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Antimicrobial Agents and Chemotherapy, August 2002, p. 2333-2336, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2333-2336.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Two Diarylurea Electron Transport Inhibitors Reduce Staphylococcus aureus Hemolytic Activity and Protect Cultured Endothelial Cells from Lysis

R. A. Proctor,^1,2* S. C. Dalal,¹ B. Kahl,³ D. Brar,¹ G. Peters,³ and W. W. Nichols⁴

Department of Medical Microbiology and Immunology,¹ Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin,² Department of Medical Microbiology, Münster University, Münster, Germany,³ Zeneca Pharmaceuticals, AstraZeneca, Waltham, Massachusetts⁴

Received 10 July 2001/ Returned for modification 10 April 2002/ Accepted 15 April 2002

Reduction in electron transport is associated with decreased production in alpha-toxin despite the fact that Staphylococcus aureus is able to grow from 1 CFU to >10⁷ CFU. Similarly, under anaerobic conditions, S. aureus does not produce alpha-toxin. Although the pathways that connect oxidative metabolism and toxin production are unknown, agents are available that exhibit greater inhibition of plant versus mammalian electron transport. Herbicides block electron transport in plants by inhibiting the formation of phosphoquinol (QH₂) in plants. Commercial use in farming is possible because these compounds are much less active against the quinones found mammalian mitochondria. Because bacterial electron transport systems are closer to plant than mammalian systems, we hypothesized that inhibitors of respiration might be able to reduce S. aureus electron transport and block the production of alpha-toxin. We studied two compounds and found that the effective dose for the inhibition of bacterial respiration was 50 to >3,500 times lower than the concentration required to cause similar inhibition of rat mitochondrial respiration. Compounds I and II also reduced toxin production in S. aureus without causing overt toxicity to cultured endothelial cells. Finally, the compounds reduced the damage caused by S. aureus when cocultured with the endothelial cells. This raises the possibility that compounds that inhibit bacterial respiration might be prove valuable for the prevention of toxin production in S. aureus.

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* Corresponding author. Mailing address: 407 SMI, Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Madison, WI 53706. Phone: (608) 263-5591. Fax: (608) 262-8418. E-mail: rap{at}facstaff.wisc.edu.

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Antimicrobial Agents and Chemotherapy, August 2002, p. 2333-2336, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2333-2336.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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