Novel imidazoline antimicrobial scaffold that inhibits DNA replication with activity against mycobacteria and drug resistant gram-positive cocci Journal Article
| Authors: | Harris, K. K.; Fay, A.; Yan, H. G.; Kunwar, P.; Socci, N. D.; Pottabathini, N.; Juventhala, R. R.; Djaballah, H.; Glickman, M. S. |
| Article 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. |
| Keywords: | controlled study; unclassified drug; gene sequence; single nucleotide polymorphism; nonhuman; dna replication; dna synthesis; translation initiation; animal tissue; amino acid substitution; animal experiment; animal model; high throughput screening; in vitro study; drug screening; structure activity relation; antibiotic resistance; mycobacterium tuberculosis; protein synthesis; rna synthesis; methicillin resistant staphylococcus aureus; vancomycin resistant enterococcus; vancomycin; corynebacterineae; rifampicin; pneumococcal infection; streptococcus pneumoniae; antimycobacterial agent; methicillin resistant staphylococcus aureus infection; enterococcus faecium; bacterial growth; operon; kanamycin; replisome; dna directed dna polymerase gamma; minimum inhibitory concentration; bactericidal activity; posibacteria; isoniazid; ethidium bromide; article; ic50; antitoxin; imidazoline derivative; ski 356313; genomic fragment |
| Journal Title: | ACS Chemical Biology |
| Volume: | 9 |
| Issue: | 11 |
| ISSN: | 1554-8929 |
| Publisher: | American Chemical Society |
| Date Published: | 2014-11-21 |
| Start Page: | 2572 |
| End Page: | 2583 |
| Language: | English |
| DOI: | 10.1021/cb500573z |
| PROVIDER: | scopus |
| PMCID: | PMC4245167 |
| PUBMED: | 25222597 |
| DOI/URL: | |
| Notes: | Export Date: 2 January 2015 -- Source: Scopus |
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