Multidrug Efflux Pumps at the Crossroad between Antibiotic Resistance and Bacterial Virulence

Abstract

Multidrug efflux pumps can be involved in bacterial resistance to antibiotics at different levels. Some efflux pumps are constitutively expressed at low levels and contribute to intrinsic resistance. In addition, their overexpression may allow higher levels of resistance. This overexpression can be transient, in the presence of an effector (phenotypic resistance), or constitutive when mutants in the regulatory elements of the expression of efflux pumps are selected (acquired resistance). Efflux pumps are present in all cells, from human to bacteria and are highly conserved, which indicates that they are ancient elements in the evolution of different organisms. Consequently, it has been suggested that, besides antibiotic resistance, bacterial multidrug efflux pumps would likely contribute to other relevant processes of the microbial physiology. In the current article, we discuss some specific examples of the role that efflux pumps may have in the bacterial virulence of animals’ and plants’ pathogens, including the processes of intercellular communication. Based in these evidences, we propose that efflux pumps are at the crossroad between resistance and virulence of bacterial pathogens. Consequently, the comprehensive study of multidrug efflux pumps requires addressing these functions, which are of relevance for the bacterial–host interactions during infection.

Nanomaterials for alternative antibacterial therapy

“…Overexpression of transmembrane multidrug efflux pumps as well as reduced uptake results in sub-toxic levels of drugs within the microbial cells. 20 In P. aeruginosa, mutation in regulatory protein that normally dampens the gene encoding efflux proteins results in enhanced outpour. E. coli uses transmembrane proton gradient to expel multiple antibiotics through its numerous efflux pumps.…”

The analysis of the role of MexAB-OprM on quorum sensing homeostasis shows that the apparent redundancy of Pseudomonasaeruginosamultidrug efflux pumps allows keeping the robustness and the plasticity of this intercellular signaling network

“…One of the ways for achieving such modulation is by interfering with the available concentrations of the signals that trigger the regulatory networks. For this purpose, multidrug efflux pumps can be particularly well suited, because the activity of these antibiotic resistance determinants can affect the bacterial physiology through the extrusion of endogenous/exogenous molecular compounds with relevance for bacterial physiology [3, 7]. As a consequence of this extrusion, the expression of a large number of genes, including those encoding virulence determinants, may be altered, which has been usually considered as the fitness cost associated to the acquisition of antibiotic resistance.…”

“…It is worth noticing that genes that contribute to P. aeruginosa intrinsic antibiotic resistance are, in several occasions, key components of bacterial physiology [3, 4]. This is the case of the Resistance, Nodulation and cell-Division (RND) family of efflux pumps, which, besides being important mechanisms of antibiotic resistance in P. aeruginosa [5, 6], also may play a key role in its pathogenesis and adaption to host environment [3, 7]. In this work, we address the role of the MexAB-OprM efflux system, one of the most relevant RND systems for intrinsic and acquired antibiotic resistance of P. aeruginosa [8, 9], on the modulation of quorum sensing (QS) responses in this bacterium.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

“…In Gram-negative bacteria Fe 3+ -siderophore complexes are recognized by selective outer-membrane TonB-dependent transporters [57] that bind the complex and translocate it into the periplasmic space. One of the mechanisms of bacterial resistance to antibiotics are the multidrug efflux pumps [58]. To overcome this aspect of bacterial resistance, a "Trojan horse" strategy has been conceived, consisting of attaching an antibiotic molecule to a siderophore [59].…”