Practical Applications and Feasibility of Efflux Pump Inhibitors in the Clinic--A Vision for Applied Use

Biochem Pharmacol. 2006 Mar 30;71(7):910-8. doi: 10.1016/j.bcp.2005.12.008. Epub 2006 Jan 19.

Abstract

The world of antibiotic drug discovery and development is driven by the necessity to overcome antibiotic resistance in common Gram-positive and Gram-negative pathogens. However, the lack of Gram-negative activity among both recently approved antibiotics and compounds in the developmental pipeline is a general trend despite the fact that the plethora of covered drug targets are well-conserved across the bacterial kingdom. Such intrinsic resistance in Gram-negative bacteria is largely attributed to the activity of multidrug resistance (MDR) efflux pumps. Moreover, these pumps also play a significant role in acquired clinical resistance. Together, these considerations make efflux pumps attractive targets for inhibition in that the resultant efflux pump inhibitor (EPI)/antibiotic combination drug should exhibit increased potency, enhanced spectrum of activity and reduced propensity for acquired resistance. To date, at least one class of broad-spectrum EPI has been extensively characterized. While these efforts indicated a significant potential for developing small molecule inhibitors against efflux pumps, they did not result in a clinically useful compound. Stemming from the continued clinical pressure for novel approaches to combat drug resistant bacterial infections, second-generation programs have been initiated and show early promise to significantly improve the clinical usefulness of currently available and future antibiotics against otherwise recalcitrant Gram-negative infections. It is also apparent that some changes in regulatory decision-making regarding resistance would be very helpful in order to facilitate approval of agents aiming to reverse resistance and prevent its further development.

Publication types

  • Review

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Cell Membrane Permeability / drug effects
  • Cell Membrane Permeability / physiology
  • Cell Wall / drug effects
  • Cell Wall / physiology
  • Drug Resistance, Multiple, Bacterial / drug effects*
  • Drug Resistance, Multiple, Bacterial / physiology
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacteria / metabolism
  • Humans
  • Membrane Transport Proteins / drug effects*

Substances

  • Anti-Bacterial Agents
  • Membrane Transport Proteins