony variants (SCVs) during infections. These cause significant clinical problems because they are difficult to detect in standard microbiological screening and are associated with persistent infections. The major causes of the SCV phenotype are mutations that inhibit respiration by inactivation of genes of the menadione or hemin biosynthesis pathways. This reduces the production of ATP required to support fast growth. Importantly, it also decreases cross-membrane potential in SCVs, resulting in decreased uptake of cationic compounds, with reduced susceptibility to aminoglycoside antibiotics as a consequence. Because SCVs are slow-growing (mutations in men genes are associated with growth rates in rich medium similar to 30% of the wild-type growth rate) bacterial cultures are very susceptible to rapid takeover by faster-growing mutants (revertants or suppressors). In the case of reversion, the resulting fast growth is obviously associated with the loss of antibiotic resistance. However, direct reversion is relatively rare due to the very small genetic target size for such mutations. We explored the phenotypic consequences of SCVs evolving faster growth by routes other than direct reversion, and in particular whether any of those routes allowed for the maintenance of antibiotic resistance. In a recent paper (mBio 8: e00358-17) we demonstrated the existence of several different routes of SCV evolution to faster growth, one of which maintained the antibiotic resistance phenotype. This discovery suggests that SCVs might be more adaptable and problematic that previously thought. They are capable of surviving as a slow-growing persistent form, before evolving into a significantly faster-growing form without sacrificing their antibiotic resistance phenotype.

Keywords
SCV (small colony variant), suppressors, SrrAB, tRNA mutations, intragenic suppressor, extragenic suppressor, ATP generation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-332676 (URN)10.15698/mic2017.08.587 (DOI)000407316900005 ()28845425 (PubMedID)
Funder
Swedish Research Council, 2013-02904, 2016-04449
Available from: 2017-10-31 Created: 2017-10-31 Last updated: 2018-01-13Bibliographically approved
Huseby, D. L., Pietsch, F., Brandis, G., Garoff, L., Tegehall, A. & Hughes, D. (2017). Mutation supply and relative fitness shape the genotypes of ciprofloxacin-resistant Escherichia coli. Molecular biology and evolution, 34(5), 1029-1039
Open this publication in new window or tab >>Mutation supply and relative fitness shape the genotypes of ciprofloxacin-resistant Escherichia coli
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2017 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 34, no 5, p. 1029-1039Article in journal (Refereed) Published
Abstract [en]

Ciprofloxacin is an important antibacterial drug targeting Type II topoisomerases, highly active against Gram-negatives including Escherichia coli. The evolution of resistance to ciprofloxacin in E. coli always requires multiple genetic changes, usually including mutations affecting two different drug target genes, gyrA and parC. Resistant mutants selected in vitro or in vivo can have many different mutations in target genes and efflux regulator genes that contribute to resistance. Among resistant clinical isolates the genotype, gyrA S83L D87N, parC S80I is significantly overrepresented suggesting that it has a selective advantage. However, the evolutionary or functional significance of this high frequency resistance genotype is not fully understood. By combining experimental data and mathematical modeling, we addressed the reasons for the predominance of this specific genotype. The experimental data were used to model trajectories of mutational resistance evolution under different conditions of drug exposure and population bottlenecks. We identified the order in which specific mutations are selected in the clinical genotype, showed that the high frequency genotype could be selected over a range of drug selective pressures, and was strongly influenced by the relative fitness of alternative mutations and factors affecting mutation supply. Our data map for the first time the fitness landscape that constrains the evolutionary trajectories taken during the development of clinical resistance to ciprofloxacin and explain the predominance of the most frequently selected genotype. This study provides strong support for the use of in vitro competition assays as a tool to trace evolutionary trajectories, not only in the antibiotic resistance field.

Keywords
ciprofloxacin, multistep evolution, population bottleneck, modeling evolution, clinical isolates
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-264874 (URN)10.1093/molbev/msx052 (DOI)000399373300001 ()28087782 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research Knut and Alice Wallenberg Foundation
Available from: 2015-10-20 Created: 2015-10-19 Last updated: 2018-09-04Bibliographically approved
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