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PNAS 103 (51): 19484-19489

Copyright © 2006 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MICROBIOLOGY

Antibiotics as intermicrobial signaling agents instead of weapons

J. F. Linares*,{dagger}, I. Gustafsson*,{ddagger}, F. Baquero§, and J. L. Martinez*,¶

*Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, Darwin 3, Campus Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain; {ddagger}Clinical Microbiology, County Hospital, SE-301 85 Halmstad, Sweden; and §Unidad Asociada al Centro Nacional de Biotecnología "Resistencia a los Antibióticos y Virulencia Bacteriana," Departamento de Microbiología, Hospital Ramón y Cajal, 28034 Madrid, Spain

Communicated by H. Boyd Woodruff, Soil Microbiology Associates, Watchung, NJ, October 13, 2006

Received for publication July 11, 2006.

Abstract: It has been widely assumed that the ecological function of antibiotics in nature is fighting against competitors. This made them a good example of the Darwinian struggle-for-life in the microbial world. Based on this idea, it also has been believed that antibiotics, even at subinhibitory concentrations, reduce virulence of bacterial pathogens. Herein, using a combination of genomic and functional assays, we demonstrate that specific antibiotics (namely tobramycin, tetracycline, and norfloxacin) at subinhibitory concentrations trigger expression of determinants influencing the virulence of the major opportunistic bacterial pathogen Pseudomonas aeruginosa. All three antibiotics induce biofilm formation; tobramycin increases bacterial motility, and tetracycline triggers expression of P. aeruginosa type III secretion system and consequently bacterial cytotoxicity. Besides their relevance in the infection process, those determinants are relevant for the ecological behavior of this bacterial species in natural, nonclinical environments, either by favoring colonization of surfaces (biofilm, motility) or for fighting against eukaryotic predators (cytotoxicity). Our results support the notion that antibiotics are not only bacterial weapons for fighting competitors but also signaling molecules that may regulate the homeostasis of microbial communities. At low concentrations, they can even be beneficial for the behavior of susceptible bacteria in natural environments. This is a complete change on our vision on the ecological function of antibiotics with clear implications both for the treatment of infectious diseases and for the understanding of the microbial relationships in the biosphere.

Key Words: environment • hormesis • signals • antibiotics • Pseudomonas aeruginosa

Freely available online through the PNAS open access option.

Author contributions: J.F.L. and I.G. contributed equally to this work; J.L.M. designed research; J.F.L. and I.G. performed research; J.F.L., I.G., F.B., and J.L.M. analyzed data; and F.B. and J.L.M. wrote the paper.

{dagger}Present address: Department of Genome Science, Genome Research Institute, University of Cincinnati, 2180 East Galbraith Road, Cincinnati, OH 45237.

The authors declare no conflict of interest.

To whom correspondence should be addressed. E-mail: jlmtnez{at}cnb.uam.es

© 2006 by The National Academy of Sciences of the USA

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