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

Abstract

The analysis of the role of MexAB-OprM on quorum sensing homeostasis shows 2 that the apparent redundancy of Pseudomonas aeruginosa multidrug efflux pumps 3 allows keeping the robustness and the plasticity of this intercellular signaling 4 network 5 6 Running: Efflux systems' redundancy on quorum sensing homeostasis 7 8 9 Abstract 22the resistance/virulence crosstalk since, besides contributing to antibiotic resistance, 47 they can also modulate the quorum sensing (QS) response. We show that mutants 48 overexpressing the MexAB-OprM efflux pump, present an impaired QS response due to 49 the reduced availability of the QS signal precursor octanoate, not because they extrude, 50 as previously stated, the QS signal 3-oxo-C12-HSL. Together with previous studies, this 51 indicates that, although the consequences of overexpressing efflux pumps are similar 52 (impaired QS response), the mechanisms are different. This 'apparent redundancy' of 53 RND efflux systems can be understood as a P. aeruginosa strategy to keep the 54 robustness of the QS regulatory network and modulate its output in response to different 55 signals. 57Pseudomonas aeruginosa is an opportunistic pathogen of special concern due to its 58 capability to produce a large variety of serious human infections and to its low 59 susceptibility to different antibiotics [1, 2]. It is worth noticing that genes that contribute 60 to P. aeruginosa intrinsic antibiotic resistance are, in several occasions, key components 61 of bacterial physiology [3, 4]. This is the case of the Resistance, Nodulation and cell-62 Division (RND) family of efflux pumps, which, besides being important mechanisms of 63 antibiotic resistance in P. aeruginosa [5, 6], also may play a key role in its pathogenesis 64 and adaption to host environment [3, 7]. In this work, we address the role of the 65MexAB-OprM efflux system, one of the most relevant RND systems for intrinsic and 66 acquired antibiotic resistance of P. aeruginosa [8, 9], on the modulation of quorum 67 sensing (QS) responses in this bacterium. 68The QS response consists in a population-scale cooperative behavior promoted by cell-69to-cell communication systems that control the expression of a large set of genes in a 70 cell-density way [10]. This intercellular communication system is based on the 71 synthesis, delivery and progressive accumulation of autoinducer compounds, known as 72 QS signal molecules (QSSMs), which are recognized by specific cell receptors. When 73QSSMs concentrations reach a threshold, the QS response is triggered in the population. 74This population-scale response regulates a wide number of diverse physiological 75 processes [11], including production of private and public goods [12], biofilm formation 76[13], host-bacteria interactions [14] and virulence factors production [15]. The QS 77 responses usually impose a fitness burden at single cell level but with social benefit at 78 population level [16, 17]. 79The QS regulatory network of P. aeruginosa is based on the production of two different 80 kinds...

Mechanisms and Control Strategies of Antibiotic Resistance in Pathological Biofilms

“…Moreover, the MexAB-OprM pump also contributes to ofloxacin resistance in P. aeruginosa biofilm [ 48 ]. Efflux pumps can also modulate quorum sensing responses, although the definitive relationship between the two remains unclear [ 49 , 50 ]. Taken together, multidrug efflux pumps are critical players in antibiotic resistance in clinical biofilms.…”