Exploiting adaptive laboratory evolution of Streptomyces clavuligerus for antibiotic discovery and overproduction.

TitleExploiting adaptive laboratory evolution of Streptomyces clavuligerus for antibiotic discovery and overproduction.
Publication TypeJournal Article
Year of Publication2012
AuthorsCharusanti P, Fong NL, Nagarajan H, Pereira AR, Li HJ, Abate EA, Su Y, Gerwick WH, Palsson BO
JournalPLoS One
Volume7
Issue3
Paginatione33727
PubMed Date2012-4-4
ISSN1932-6203
KeywordsAnti-Bacterial Agents, Bacterial Proteins, Biological Evolution, Drug Resistance, Bacterial, Genome, Bacterial, Lactams, Methicillin-Resistant Staphylococcus aureus, Plasmids, Polymorphism, Single Nucleotide, Streptomyces
Abstract

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.

PubMed ID22470465

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