The development of efflux pump inhibitors to treat Gram-negative infections

Introduction: One of the possibilities for reducing the emergence and spread of antibiotic resistance is the use of anti-resistance compounds capable of resensitizing resistant microorganisms to current antimicrobials. For this purpose, multidrug efflux pumps, whose inhibition may increase bacterial susceptibility to several antibiotics, including macrolides to which Gram-negatives are considered intrinsically resistant, have emerged as suitable targets. Areas covered: In the current review, the authors discuss different mechanisms that can be exploited for inhibiting multidrug efflux pumps and describe the properties and the potential therapeutic value of already studied efflux pumps inhibitors. Although efforts have already been made to develop these inhibitors, there are currently no good candidates for treating infectious diseases. Consequently, the authors also discuss potential approaches for their development. Expert opinion: Classical anti-resistance drugs such as beta-lactamases inhibitors, while useful, are only purposeful for treating infections caused by beta-lactamase producers. However, inhibitors of multidrug efflux pumps, which are present on all organisms, can sensitize both susceptible and resistant bacteria to antibiotics belonging to several different structural families. Since some efflux pumps are involved in bacterial infections, their inhibition may also reduce the infectivity of Gram-negative bacterial pathogens.