Exploiting Adaptive Laboratory Evolution of Streptomyces clavuligerus for Antibiotic Discovery and Overproduction
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Adaptation is normally viewed as the enemy of the antibiotic discovery and development process because adaptation among pathogens to antibiotic exposure leads to resistance. We present a method here that, in contrast, exploits the power of adaptation among antibiotic producers to accelerate the discovery of antibiotics. A competition-based adaptive laboratory evolution scheme is presented whereby an antibiotic-producing microorganism is competed against a target pathogen and serially passed over time until the producer evolves the ability to synthesize a chemical entity that inhibits growth of the pathogen. When multiple Streptomyces clavuligerus replicates were adaptively evolved against methicillin-resistant Staphylococcus aureus N315 in this manner, a strain emerged that acquired the ability to constitutively produce holomycin. In contrast, no holomycin could be detected from the unevolved wild-type strain. Moreover, genome re-sequencing revealed that the evolved strain had lost pSCL4, a large 1.8 Mbp plasmid, and acquired several single nucleotide polymorphisms in genes that have been shown to affect secondary metabolite biosynthesis. These results demonstrate that competition-based adaptive laboratory evolution can constitute a platform to create mutants that overproduce known antibiotics and possibly to discover new compounds as well.
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malT regulatory mutations, although common in aerobic conditions, were absent during oxygen-limited chemostat growth, where mutations in the glucose permease ptsG were common.
“Strikingly, the authors also noticed that malT regulatory mutations, although common in aerobic conditions, were absent during oxygen-limited chemostat growth, where mutations in the glucose permease ptsG were common [48].”
From Adaptive laboratory evolution—Principles and applications for biotechnology (2013) · cites this paper as [48]
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Adaptive laboratory evolution—Principles and applications for biotechnology
Dragosits, M., & Mattanovich, D. (2013) · Microbial Cell Factories · doi:10.1186/1475-2859-12-64 · Cited by 827 · see citing works
- Authors
- Charusanti, P., Fong, N. L., Nagarajan, H., Pereira, A. R., Li, H. J., Abate, E. A., Su, Y., Gerwick, W. H., & Palsson, B. O.
- Affiliations
- University of California San Diego (US)
- Scripps Institution of Oceanography (US)
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-03-21
- Volume
- 7
- Issue
- 3
- Pages
- e33727
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3312335
- OpenAlex
- W1967709900
- Cited by
- 93
- References
- 73
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 9 · 2021: 10 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 10 · 2013: 14 · 2012: 1
- FWCI
- 6.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Harvard University
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM062791, GM 062791, R01GM071808, GM071808)
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Keywords
- adaptive laboratory evolution, Streptomyces clavuligerus, antibiotic discovery, antibiotic overproduction, holomycin, methicillin-resistant Staphylococcus aureus, plasmid loss, secondary metabolite biosynthesis, single nucleotide polymorphisms
- MeSH terms
- Anti-Bacterial Agents, Bacterial Proteins, Biological Evolution, Lactams, Plasmids, Streptomyces, Genome, Bacterial, Polymorphism, Single Nucleotide, Drug Resistance, Bacterial, Methicillin-Resistant Staphylococcus aureus
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