The overall objective of this project is to develop a novel chemical class of broad-spectrum therapeutic agents, the bis-indole lead series, for use against Gram-negative category A and B bacterial biodefense threats, and file an IND by the end of the five year grant. The limited number and efficacy of current therapies, increasing drug resistance, and the possibility of deliberate engineering of antibiotic resistant strains argue for the urgent development of new more potent, broad-acting antibacterial agents capable of combating these biodefense threats. Compounds in this new chemical series exhibit broad-spectrum antibacterial activity, displaying potent inhibition (MICs of 0.3-.30ug/ml) of the growth of Gram-negative bacterial species, including a number of Category A and B agents such as Yersinia pestis, Francisella tularensis, Burkholderia mallei and pseudomallei. These compounds are also active against ciprofloxacin-resistant Bacillus anthracis (MIC 0.2-0.4ug/ml) and a variety of other Gram-positive and Gram-negative bacterial species. They act by a rapid bactericidal mechanism, exhibiting 3-log's of killing in 1-4 hours at concentrations near the MIC values. The mechanism of action is unknown. We have not been able to isolate mutants resistant to the primary lead scaffold MBX 1066. The lead series is effective in murine models of Gram-negative infections (ED50 <10 mg/kg). In addition, the compounds are well-tolerated in mice (MTD >400 mg/kg). Finally, these compounds are relatively easy and inexpensive to synthesize, with a very favorable cost of goods. These overall characteristics advocate for the rapid development of these compounds as broad spectrum antibacterial agents for use against biodefense category A and B bacterial pathogens. In this application, we propose to chemically optimize the bis-indole lead series in a rational drug discovery effort focused on improving broad-spectrum potency against gram-negative category A and B bacterial threats, demonstrate efficacy in animal models and establish the mechanism of action. Once a final clinical candidate has been chosen, we will conduct IND-enabling (GLP) pharmacokinetic, toxicology and safety pharmacology studies, in two species, and submit an IND.

Public Health Relevance

Gram-negative category A and B bacterial biodefense pathogens represent a serious threat to the United States. The very limited number and efficacy of current therapies, increasing drug resistance, and the possibility of deliberate engineering of antibiotic resistant strains argue for the urgent development of new more potent, broad-acting antibacterial agents capable of combating these threats. The objective is to develop a new chemical class of broad-spectrum therapeutic agents for use against these threats

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI082052-05
Application #
8481504
Study Section
Special Emphasis Panel (ZAI1-MMT-M (J3))
Program Officer
Franceschi, Francois J
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$884,280
Indirect Cost
$224,779
Name
Microbiotix, Inc
Department
Type
DUNS #
158864715
City
Worcester
State
MA
Country
United States
Zip Code
01605
Nguyen, Son T; Williams, John D; Butler, Michelle M et al. (2014) Synthesis and antibacterial evaluation of new, unsymmetrical triaryl bisamidine compounds. Bioorg Med Chem Lett 24:3366-72
Williams, John D; Ding, Xiaoyuan; Nguyen, Son et al. (2013) Syntheses of Benzo[b]furan-6-carbonitrile and 6-Cyanobenzo[b]furan-2-boronic Acid Pinacol Ester. Synth Commun 43:
Williams, John D; Nguyen, Son T; Gu, Shen et al. (2013) Potent and broad-spectrum antibacterial activity of indole-based bisamidine antibiotics: synthesis and SAR of novel analogs of MBX 1066 and MBX 1090. Bioorg Med Chem 21:7790-806