PMID- 25222597
OWN - NLM
STAT- MEDLINE
DCOM- 20150713
LR  - 20211021
IS  - 1554-8937 (Electronic)
IS  - 1554-8929 (Print)
IS  - 1554-8929 (Linking)
VI  - 9
IP  - 11
DP  - 2014 Nov 21
TI  - Novel imidazoline antimicrobial scaffold that inhibits DNA replication with 
      activity against mycobacteria and drug resistant Gram-positive cocci.
PG  - 2572-83
LID - 10.1021/cb500573z [doi]
AB  - Bacterial antimicrobial resistance is an escalating public health threat, yet the 
      current antimicrobial pipeline remains alarmingly depleted, making the 
      development of new antimicrobials an urgent need. Here, we identify a novel, 
      potent, imidazoline antimicrobial compound, SKI-356313, with bactericidal 
      activity against Mycobacterium tuberculosis and Gram-positive cocci, including 
      vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant 
      Staphylococcus aureus (MRSA). SKI-356313 is active in murine models of 
      Streptococcus pneumoniae and MRSA infection and is potently bactericidal for both 
      replicating and nonreplicating M. tuberculosis. Using a combination of genetics, 
      whole genome sequencing, and a novel target ID approach using real time imaging 
      of core macromolecular biosynthesis, we show that SKI-356313 inhibits DNA 
      replication and displaces the replisome from the bacterial nucleoid. These 
      results identify a new antimicrobial scaffold with a novel mechanism of action 
      and potential therapeutic utility against nonreplicating M. tuberculosis and 
      antibiotic resistant Gram-positive cocci.
FAU - Harris, Kendra K
AU  - Harris KK
AD  - Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School 
      of Medical Sciences , New York, New York 10021, United States.
FAU - Fay, Allison
AU  - Fay A
FAU - Yan, Han-Guang
AU  - Yan HG
FAU - Kunwar, Pratima
AU  - Kunwar P
FAU - Socci, Nicholas D
AU  - Socci ND
FAU - Pottabathini, Narender
AU  - Pottabathini N
FAU - Juventhala, Ramakrishna R
AU  - Juventhala RR
FAU - Djaballah, Hakim
AU  - Djaballah H
FAU - Glickman, Michael S
AU  - Glickman MS
LA  - eng
GR  - T32CA009149/CA/NCI NIH HHS/United States
GR  - R25 TW009337/TW/FIC NIH HHS/United States
GR  - T32 CA009149/CA/NCI NIH HHS/United States
GR  - T32GM007739/GM/NIGMS NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - P30CA008748/CA/NCI NIH HHS/United States
GR  - T32 GM007739/GM/NIGMS NIH HHS/United States
GR  - T32TW009337/TW/FIC NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140915
PL  - United States
TA  - ACS Chem Biol
JT  - ACS chemical biology
JID - 101282906
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Imidazolines)
SB  - IM
MH  - Animals
MH  - Anti-Bacterial Agents/chemistry/*pharmacology
MH  - DNA Replication/*drug effects
MH  - Gram-Positive Cocci/*drug effects/genetics
MH  - Imidazolines/chemistry/*pharmacology
MH  - Mice
MH  - Mutation
MH  - Mycobacterium/*drug effects/genetics
MH  - Structure-Activity Relationship
PMC - PMC4245167
EDAT- 2014/09/16 06:00
MHDA- 2015/07/15 06:00
PMCR- 2015/09/15
CRDT- 2014/09/16 06:00
PHST- 2014/09/16 06:00 [entrez]
PHST- 2014/09/16 06:00 [pubmed]
PHST- 2015/07/15 06:00 [medline]
PHST- 2015/09/15 00:00 [pmc-release]
AID - 10.1021/cb500573z [doi]
PST - ppublish
SO  - ACS Chem Biol. 2014 Nov 21;9(11):2572-83. doi: 10.1021/cb500573z. Epub 2014 Sep 
      15.