Type
Text
Type
Dissertation
Advisor
Kerber, Robert | Ojima, Iwao | Drueckhammer, Dale | Kaneko, Takushi.
Date
2015-08-01
Keywords
Chemistry | Antibacterial agent, Anti-tubercular, FtsZ, Trisubstituted benzimdazole
Department
Department of Chemistry.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/77085
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
FtsZ protein, which bears limited sequence homology to tubulin in eukaryotic cells, is involved in bacterial cell division. Interference with the assembly/disassembly dynamics of this protein affects the cell division processes, leading to inhibition of septation. Our laboratory has synthesized libraries of novel 2,5,6- and 2,5,7-trisubstituted benzimidazoles to target this vital cell division protein for antibacterial drug discovery. Specifically, we have identified >200 compounds possessing activity against the infectious bacterial pathogen, Mycobacterium tuberculosis (Mtb). These compounds exhibit excellent activity against drug-sensitive and drug-resistant Mtb strains along with displaying potency against Mtb grown under hypoxic conditions. In addition, these compounds inhibit Mtb FtsZ polymerization while enhancing its GTPase activity which was ascertained via light scattering assays, GTPase assays and Transmission electron microscopy (TEM) imaging studies. Extensive optimization studies on the initial lead compound SB-P3G2 possessing a 6-diethylamino group has led us to a series of 6-dimethylamino substituted benzimidazoles with superior in vitro activity against Mtb (MIC 0.06 - 0.63 µg/mL). In the murine acute model of TB infection, a representative compound from this series, SB-P17G-A38, when dosed orally or intraperitoneally, dramatically reduced the bacterial load in the lung by 6 Log10 CFU and 5 Log10 CFU in the spleen. These results are very exciting since treatment with SB-P17G-A38 essentially eliminated all live bacteria from the spleen of the infected mice. Furthermore, the trisubstituted benzimidazole libraries have been screened against other bacterial pathogens like F. tularensis, Y. pestis and B. thailandensis, to successfully identify several hit compounds active at MIC ≤ 5 µg/mL. This elucidates the broad spectrum potency of these compounds. We have also synthesized non-cytotoxic taxanes which selectively inhibit Mtb cell growth (MIC 1.25-2.5 µM). The target of the lead taxanes, SB-RA-2001 and SB-RA-5001, has been validated as Mtb FtsZ via TEM imaging. To expand on the benzimidazole scaffold, a series of 2,5,6-trisubstituted benzoxazoles have also been synthesized and evaluated for anti-tubercular activity. This series of compounds although in a nascent stage, offers a new pharmacophores for the discovery of antibacterial agents. | FtsZ protein, which bears limited sequence homology to tubulin in eukaryotic cells, is involved in bacterial cell division. Interference with the assembly/disassembly dynamics of this protein affects the cell division processes, leading to inhibition of septation. Our laboratory has synthesized libraries of novel 2,5,6- and 2,5,7-trisubstituted benzimidazoles to target this vital cell division protein for antibacterial drug discovery. Specifically, we have identified >200 compounds possessing activity against the infectious bacterial pathogen, Mycobacterium tuberculosis (Mtb). These compounds exhibit excellent activity against drug-sensitive and drug-resistant Mtb strains along with displaying potency against Mtb grown under hypoxic conditions. In addition, these compounds inhibit Mtb FtsZ polymerization while enhancing its GTPase activity which was ascertained via light scattering assays, GTPase assays and Transmission electron microscopy (TEM) imaging studies. Extensive optimization studies on the initial lead compound SB-P3G2 possessing a 6-diethylamino group has led us to a series of 6-dimethylamino substituted benzimidazoles with superior in vitro activity against Mtb (MIC 0.06 - 0.63 µg/mL). In the murine acute model of TB infection, a representative compound from this series, SB-P17G-A38, when dosed orally or intraperitoneally, dramatically reduced the bacterial load in the lung by 6 Log10 CFU and 5 Log10 CFU in the spleen. These results are very exciting since treatment with SB-P17G-A38 essentially eliminated all live bacteria from the spleen of the infected mice. Furthermore, the trisubstituted benzimidazole libraries have been screened against other bacterial pathogens like F. tularensis, Y. pestis and B. thailandensis, to successfully identify several hit compounds active at MIC ≤ 5 µg/mL. This elucidates the broad spectrum potency of these compounds. We have also synthesized non-cytotoxic taxanes which selectively inhibit Mtb cell growth (MIC 1.25-2.5 µM). The target of the lead taxanes, SB-RA-2001 and SB-RA-5001, has been validated as Mtb FtsZ via TEM imaging. To expand on the benzimidazole scaffold, a series of 2,5,6-trisubstituted benzoxazoles have also been synthesized and evaluated for anti-tubercular activity. This series of compounds although in a nascent stage, offers a new pharmacophores for the discovery of antibacterial agents. | 451 pages
Recommended Citation
Awasthi, Divya, "Discovery of Neoteric Antibacterial Agents Targeting the Cell Division Protein FtsZ" (2015). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 2922.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/2922