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The resistance-nodulation-division (RND) family is the most important group of multidrug efflux pumps in Gram-negative bacteria. Their inhibition increases the susceptibility of these microorganisms to antibiotics. The study of the effect of efflux pumps’ overexpression on bacterial physiology in antibiotic-resistant mutants allows for the identification of exploitable weaknesses associated with resistance acquisition. The authors describe different RND multidrug efflux pumps’ inhibition strategies and provide examples of inhibitors. This review also discusses inducers of the expression of efflux pumps, used in human therapy that can produce transient resistance to antibiotics in vivo. Since RND efflux pumps may have a role in bacterial virulence, the use of these systems as targets in the search of antivirulence compounds is also discussed. Finally, this review analyzes how the study of trade-offs associated with resistance acquisition mediated by efflux pumps’ overexpression may guide strategies to tackle such resistance. Increasing the knowledge of the regulation, structure and function of efflux pumps provides information for the rational design of RND efflux pump inhibitors. These inhibitors would increase bacterial susceptibility to several antibiotics and, occasionally, will reduce bacterial virulence. Furthermore, the information on the effect that efflux pumps’ overexpression has on bacterial physiology may serve to develop new anti-resistance strategies.

Efflux in Gram-negative bacteria: what are the latest opportunities for drug discovery?