title: Novel imidazoline antimicrobial scaffold that inhibits DNA replication with activity against mycobacteria and drug resistant Gram-positive cocci.
abstract: 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.
authors.affiliation: Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences , New York, New York 10021, United States.
authors.forename: Kendra K
authors.initials: KK
authors.lastname: Harris
authors.forename: Allison
authors.initials: A
authors.lastname: Fay
authors.forename: Han-Guang
authors.initials: HG
authors.lastname: Yan
authors.forename: Pratima
authors.initials: P
authors.lastname: Kunwar
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.forename: Narender
authors.initials: N
authors.lastname: Pottabathini
authors.forename: Ramakrishna R
authors.initials: RR
authors.lastname: Juventhala
authors.forename: Hakim
authors.initials: H
authors.lastname: Djaballah
authors.forename: Michael S
authors.initials: MS
authors.lastname: Glickman
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects*; D006095:Gram-Positive Cocci / Q000187:drug effects* / Q000235:genetics; D048288:Imidazolines / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D009154:Mutation; D009161:Mycobacterium / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D048288:Imidazolines