Evolution of high-level resistance during low-level antibiotic exposure
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It has become increasingly clear that low levels of antibiotics present in many environments can select for resistant bacteria, yet the evolutionary pathways for resistance development during exposure to low amounts of antibiotics remain poorly defined. Here we show that Salmonella enterica exposed to sub-MIC levels of streptomycin evolved high-level resistance via novel mechanisms that are different from those observed during lethal selections. During lethal selection only rpsL mutations are found, whereas at sub-MIC selection resistance is generated by several small-effect resistance mutations that combined confer high-level resistance via three different mechanisms: (i) alteration of the ribosomal RNA target ( gidB mutations), (ii) reduction in aminoglycoside uptake ( cyoB , nuoG , and trkH mutations), and (iii) induction of the aminoglycoside-modifying enzyme AadA ( znuA mutations). These results demonstrate how the strength of the selective pressure influences evolutionary trajectories and that even weak selective pressures can cause evolution of high-level resistance.
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An important consideration with sustained release systems is the potential for prolonged exposure to sub-therapeutic concentrations, which may lead to drug resistance.
“An important consideration with sustained release systems is the potential for prolonged exposure to sub-therapeutic concentrations, which may lead to drug resistance 19 .”
From Nanotechnology approaches for global infectious diseases (2021) · cites this paper as [19]
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One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products.
Datsenko, K., & Wanner, B. (2000) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.120163297 · Cited by 15,902 · see citing works
Antibiotics in the aquatic environment – A review – Part I
Kümmerer, K. (2009) · Chemosphere · doi:10.1016/j.chemosphere.2008.11.086 · Cited by 4,485 · see citing works
Antibiotics and Antibiotic Resistance Genes in Natural Environments
Martínez, J. L. (2008) · Science · doi:10.1126/science.1159483 · Cited by 1,802 · see citing works
Microbiological effects of sublethal levels of antibiotics
Andersson, D. I., & Hughes, D. (2014) · Nature Reviews Microbiology · doi:10.1038/nrmicro3270 · Cited by 1,764 · see citing works
Self-citationSelection of Resistant Bacteria at Very Low Antibiotic Concentrations
Gullberg, E., Cao, S., Berg, O. G., Ilbäck, C., Sandegren, L., Hughes, D., & Andersson, D. I. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002158 · Cited by 1,667 · see citing works
Self-citationPharmaceutical antibiotic compounds in soils – a review
Thiele‐Bruhn, S. (2003) · Journal of Plant Nutrition and Soil Science · doi:10.1002/jpln.200390023 · Cited by 1,313 · see citing works
Proctor, R. A., von Eiff, C., Kahl, B. C., Becker, K., McNamara, P., Herrmann, M., & Peters, G. (2006) · Nature Reviews Microbiology · doi:10.1038/nrmicro1384 · Cited by 1,175 · see citing works
Role of mutator alleles in adaptive evolution
Taddéi, F., Radman, M., Smith, J. M., Toupance, B., Gouyon, P. H., & Godelle, B. (1997) · Nature · doi:10.1038/42696 · Cited by 678 · see citing works
Bacterial uptake of aminoglycoside antibiotics
Taber, H. W., Mueller, J. P., Miller, P. F., & Arrow, A. S. (1987) · Microbiological Reviews · doi:10.1128/mr.51.4.439-457.1987 · Cited by 599 · see citing works
Selection of a Multidrug Resistance Plasmid by Sublethal Levels of Antibiotics and Heavy Metals
Gullberg, E., Albrecht, L. M., Karlsson, C., Sandegren, L., & Andersson, D. I. (2014) · mBio · doi:10.1128/mbio.01918-14 · Cited by 560 · see citing works
Self-citationThe ZnuABC high‐affinity zinc uptake system and its regulator Zur in <i>Escherichia coli</i>
Patzer, S. I., & Hantke, K. (1998) · Molecular Microbiology · doi:10.1046/j.1365-2958.1998.00883.x · Cited by 490 · see citing works
Determining Mutation Rates in Bacterial Populations
Rosche, W. A., & Foster, P. L. (2000) · Methods · doi:10.1006/meth.1999.0901 · Cited by 482 · see citing works
OZAKI, M., Mizushima, S.-I., & Nomura, M. (1969) · Nature · doi:10.1038/222333a0 · Cited by 459 · see citing works
Coleman, J. E. (1998) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(98)80064-1 · Cited by 362 · see citing works
Ried, J. L., & Collmer, A. (1987) · Gene · doi:10.1016/0378-1119(87)90127-2 · Cited by 356 · see citing works
Bacterial evolution of antibiotic hypersensitivity
Lázár, V., Singh, G. P., Spohn, R., Nagy, I., Horváth, B., Hrtyan, M., Busa‐Fekete, R., Bogos, B., Méhi, O., Csörgő, B., et al. (2013) · Molecular Systems Biology · doi:10.1038/msb.2013.57 · Cited by 352 · see citing works
Perederina, A. A., Svetlov, V. V., Vassylyeva, M. N., Tahirov, T. H., Yokoyama, S., Artsimovitch, I., & Vassylyev, D. G. (2004) · Cell · doi:10.1016/j.cell.2004.06.030 · Cited by 351 · see citing works
DksA potentiates direct activation of amino acid promoters by ppGpp
Paul, B. J., Berkmen, M. B., & Gourse, R. L. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501170102 · Cited by 328 · see citing works
Proliferation of mutators in A cell population
Mao, E. F., Lane, L. L., Lee, J., & Miller, J. H. (1997) · Journal of Bacteriology · doi:10.1128/jb.179.2.417-422.1997 · Cited by 325 · see citing works
Okamoto, S., Tamaru, A., Nakajima, C., Nishimura, K. J., Tanaka, Y., Tokuyama, S., Suzuki, Y., & Ochi, K. (2007) · Molecular Microbiology · doi:10.1111/j.1365-2958.2006.05585.x · Cited by 302 · see citing works
Should evolutionary geneticists worry about higher-order epistasis?
Weinreich, D. M., Lan, Y., Wylie, C. S., & Heckendorn, R. B. (2013) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2013.10.007 · Cited by 277 · see citing works
Öz, T., Güvenek, A., Yildiz, S., Karaboga, E., Tamer, Y. T., Mumcuyan, N., Ozan, V. B., Senturk, H., Cokol, M., Yeh, P. J., et al. (2014) · Molecular Biology and Evolution · doi:10.1093/molbev/msu191 · Cited by 277 · see citing works
Khan, G. A., Berglund, B., Khan, K. M., Lindgren, P., & Fick, J. B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0062712 · Cited by 256 · see citing works
COMPETITION BETWEEN HIGH AND LOW MUTATING STRAINS OF<i>ESCHERICHIA COLI</i>
Chao, L., & Cox, E. C. (1983) · Evolution · doi:10.1111/j.1558-5646.1983.tb05521.x · Cited by 255 · see citing works
Bryan, L. E., & Kwan, S. Y. (1983) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.23.6.835 · Cited by 251 · see citing works
Minimal selective concentrations of tetracycline in complex aquatic bacterial biofilms
Lundström, S. V., Östman, M., Bengtsson‐Palme, J., Rutgersson, C., Thoudal, M., Sircar, T., Blanck, H., Eriksson, K. M., Tysklind, M., Flach, C., et al. (2016) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2016.02.103 · Cited by 231 · see citing works
Patzer, S. I., & Hantke, K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001775200 · Cited by 218 · see citing works
Funatsu, G., & Wittmann, H. G. (1972) · Journal of Molecular Biology · doi:10.1016/0022-2836(72)90108-8 · Cited by 211 · see citing works
Energy coupling to net K+ transport in Escherichia coli K-12.
Rhoads, D. B., & Epstein, W. (1977) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)40669-7 · Cited by 195 · see citing works
Escherichia coli mutator genes
Horst, J. (1999) · Trends in Microbiology · doi:10.1016/s0966-842x(98)01424-3 · Cited by 181 · see citing works
Antibacterial Activity of Soil‐Bound Antibiotics
Chander, Y., Kumar, K., Goyal, S. M., & Gupta, S. C. (2005) · Journal of Environmental Quality · doi:10.2134/jeq2005.0017 · Cited by 172 · see citing works
Control ofspoT-dependent ppGpp Synthesis and Degradation inEscherichia coli
Murray, D. K., & Bremer, H. (1996) · Journal of Molecular Biology · doi:10.1006/jmbi.1996.0300 · Cited by 161 · see citing works
Bryan, L. E., & Elzen, H. M. V. D. (1976) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.9.6.928 · Cited by 157 · see citing works
Lenski, R. E., Mongold, J. A., Sniegowski, P. D., Travisano, M., Vasi, F., Gerrish, P. J., & Schmidt, T. M. (1998) · Antonie van Leeuwenhoek · doi:10.1023/a:1000675521611 · Cited by 152 · see citing works
Liu, A., Fong, A., Becket, E., Yuan, J., Tamae, C., Medrano, L., Maiz, M., Wahba, C., Lee, C., Lee, K., et al. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01182-10 · Cited by 151 · see citing works
Tenaillon, O., Taddéi, F., Radman, M., & Matić, I. (2001) · Research in Microbiology · doi:10.1016/s0923-2508(00)01163-3 · Cited by 143 · see citing works
ppGpp regulation of RpoS degradation via anti-adaptor protein IraP
Bougdour, A., & Gottesman, S. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705561104 · Cited by 143 · see citing works
Jørgensen, K. M., Wassermann, T., Jensen, P. Ø., et al. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00493-13 · Cited by 134 · see citing works
The Context-Dependence of Mutations: A Linkage of Formalisms
Poelwijk, F. J., Krishna, V., & Ranganathan, R. (2016) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004771 · Cited by 131 · see citing works
Lindberg, R. H., Björklund, K., Rendahl, P., et al. (2006) · Water Research · doi:10.1016/j.watres.2006.11.014 · Cited by 129 · see citing works
Evolution of Antibiotic Resistance without Antibiotic Exposure
Knöppel, A., Näsvall, J., & Andersson, D. I. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01495-17 · Cited by 116 · see citing works
Self-citationDksA and ppGpp directly regulate transcription of the Escherichia coli flagellar cascade
Lemke, J. J., Durfee, T., & Gourse, R. L. (2009) · Molecular Microbiology · doi:10.1111/j.1365-2958.2009.06939.x · Cited by 98 · see citing works
Activation of cryptic aminoglycoside resistance in Salmonella enterica
Koskiniemi, S., Pränting, M., Gullberg, E., Näsvall, J., & Andersson, D. I. (2011) · Molecular Microbiology · doi:10.1111/j.1365-2958.2011.07657.x · Cited by 97 · see citing works
Self-citationWesthoff, S., van Leeuwe, T. M., Qachach, O. I., Zhang, Z., van Wezel, G. P., & Rozen, D. E. (2017) · The ISME Journal · doi:10.1038/ismej.2016.194 · Cited by 84 · see citing works
Chow, L., Waldron, L. S., & Gillings, M. R. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.00803 · Cited by 81 · see citing works
Mechanism and Fitness Costs of PR-39 Resistance in Salmonella enterica Serovar Typhimurium LT2
Pränting, M., Negrea, A., Rhen, M., & Andersson, D. I. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00205-08 · Cited by 74 · see citing works
Self-citationRole of a Zn-independent DksA in Zn homeostasis and stringent response
Blaby, C., Furman, R., Rodionov, D. A., Artsimovitch, I., & de Crécy‐Lagard, V. (2010) · Molecular Microbiology · doi:10.1111/j.1365-2958.2010.07475.x · Cited by 66 · see citing works
Perron, K., Comte, R., & van Delden, C. (2005) · Molecular Microbiology · doi:10.1111/j.1365-2958.2005.04597.x · Cited by 65 · see citing works
Khan, S., Beattie, T. K., & Knapp, C. W. (2017) · Ecotoxicology · doi:10.1007/s10646-017-1762-y · Cited by 63 · see citing works
Purification and properties of stringent factor.
Block, R., & Haseltine, A. W. (1975) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)41801-2 · Cited by 58 · see citing works
<i>bz-rates</i>: A Web Tool to Estimate Mutation Rates from Fluctuation Analysis
Gillet-Markowska, A., Louvel, G., & Fischer, G. (2015) · G3 Genes|Genomes|Genetics · doi:10.1534/g3.115.019836 · Cited by 58 · see citing works
Bottery, M. J., Wood, A. J., & Brockhurst, M. A. (2016) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02441-15 · Cited by 49 · see citing works
Evolution of Cost-Free Resistance under Fluctuating Drug Selection in Pseudomonas aeruginosa
Melnyk, A. H., McCloskey, N. S., Hinz, A. J., Dettman, J. R., & Kassen, R. (2017) · mSphere · doi:10.1128/msphere.00158-17 · Cited by 49 · see citing works
Exact results for amplitude spectra of fitness landscapes
Neidhart, J., Szendro, I. G., & Krug, J. (2013) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2013.05.002 · Cited by 45 · see citing works
Relation of aerobiosis and ionic strength to the uptake of dihydrostreptomycin in Escherichia coli
Campbell, B. D., & Kadner, R. J. (1980) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/0005-2728(80)90002-x · Cited by 45 · see citing works
Dardonville, B., & Raibaud, O. (1990) · Journal of Bacteriology · doi:10.1128/jb.172.4.1846-1852.1990 · Cited by 42 · see citing works
Spagnolo, F., Rinaldi, C., Sajorda, D. R., et al. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01359-15 · Cited by 40 · see citing works
Näsvall, J., Knöppel, A., & Andersson, D. I. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1078 · Cited by 40 · see citing works
Self-citationPränting, M., & Andersson, D. I. (2010) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkq059 · Cited by 39 · see citing works
Self-citationZaborskytė, G., Andersen, J. B., Kragh, K. N., & Ciofu, O. (2016) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02292-16 · Cited by 37 · see citing works
Wassermann, T., Jørgensen, K. M., Ivanyshyn, K., et al. (2016) · Microbiology · doi:10.1099/mic.0.000273 · Cited by 29 · see citing works
pH Dependence of the Stress Regulator DksA
Furman, R., Danhart, E., NandyMazumdar, M., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120746 · Cited by 23 · see citing works
Gill, A. E., & Amyes, S. G. B. (2004) · Journal of Chemotherapy · doi:10.1179/joc.2004.16.4.347 · Cited by 16 · see citing works
Koskiniemi, S., Hughes, D., & Andersson, D. I. (2010) · Genetics · doi:10.1534/genetics.110.116376 · Cited by 16 · see citing works
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Nanotechnology approaches for global infectious diseases
Kirtane, A. R., Verma, M., Karandikar, P., Furin, J., Langer, R., & Traverso, G. (2021) · Nature Nanotechnology · doi:10.1038/s41565-021-00866-8 · Cited by 520 · see citing works
Yang, F., Scopel, E. F. C., Li, H., Sun, L.-L., Kawar, N., Cao, Y.-B., Jiang, Y.-Y., & Berman, J. (2023) · mBio · doi:10.1128/mbio.00227-23 · Cited by 62 · see citing works
- Authors
- Wistrand-Yuen, E., Knopp, M., Hjort, K., Koskiniemi, S., Berg, O. G., & Andersson, D. I.
- Affiliations
- Uppsala University (SE)
- Corresponding author
- Andersson, Dan I.
- Venue
- Nature Communications
- Published
- 2018-04-23
- Volume
- 9
- Issue
- 1
- Pages
- 1599-1599
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5913237
- OpenAlex
- W2799295634
- Cited by
- 466
- References
- 64
- Citations by year
- 2026: 54 · 2025: 55 · 2024: 58 · 2023: 64 · 2022: 55 · 2021: 62 · 2020: 68 · 2019: 39 · 2018: 9 · 2017: 1
- FWCI
- 26.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Svenska Forskningsrådet Formas
- Vetenskapsrådet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- antibiotic resistance evolution, Salmonella enterica, streptomycin resistance, rpsL mutations, aminoglycoside uptake
- MeSH terms
- Whole Genome Sequencing, Anti-Bacterial Agents, Bacterial Proteins, Dose-Response Relationship, Drug, Microbial Sensitivity Tests, Models, Genetic, Mutation, Ribosomal Proteins, Selection, Genetic, Streptomycin, Genome, Bacterial, Evolution, Molecular, Salmonella enterica, Drug Resistance, Bacterial
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