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AI-2 analogs and antibiotics: a synergistic approach to reduce bacterial biofilms

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Abstract

Quorum sensing (QS), the process of autoinducer-mediated cell–cell signaling among bacteria, facilitates biofilm formation, virulence, and many other multicellular phenotypes. QS inhibitors are being investigated as antimicrobials because of their potential to reduce symptoms of infectious disease while slowing the emergence of resistant strains. Autoinducer-2 (AI-2) analogs have been shown to inhibit genotypic QS responses among many bacteria. We demonstrate for the first time, the ability of C1-alkyl AI-2 analog, isobutyl-DPD, to significantly inhibit the maturation of Escherichia coli biofilms grown in vitro. Using a novel microfluidic device that incorporates dynamic, real-time measurements of biofilm density, we also show that a combinatorial approach wherein isobutyl-DPD ((S)-4,5-dihydroxy-2,3-pentanedione) is used with the antibiotic gentamicin is quite effective in rendering near complete clearance of pre-existing E. coli biofilms. Similarly, another AI-2 analog, phenyl-DPD, also used in combination with near MIC levels of gentamicin, resulted in clearance of preformed Pseudomonas aeruginosa biofilms. Clearance of pre-existing biofilms has remained a significant health care challenge; these results warrant consideration of a new approach based on the combination of “quenching” QS signal transduction processes with traditional antibiotic treatment.

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Acknowledgments

The authors appreciate the funding support provided by the R. W. Deutsch Foundation, the Defense Threat Reduction Agency (DTRA), the Camille Dreyfus Foundation, NSF Grant CHE0746446, and the National Science Foundation Emerging Frontiers in Research and Innovation program (NSF-EFRI). The authors appreciate the support of the Maryland Nanocenter and its Fablab in fabricating the microfluidic devices and also appreciate the assistance of the University of Maryland Imaging Core Facility with confocal microscopy. They would additionally like to thank their collaborators in the University of Maryland Biochip Collaborative.

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Correspondence to William E. Bentley.

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Varnika Roy and Mariana T. Meyer have contributed equally to this work.

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Roy, V., Meyer, M.T., Smith, J.A.I. et al. AI-2 analogs and antibiotics: a synergistic approach to reduce bacterial biofilms. Appl Microbiol Biotechnol 97, 2627–2638 (2013). https://doi.org/10.1007/s00253-012-4404-6

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