It is evident that the widespread misuse of antimicrobial drugs has caused bacterial resistance to all classes of antibiotics. At present, one of the most serious problems worldwide is the multi-drug resistant tuberculosis (MDR-TB), which is classified as an emerging infectious disease threat and a category C priority pathogen by NIAID/NIH. In addition, the recent emergence of extensively drug resistant strains of TB (XDR-TB) that are resistant to both first and second line drugs is even more alarming. Another threat is the infections due to drug-resistant Enterococci (VRE) and Staphylococcus aureus (MRSA), which are serious problems in hospitalized or immunocompromised individuals. There has been a rapid increase in the incidence of VRE infections, as well as a dramatic increase in the incidence of MRSA infections. Unfortunately, at present, there are only very limited therapeutic options available for patients with these infections. Therefore, there is an urgent need for the development of novel antimicrobials against new targets essential for growth, whose inhibition should give a lethal phenotype. Thus, we have selected FtsZ, the tubulin homologue in bacterial cells and essential to bacterial cell division, as the specific target to develop a new class of antimicrobial agents. The bacterial tubulin homologue FtsZ is an essential cell-division protein in bacteria that polymerizes in a GTP-dependent manner, forming a cytokinetic ring at the septum site. Accordingly, FtsZ is a very promising target for discovery and development of new broad-spectrum antimicrobial drugs because of its central role in bacterial cell division. The Principal Investigator (PI) has expertise in anticancer agents targeting tubulin/microtubules and has hypothesized that a certain class of taxanes (microtubule-stabilizer) and benzimidazoles (tubulin polymerization inhibitors) should inhibit the depolymerization or polymerization of FtsZ from Mycobacterium tuberculosis (MTB), MRSA and VRE. The fact that the sequence homology between FtsZ and tubulin is low (<20% identity) strongly indicates an excellent possibility in discovering FtsZ-specific taxanes and benzimidazoles that are non-cytotoxic to human host cells. Building upon highly encouraging preliminary results, the following specific aims will be investigated: (1) Design, Synthesis, Screening and Optimization of Taxanes and Benzimidazoles (2) Investigation into the Mechanism of Action in vitro (3) Investigation into the Mechanism of Action in Live Cells (4) In vivo Efficacy Evaluation with Animal Models Highly integrated collaborative activities will be performed through close cooperation between the Institute for Chemical Biology and Drug Discovery (ICB&DD) at Stony Brook University and The Mycobacteriology Laboratory at Colorado State University.

Public Health Relevance

Multi-drug resistant and extensively drug resistant tuberculosis (MDR-TB and XDR-TB) are classified as an emerging infectious disease threat and category C priority pathogens by NIAID/NIH. Another emerging threat is the infections due to drug-resistant Staphylococcus aureus (MRSA) and Enterococci (VRE), which are serious problems in hospitalized or immunocompromised individuals. Unfortunately, at present, there are only very limited therapeutic options available for patients with these infections. Therefore, there is an urgent need for the development of novel antimicrobials against new targets essential for growth, whose inhibition should give a lethal phenotype. Thus, we have selected FtsZ, the tubulin homologue in bacterial cells and essential to bacterial cell division, as the specific target to develop a new class of antimicrobial agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078251-03
Application #
7994775
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lacourciere, Karen A
Project Start
2008-12-01
Project End
2013-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
3
Fiscal Year
2011
Total Cost
$376,282
Indirect Cost
Name
State University New York Stony Brook
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Haranahalli, Krupanandan; Tong, Simon; Ojima, Iwao (2016) Recent advances in the discovery and development of antibacterial agents targeting the cell-division protein FtsZ. Bioorg Med Chem 24:6354-6369
Ojima, Iwao; Lichtenthal, Brendan; Lee, Siyeon et al. (2016) Taxane anticancer agents: a patent perspective. Expert Opin Ther Pat 26:1-20
Knudson, Susan E; Awasthi, Divya; Kumar, Kunal et al. (2015) Cell division inhibitors with efficacy equivalent to isoniazid in the acute murine Mycobacterium tuberculosis infection model. J Antimicrob Chemother 70:3070-3
Park, Bora; Awasthi, Divya; Chowdhury, Soumya R et al. (2014) Design, synthesis and evaluation of novel 2,5,6-trisubstituted benzimidazoles targeting FtsZ as antitubercular agents. Bioorg Med Chem 22:2602-12
Singh, Dipty; Bhattacharya, Anusri; Rai, Ankit et al. (2014) SB-RA-2001 inhibits bacterial proliferation by targeting FtsZ assembly. Biochemistry 53:2979-92
Knudson, Susan E; Kumar, Kunal; Awasthi, Divya et al. (2014) In vitro-in vivo activity relationship of substituted benzimidazole cell division inhibitors with activity against Mycobacterium tuberculosis. Tuberculosis (Edinb) 94:271-6
Ojima, Iwao; Kumar, Kunal; Awasthi, Divya et al. (2014) Drug discovery targeting cell division proteins, microtubules and FtsZ. Bioorg Med Chem 22:5060-77
Awasthi, Divya; Kumar, Kunal; Knudson, Susan E et al. (2013) SAR studies on trisubstituted benzimidazoles as inhibitors of Mtb FtsZ for the development of novel antitubercular agents. J Med Chem 56:9756-70
Kumar, Kunal; Awasthi, Divya; Lee, Seung-Yub et al. (2013) Benzimidazole-based antibacterial agents against Francisella tularensis. Bioorg Med Chem 21:3318-26
Slayden, Richard A; Jackson, Mary; Zucker, Jeremy et al. (2013) Updating and curating metabolic pathways of TB. Tuberculosis (Edinb) 93:47-59

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