Quorum Sensing Signaling and Quenching in the Multidrug-Resistant Pathogen Stenotrophomonas maltophilia

Abstract

Stenotrophomonas maltophilia is an opportunistic Gram-negative pathogen with increasing incidence in clinical settings. The most critical aspect of S. maltophilia is its frequent resistance to a majority of the antibiotics of clinical use. Quorum Sensing (QS) systems coordinate bacterial populations and act as major regulatory mechanisms of pathogenesis in both pure cultures and poly-microbial communities. Disruption of QS systems, a phenomenon known as Quorum Quenching (QQ), represents a new promising paradigm for the design of novel antimicrobial strategies. In this context, we review the main advances in the field of QS in S. maltophilia by paying special attention to Diffusible Signal Factor (DSF) signaling, Acyl Homoserine Lactone (AHL) responses and the controversial Ax21 system. Advances in the DSF system include regulatory aspects of DSF synthesis and perception by both rpf-1 and rpf-2 variant systems, as well as their reciprocal communication. Interaction via DSF of S. maltophilia with unrelated organisms including bacteria, yeast and plants is also considered. Finally, an overview of the different QQ mechanisms involving S. maltophilia as quencher and as object of quenching is presented, revealing the potential of this species for use in QQ applications. This review provides a comprehensive snapshot of the interconnected QS network that S. maltophilia uses to sense and respond to its surrounding biotic or abiotic environment. Understanding such cooperative and competitive communication mechanisms is essential for the design of effective anti QS strategies.

Keywords: antimicrobial resistance; multi-drug resistance; nosocomial infections; quorum quenching; quorum sensing.

Figure 1

Proposed QS signaling network in S. maltophilia. (A) In rpf-1 strains, RpfC-1 (including 10 TMR) stimulates RpfF-1 basal activity—that increases with cell density—and synthesizes DSF (cis-11-Methyl-2-dodecenoic acid) that accumulates in the extracellular environment. Once DSF concentration reaches a critical threshold, RpfC-1 senses DSF, and induces a phosphorylation cascade throughout its cytoplasmic domains ending in the response regulator RpfG, which degrades cyclic diguanylate monophosphate (c-di-GMP) to GMP activating the transcriptional regulator Clp that stimulates expression of genes involved in biofilm formation, motility, and virulence. (B) In rpf-2 strains, RpfC-2 (5 TMR) permanently represses RpfF-2, resulting in no DSF detection in axenic conditions. DSF produced by neighboring bacteria (e.g., rpf-1 strain) is sensed by RpfC-2 allowing free-active RpfF-2 and subsequent DSF synthesis. (C) DSF also stimulates the production of outer membrane vesicles (OMV) containing high amounts of the two Ax21 proteins (Smlt0184 and Smlt0387). Both Ax21 proteins present a signal peptide that is processed by the general secretory (Sec) system. (D) Exogenous AHL signals, specifically C8-HSL and oxo-C8-HSL, are sensed by the LuxR solo SmoR (Smlt1839), annotated as “LuxR chaperone HchA-associated,” activating the transcription of its own operon and promoting swarming motility. Dotted lines represent predicted or supposed interactions on the basis of reported experimental evidences. Protein domains are abbreviated as follows. HK, Histidine kinase domain; REC, Receiver domain; HPT, Histidine phosphotransferase domain; HD-GYP, Phosphodiesterase domain containing an additional GYP motif; HTH, Helix-Turn-Helix domain.