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Antimicrobial Agents and Chemotherapy, October 2009, p. 4283-4291, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.01709-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Novel Broad-Spectrum Bis-(Imidazolinylindole) Derivatives with Potent Antibacterial Activities against Antibiotic-Resistant Strains ^,

Rekha G. Panchal,^1* Ricky L. Ulrich,¹ Douglas Lane,² Michelle M. Butler,³ Chad Houseweart,³ Timothy Opperman,³ John D. Williams,³ Norton P. Peet,³ Donald T. Moir,³ Tam Nguyen,² Rick Gussio,⁴ Terry Bowlin,³ and Sina Bavari^1*

United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, Maryland 21702-5011,¹ Target Structure Based Drug Discovery Group, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702-1201,² Microbiotix Inc., One Innovation Dr., Worcester, Massachusetts 01605,³ Target Structure Based Drug Discovery Group, Information Technology Branch, Developmental Therapeutic Program, National Cancer Institute, Frederick, Maryland 21702-1201⁴

Received 23 December 2008/ Returned for modification 10 February 2009/ Accepted 1 July 2009

Given the limited number of structural classes of clinically available antimicrobial drugs, the discovery of antibacterials with novel chemical scaffolds is an important strategy in the development of effective therapeutics for both naturally occurring and engineered resistant strains of pathogenic bacteria. In this study, several diarylamidine derivatives were evaluated for their ability to protect macrophages from cell death following infection with Bacillus anthracis, a gram-positive spore-forming bacterium. Four bis-(imidazolinylindole) compounds were identified with potent antibacterial activity as measured by the protection of macrophages and by the inhibition of bacterial growth in vitro. These compounds were effective against a broad range of gram-positive and gram-negative bacterial species, including several antibiotic-resistant strains. Minor structural variations among the four compounds correlated with differences in their effects on bacterial macromolecular synthesis and mechanisms of resistance. In vivo studies revealed protection by two of the compounds of mice lethally infected with B. anthracis, Staphylococcus aureus, or Yersinia pestis. Taken together, these results indicate that the bis-(imidazolinylindole) compounds represent a new chemotype for the development of therapeutics for both gram-positive and gram-negative bacterial species as well as against antibiotic-resistant infections.

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* Corresponding author. Mailing address: United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702-5011. Phone for Rekha G. Panchal: (301) 619-4985. Fax: (301) 619-2348. E-mail: rekha.panchal{at}amedd.army.mil. Phone for Sina Bavari: (301) 619-4246. Fax: (301) 619-2348. E-mail: sina.bavari{at}amedd.army.mil

Published ahead of print on 27 July 2009.

Supplemental material for this article may be found at http://aac.asm.org/.

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Antimicrobial Agents and Chemotherapy, October 2009, p. 4283-4291, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.01709-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.