Towards Development of Small Molecule Lipid II Inhibitors as Novel Antibiotics

Autor: Alexander D. MacKerell, Jing Huang, Robert C. diTargiani, Lei Fang, Timothy J. Opperman, Steven M. Kwasny, Erik de Leeuw, Benedict R. Capacio, M. Ross Pennington, Steven C. Cardinale, Kelly A. Basi, Steven Fletcher, Jamal Chauhan
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Cytotoxicity
Staphylococcus
Antibiotics
lcsh:Medicine
Toxicology
Pathology and Laboratory Medicine
Biochemistry
Mice
Oral administration
Medicine and Health Sciences
Staphylococcus Aureus
lcsh:Science
Multidisciplinary
Lipid II
Antimicrobials
Drugs
Pseudomonas Aeruginosa
Blood Proteins
Lipids
Small molecule
Bacterial Pathogens
Anti-Bacterial Agents
3. Good health
Medical Microbiology
Microsomes
Liver
Pathogens
Cellular Structures and Organelles
Research Article
medicine.drug_class
030106 microbiology
Enterococcus Faecalis
Microbial Sensitivity Tests
Molecular Dynamics Simulation
Biology
Microbiology
03 medical and health sciences
Cell Walls
Pharmacokinetics
In vivo
Microbial Control
Pseudomonas
medicine
Animals
Humans
Microbial Pathogens
Pharmacology
Bacteria
lcsh:R
Organisms
Biology and Life Sciences
Cell Biology
Surface Plasmon Resonance
In vitro
030104 developmental biology
Antibacterials
lcsh:Q
Enterococcus
Zdroj: PLoS ONE, Vol 11, Iss 10, p e0164515 (2016)
PLoS ONE
ISSN: 1932-6203
Popis: Recently we described a novel di-benzene-pyrylium-indolene (BAS00127538) inhibitor of Lipid II. BAS00127538 (1-Methyl-2,4-diphenyl-6-((1E,3E)-3-(1,3,3-trimethylindolin-2-ylidene)prop-1-en-1-yl)pyryl-1-ium) tetrafluoroborate is the first small molecule Lipid II inhibitor and is structurally distinct from natural agents that bind Lipid II, such as vancomycin. Here, we describe the synthesis and biological evaluation of 50 new analogs of BAS00127538 designed to explore the structure-activity relationships of the scaffold. The results of this study indicate an activity map of the scaffold, identifying regions that are critical to cytotoxicity, Lipid II binding and range of anti-bacterial action. One compound, 6jc48-1, showed significantly enhanced drug-like properties compared to BAS00127538. 6jc48-1 has reduced cytotoxicity, while retaining specific Lipid II binding and activity against Enterococcus spp. in vitro and in vivo. Further, this compound showed a markedly improved pharmacokinetic profile with a half-life of over 13 hours upon intravenous and oral administration and was stable in plasma. These results suggest that scaffolds like that of 6jc48-1 can be developed into small molecule antibiotic drugs that target Lipid II.
Databáze: OpenAIRE
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