ABSTRACT
MDRs in Clinically Relevant Drug Resistance .................................................... 46 Antiinfective Drug Discovery and Effl ux Pump Inhibitors ................................. 53 Perspectives for Developing MDR Inhibitors ....................................................... 56 Natural MDR Inhibitors ....................................................................................... 59 Concluding Remarks ............................................................................................ 61 References ............................................................................................................. 61
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. It is despite the fact that the plethora of covered drug targets is well conserved in both Gram-positive and Gram-negative bacteria. Multidrug resistance (MDR) effl ux pumps play a prominent and proven role in Gram-negative intrinsic resistance. Moreover, these pumps also play a signifi cant role in acquired clinical resistance. Together, these considerations make effl ux pumps attractive targets for inhibition in that the resultant effl ux 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 signifi cant potential for developing small molecule inhibitors against effl ux 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 signifi cantly 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.
