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Antimicrobial Agents and Chemotherapy, December 2009, p. 5236-5244, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00555-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Eradication of Intracellular Salmonella enterica Serovar Typhimurium with a Small-Molecule, Host Cell-Directed Agent{triangledown}

Hao-Chieh Chiu,1 Samuel K. Kulp,1 Shilpa Soni,2,3 Dasheng Wang,1 John S. Gunn,2,3,4 Larry S. Schlesinger,2,3,4 and Ching-Shih Chen1*

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy,1 Center for Microbial Interface Biology,2 Department of Molecular Virology, Immunology and Medical Genetics,3 Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 432104

Received 24 April 2009/ Returned for modification 6 July 2009/ Accepted 28 September 2009

Eradication of intracellular pathogenic bacteria with host-directed chemical agents has been an anticipated innovation in the treatment of antibiotic-resistant bacteria. We previously synthesized and characterized a novel small-molecule agent, AR-12, that induces autophagy and inhibits the Akt kinase in cancer cells. As both autophagy and the Akt kinase have been shown recently to play roles in the intracellular survival of several intracellular bacteria, including Salmonella enterica serovar Typhimurium, we investigated the effect of AR-12 on the intracellular survival of Salmonella serovar Typhimurium in macrophages. Our results show that AR-12 induces autophagy in macrophages, as indicated by increased autophagosome formation, and potently inhibits the survival of serovar Typhimurium in macrophages in association with increased colocalization of intracellular bacteria with autophagosomes. Intracellular bacterial growth was partially rescued in the presence of AR-12 by the short hairpin RNA-mediated knockdown of Beclin-1 or Atg7 in macrophages. Moreover, AR-12 inhibits Akt kinase activity in infected macrophages, which we show to be important for its antibacterial effect as the enforced expression of constitutively activated Akt1 in these cells reverses the AR-12-induced inhibition of intracellular serovar Typhimurium survival. Finally, oral administration of AR-12 at 2.5 mg/kg/day to serovar Typhimurium-infected mice reduced hepatic and splenic bacterial burdens and significantly prolonged survival. These findings show that AR-12 represents a proof of principle that the survival of intracellular bacteria can be suppressed by small-molecule agents that target both innate immunity and host cell factors modulated by bacteria.

* Corresponding author. Mailing address: Division of Medicinal Chemistry, College of Pharmacy, 336 L. M. Parks Hall, 500 West 12th Avenue, Columbus, OH 43210. Phone: (614) 688-4008. Fax: (614) 688-8556. E-mail: chen.844{at}osu.edu

{triangledown} Published ahead of print on 5 October 2009.

Antimicrobial Agents and Chemotherapy, December 2009, p. 5236-5244, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00555-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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