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Antimicrobial Agents and Chemotherapy, September 2008, p. 3202-3209, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00006-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inhibitors of Bacterial Multidrug Efflux Pumps Potentiate Antimicrobial Photoinactivation{triangledown}

George P. Tegos,1,2 Kayo Masago,1,3 Fatima Aziz,1,4 Andrew Higginbotham,5 Frank R. Stermitz,5 and Michael R. Hamblin1,2,6*

Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts,1 Department of Dermatology, Harvard Medical School, Boston, Massachusetts,2 Department of Materials Science and Engineering, Graduate School of Engineering, University of Tokyo, Tokyo, Japan,3 Aga Khan Medical School, Karachi, Pakistan,4 Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523,5 Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts6

Received 2 January 2008/ Returned for modification 2 March 2008/ Accepted 1 May 2008

Antimicrobial photodynamic inactivation (APDI) combines a nontoxic photoactivatable dye or photosensitizer (PS) with harmless visible light to generate singlet oxygen and reactive oxygen species that kill microbial cells. Cationic phenothiazinium dyes, such as toluidine blue O (TBO), are the only PS used clinically for APDI, and we recently reported that this class of PS are substrates of multidrug efflux pumps in both gram-positive and gram-negative bacteria. We now report that APDI can be significantly potentiated by combining the PS with an efflux pump inhibitor (EPI). Killing of Staphylococcus aureus mediated by TBO and red light is greatly increased by coincubation with known inhibitors of the major facilitator pump (NorA): the diphenyl urea INF271, reserpine, 5'-methoxyhydnocarpin, and the polyacylated neohesperidoside, ADH7. The potentiation effect is greatest in the case of S. aureus mutants that overexpress NorA and least in NorA null cells. Addition of the EPI before TBO has a bigger effect than addition of the EPI after TBO. Cellular uptake of TBO is increased by EPI. EPI increased photodynamic inactivation killing mediated by other phenothiazinium dyes, such as methylene blue and dimethylmethylene blue, but not that mediated by nonphenothiazinium PS, such as Rose Bengal and benzoporphyrin derivative. Killing of Pseudomonas aeruginosa mediated by TBO and light was also potentiated by the resistance nodulation division pump (MexAB-OprM) inhibitor phenylalanine-arginine beta-naphthylamide but to a lesser extent than for S. aureus. These data suggest that EPI could be used in combination with phenothiazinium salts and light to enhance their antimicrobial effect against localized infections.

* Corresponding author. Mailing address: BAR414, Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA 02114. Phone: (617) 726-6182. Fax: (617) 726-8566. E-mail: hamblin{at}helix.mgh.harvard.edu

{triangledown} Published ahead of print on 12 May 2008.

Antimicrobial Agents and Chemotherapy, September 2008, p. 3202-3209, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00006-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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