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Novel small-molecule inhibitors of mycobacterial RNAP "AAPS"

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TitleInfo
Title
Novel small-molecule inhibitors of mycobacterial RNAP "AAPS"
Name (type = personal)
NamePart (type = family)
Mandal
NamePart (type = given)
Soma
NamePart (type = date)
1982-
DisplayForm
Soma Mandal
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Ebright
NamePart (type = given)
Richard H
DisplayForm
Richard H Ebright
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Arnold
NamePart (type = given)
Edward
DisplayForm
Edward Arnold
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Olson
NamePart (type = given)
Wilma
DisplayForm
Wilma Olson
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Nickels
NamePart (type = given)
Bryce
DisplayForm
Bryce Nickels
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2014
DateOther (qualifier = exact); (type = degree)
2014-01
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Tuberculosis global epidemics is a serious threat to human population, the disease is estimated to be the second highest cause of death due to infection. In this study we present a lead hit-compound “AAP1” identified through high-throughput screening performed against Mycobacterium tuberculosis RNA polymerase (RNAP). AAP1 displays great potential as a mycobacterial RNAP inhibitor and mycobacterial growth inhibitor. AAP1 can be synthesized from commercially available precursors in single reaction step. AAP1 has a modular structure, facilitating the synthesis of novel AAP1 analogs and facilitating the interpretation of structure-activity relationships for novel AAP1 analogs. Currently, more than 400 AAP1 analogs have been synthesized and tested and based on improved characteristics, an AAP1 analog AAP12 is used in this study with AAP1 (AAPs). By isolating, sequencing, and characterizing spontaneous resistant mutants, we have shown that mycobacterial RNAP is the functional cellular target for the antibacterial activity of AAPs By isolating, sequencing, and characterizing resistant mutants, we have shown AAPs function through a site on RNAP that is different from, and does not overlap with the binding sites for rifamycins. The site is located at the base of RNAP " lobe" and N’- terminal of β’ bridge helix and corresponds, essentially exactly, to the site for CBR703, a compound that does not inhibit mycobacterial RNAP and does not inhibit mycobacterial growth. It appears that AAPs are mycobacterial-specific ligands of RNAP β lobe and that CBR703 is a Gram-negative-specific ligand of the RNAP β lobe. By observing the effect of AAPs on individual transcription step, we have shown that AAPs affect the nucleotide addition cycle of RNAP. Based on the fact that AAPs interfere with the nucleotide addition cycle of the RNAP without making any contact with the active center residues we propose that AAPs function allosterically by binding at the N-terminal sub-region of β’ bridge helix, and by interfering with its conformational dynamics In our current work, we are systematically preparing and evaluating novel AAP1 analogs. The objectives are to increase the antimycobacterial potency, to improve physical and pharmacological properties, and to identify compounds suitable for evaluation in an animal model of tuberculosis.
Subject (authority = RUETD)
Topic
Chemistry and Chemical Biology
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_5293
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
xvii, 93 p. : ill.
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Soma Mandal
Subject (authority = ETD-LCSH)
Topic
Tuberculosis--Microbiology
Subject (authority = ETD-LCSH)
Topic
RNA polymerases
Subject (authority = ETD-LCSH)
Topic
Tuberculosis--Treatment
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/T3Q52MQZ
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Mandal
GivenName
Soma
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (point = start); (qualifier = exact)
2014-01-05 18:08:15
AssociatedEntity
Name
Soma Mandal
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
Type
Embargo
DateTime (encoding = w3cdtf); (keyDate = no); (point = start); (qualifier = exact)
2014-04-21
DateTime (encoding = w3cdtf); (keyDate = no); (point = end); (qualifier = exact)
2016-01-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after January 31, 2016.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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RULTechMD (ID = TECHNICAL1)
ContentModel
ETD
OperatingSystem (VERSION = 5.1)
windows xp
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