cb500573z_si_004.avi (1.62 MB)
Novel Imidazoline Antimicrobial Scaffold That Inhibits DNA Replication with Activity against Mycobacteria and Drug Resistant Gram-Positive Cocci
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posted on 2015-12-17, 05:57 authored by Kendra
K. Harris, Allison Fay, Han-Guang Yan, Pratima Kunwar, Nicholas
D. Socci, Narender Pottabathini, Ramakrishna R. Juventhala, Hakim Djaballah, Michael S. GlickmanBacterial
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.