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Antimicrobial Agents and Chemotherapy, April 2009, p. 1395-1402, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01087-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Contribution of Oxidative Damage to Antimicrobial Lethality{triangledown}

Xiuhong Wang1,2 and Xilin Zhao1*

Public Health Research Institute, New Jersey Medical School-UMDNJ, 225 Warren Street, Newark, New Jersey 07103,1 Department of Biochemistry, Harbin Medical University, 194 Xuefu Road, Nangang District, Harbin, Heilongjiang Province 150081, China2

Received 12 August 2008/ Returned for modification 7 January 2009/ Accepted 30 January 2009

A potential pathway linking hydroxyl radicals to antimicrobial lethality was examined by using mutational and chemical perturbations of Escherichia coli. Deficiencies of sodA or sodB had no effect on norfloxacin lethality; however, the absence of both genes together reduced lethal activity, consistent with rapid conversion of excessive superoxide to hydrogen peroxide contributing to quinolone lethality. Norfloxacin was more lethal with a mutant deficient in katG than with its isogenic parent, suggesting that detoxification of peroxide to water normally reduces quinolone lethality. An iron chelator (bipyridyl) and a hydroxyl radical scavenger (thiourea) reduced the lethal activity of norfloxacin, indicating that norfloxacin-stimulated accumulation of peroxide affects lethal activity via hydroxyl radicals generated through the Fenton reaction. Ampicillin and kanamycin, antibacterials unrelated to fluoroquinolones, displayed behavior similar to that of norfloxacin except that these two agents showed hyperlethality with an ahpC (alkyl hydroperoxide reductase) mutant rather than with a katG mutant. Collectively, these data are consistent with antimicrobial stress increasing the production of superoxide, which then undergoes dismutation to peroxide, from which a highly toxic hydroxyl radical is generated. Hydroxyl radicals then enhance antimicrobial lethality, as suggested by earlier work. Such findings indicate that oxidative stress networks may provide targets for antimicrobial potentiation.

* Corresponding author. Mailing address: Public Health Research Institute, New Jersey Medical School-UMDNJ, 225 Warren Street, Newark, NJ 07103. Phone: (973) 854-3364. Fax: (973) 854-3101. E-mail: zhaox5{at}umdnj.edu

{triangledown} Published ahead of print on 17 February 2009.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1395-1402, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01087-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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