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Berberine-INF55 (5-Nitro-2-Phenylindole) Hybrid Antimicrobials: Effects of Varying the Relative Orientation of the Berberine and INF55 Components
- Source :
- Antimicrobial Agents and Chemotherapy. 54:3219-3224
- Publication Year :
- 2010
- Publisher :
- American Society for Microbiology, 2010.
-
Abstract
- Hybrid antimicrobials containing an antibacterial linked to a multidrug resistance (MDR) pump inhibitor make up a promising new class of agents for countering efflux-mediated bacterial drug resistance. This study explores the effects of varying the relative orientation of the antibacterial and efflux pump inhibitor components in three isomeric hybrids (SS14, SS14-M, and SS14-P) which link the antibacterial alkaloid and known substrate for the NorA MDR pump berberine to different positions on INF55 (5-nitro-2-phenylindole), an inhibitor of NorA. The MICs for all three hybrids against wild-type, NorA-knockout, and NorA-overexpressing Staphylococcus aureus cells were found to be similar (9.4 to 40.2 μM), indicating that these compounds are not effectively effluxed by NorA. The three hybrids were also found to have similar curing effects in a Caenorhabditis elegans live infection model. Each hybrid was shown to accumulate in S. aureus cells to a greater extent than either berberine or berberine in the presence of INF55, and the uptake kinetics of SS14 were found to differ from those of SS14-M and SS14-P. The effects on the uptake and efflux of the NorA substrate ethidium bromide into S. aureus cells in the presence or absence of the hybrids were used to confirm MDR inhibition by the hybrids. MDR-inhibitory activity was confirmed for SS14-M and SS14-P but not for SS14. Molecular dynamics simulations revealed that SS14 prefers to adopt a conformation that is not prevalent in either SS14-M or SS14-P, which may explain why some properties of SS14 diverge from those of its two isomers. In summary, subtle repositioning of the pump-blocking INF55 moiety in berberine-INF55 hybrids was found to have a minimal effect on their antibacterial activities but to significantly alter their effects on MDR pumps.
- Subjects :
- Staphylococcus aureus
Indoles
Berberine
Stereochemistry
Microbial Sensitivity Tests
Biology
medicine.disease_cause
Structure-Activity Relationship
chemistry.chemical_compound
Bacterial Proteins
Drug Resistance, Multiple, Bacterial
Ethidium
Enterococcus faecalis
medicine
Animals
Structure–activity relationship
Pharmacology (medical)
Caenorhabditis elegans
Mechanisms of Action: Physiological Effects
Pharmacology
Antiinfective agent
Molecular Structure
Alkaloid
Anti-Bacterial Agents
Multiple drug resistance
Infectious Diseases
Biochemistry
chemistry
Drug Design
Efflux
Multidrug Resistance-Associated Proteins
Ethidium bromide
Subjects
Details
- ISSN :
- 10986596 and 00664804
- Volume :
- 54
- Database :
- OpenAIRE
- Journal :
- Antimicrobial Agents and Chemotherapy
- Accession number :
- edsair.doi.dedup.....5464ecf5c931b6adecb3500682d0b697