RRC ID 4991
Author Tal N, Schuldiner S.
Title A coordinated network of transporters with overlapping specificities provides a robust survival strategy.
Journal Proc. Natl. Acad. Sci. U.S.A.
Abstract Multidrug transporters provide a survival strategy for living organisms. As expected given their central role in survival, these transporters are ubiquitous, and in many genomes, several genes coding for putative transporters have been identified. However, in an organism such as Escherichia coli mutations in genes coding for transporters other than the major AcrAB-TolC multidrug efflux transporter have only a marginal effect on phenotype. Thus, whether the physiological role of the transporters identified is indeed drug export has been questioned. We show here that the minor effect of single mutations is due to the overlapping functionality of several transporters. This was revealed by generating multiple chromosomal deletion mutations in genes coding for transporters that share the same substrate and testing their effect on the resistance phenotype. In addition, complementation studies imply that AcrAB-TolC confers robust resistance provided that single-component transporters in the plasma membrane are functional. This finding supports the contention that hydrophobic drugs are removed in a 2-stage process: AcrAB-TolC removes substrates from the periplasmic space, while single-component transporters remove them from the cell. The overlapping specificities of the transporters ensure coverage of a wide range of xenobiotics and provide robustness in the response to environmental stress. This strategy also confers evolvability to the organism by reducing constraints on change and allowing the accumulation of nonlethal variation.
Volume 106(22)
Pages 9051-6
Published 2009-6-2
DOI 10.1073/pnas.0902400106
PII 0902400106
PMID 19451626
PMC PMC2690002
MeSH Acriflavine / metabolism Acriflavine / pharmacology Anti-Infective Agents, Local / metabolism Anti-Infective Agents, Local / pharmacology Antiporters / genetics Antiporters / metabolism* Bacterial Outer Membrane Proteins / metabolism* Drug Resistance, Bacterial / genetics* Escherichia coli / drug effects Escherichia coli / genetics Escherichia coli / metabolism* Escherichia coli Proteins / genetics Escherichia coli Proteins / metabolism* Ethidium / metabolism Ethidium / pharmacology Gene Deletion Lipoproteins / metabolism* Membrane Transport Proteins / genetics Membrane Transport Proteins / metabolism* Periplasm / metabolism
IF 9.58
Times Cited 74
Prokaryotes E. coli ME9062(BW25113) CV-25(DH5alpha) CV-4(BL21(DE3)) CV-41(JW109)