ABC Transporter Blockers and Reversal of Drug Resistance in Microorganisms.

Abstract

One of the major causes of drug resistance and chemotherapeutic failure in both cancer and anti-infective therapies is the decrease of effective drug concentrations at their target place, due to the increased action of ATP-binding cassette (ABC) transporters. ABC transporters encompass membrane proteins that couple the energy derived from ATP hydrolysis to the translocation of solutes across biological membranes. Their functions include ancient and conserved mechanisms related to physiological mechanisms in prokaryotes and eukaryotes, emphasizing the biological relevance of ABC transporters. Since ABC transporter blockers can be used in combination with current drugs to increase their effective intracellular concentration, the possible impact of ABC transporter inhibitors is of great clinical interest. Special concern exists since scarce ABC transporter blockers that may be useful to increase the efficacy of current drugs have entered clinical trials and are available to be used in therapeutic regimes. Herein we review the progress made in recent years in the identification, design, availability and applicability of compounds that may work as ABC transporter blockers, as well as the roles of these compounds not only by directly blocking ABC transporters but also in the pharmacokinetics and pharmacodynamics of therapeutic drugs used against infectious diseases. These data may be helpful in the design of strategies to circumvent drug resistance in microorganisms including parasites in clinical circumstances.