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Berberine-INF55 (5-nitro-2-phenylindole) hybrid antimicrobials: effects of varying the relative orientation of the berberine and INF55 components

Journal Article


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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 mu M), 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.

Authors


  •   Tomkiewicz, Danuta (external author)
  •   Casadei, Gabriele (external author)
  •   Larkins-Ford, Jonah (external author)
  •   Moy, Terence I. (external author)
  •   Garner, James A. (external author)
  •   Bremner, John B.
  •   Ausubel, Frederik M. (external author)
  •   Lewis, Kim (external author)
  •   Kelso, Michael J.

Publication Date


  • 2010

Citation


  • Tomkiewicz, D., Casadei, G., Larkins-Ford, J., Moy, T. I., Garner, J., Bremner, J. B., Ausubel, F. M., Lewis, K. & Kelso, M. J. (2010). Berberine-INF55 (5-nitro-2-phenylindole) hybrid antimicrobials: effects of varying the relative orientation of the berberine and INF55 components. Antimicrobial Agents and Chemotherapy, 54 (8), 3219-3224.

Scopus Eid


  • 2-s2.0-77955379580

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1438&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/402

Number Of Pages


  • 5

Start Page


  • 3219

End Page


  • 3224

Volume


  • 54

Issue


  • 8

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 mu M), 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.

Authors


  •   Tomkiewicz, Danuta (external author)
  •   Casadei, Gabriele (external author)
  •   Larkins-Ford, Jonah (external author)
  •   Moy, Terence I. (external author)
  •   Garner, James A. (external author)
  •   Bremner, John B.
  •   Ausubel, Frederik M. (external author)
  •   Lewis, Kim (external author)
  •   Kelso, Michael J.

Publication Date


  • 2010

Citation


  • Tomkiewicz, D., Casadei, G., Larkins-Ford, J., Moy, T. I., Garner, J., Bremner, J. B., Ausubel, F. M., Lewis, K. & Kelso, M. J. (2010). Berberine-INF55 (5-nitro-2-phenylindole) hybrid antimicrobials: effects of varying the relative orientation of the berberine and INF55 components. Antimicrobial Agents and Chemotherapy, 54 (8), 3219-3224.

Scopus Eid


  • 2-s2.0-77955379580

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1438&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/402

Number Of Pages


  • 5

Start Page


  • 3219

End Page


  • 3224

Volume


  • 54

Issue


  • 8