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Antimicrobial Agents and Chemotherapy, December 2003, p. 3901-3906, Vol. 47, No. 12
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.12.3901-3906.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Novispirin G10-Induced Lung Toxicity in a Klebsiella pneumoniae Infection Model

Karen H. Bartlett,^1, Paul B. McCray Jr.,² and Peter S. Thorne^1*

Department of Occupational and Environmental Health,¹ Department of Pediatrics, The University of Iowa, Iowa City, Iowa 52242²

Received 5 June 2003/ Returned for modification 19 August 2003/ Accepted 9 September 2003

Mammalian cathelicidins are a class of innate antimicrobial peptides isolated from leukocytes and epithelial cells that aid host defense against bacterial infections. Synthetic analogs of cathelicidins offer the promise of potent broad-spectrum antimicrobial efficacy. We developed a combined lung infection and ex vivo whole-blood assay model to characterize the toxicity and efficacy of synthetic cathelicidin-derived peptides. Male C57BL/6 mice were administered saline or Klebsiella pneumoniae by intratracheal instillation. Five hours later, the Klebsiella-infected mice were instilled with saline, tobramycin (1 mg/kg of body weight or 10 mg/kg), novispirin G10 (0.4 mg/kg), or a combination of tobramycin (1 mg/kg) and G10 (0.4 mg/kg). At 24 h, bronchoalveolar lavage fluid (BAL) was collected for analysis of culturable bacteria and for markers of inflammation and lung toxicity. Blood samples were analyzed for circulating cytokines. Recovery of Klebsiella from the lung, recruitment of neutrophils, and production of interleukin-6 (IL-6) in BAL samples were highly correlated (r = 0.68 and 0.84, respectively; P < 0.01). Animals treated with G10 or G10 plus tobramycin had increased hemoglobin (P < 0.001) and protein (P < 0.001) levels compared to those for Klebsiella-infected or tobramycin-alone-treated animals. The levels of circulating IL-6 in mice infected with Klebsiella were 1000- to 10,000-fold higher than in the noninfected controls. The highest levels of IL-6 were measured in mice given G10 alone or in combination with tobramycin. These studies demonstrated that G10 was relatively nontoxic in saline-treated mice but was highly toxic in mice infected with Klebsiella. This finding establishes the importance of investigating candidate antimicrobial agents in an in vivo infection model.

Present address: School of Occupational and Environmental Hygiene, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

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