PhoPQ two-component regulatory system plays a global regulatory role in antibiotic susceptibility, physiology, stress adaptation, and virulence in Stenotrophomonas maltophilia

Abstract

Background Stenotrophomonas maltophilia, an opportunistic pathogen, is ubiquitously present in various environments, signifying its high capability of environmental adaptation. Two-component regulatory system (TCS) is a powerful implement to help organisms to survive in different environments. In clinic, treatment of S. maltophilia infection is difficult because it is naturally resistant to many antibiotics, highlighting the necessity to develop novel drugs or adjuvants. Given their critical and extensively regulatory role, TCS system has been proposed as a convincing target for novel drugs or adjuvants. PhoPQ TCS, a highly conserved TCS in several pathogens, plays crucial roles in low-magnesium adaption, polymyxin resistance, and virulence. In this study, we aimed to characterize the role of PhoPQ TCS of S. maltophilia in antibiotic susceptibility, physiology, stress adaptation, and virulence. Results To characterize PhoPQ system, phoP single mutant as well as phoP and phoQ double mutant were constructed. Distinct from most phoPQ systems of other microorganisms, two features were observed during the construction of phoP and phoQ single deletion mutant. Firstly, the phoQ mutant was not successfully obtained. Secondly, the compromised phenotypes of phoP mutant were not reverted by complementing an intact phoP gene, but were partially restored by complementing a phoPQ operon. Thus, wild-type KJ, phoP mutant (KJΔPhoP), phoPQ mutant (KJΔPhoPQ), and complemented strain (KJΔPhoPQ (pPhoPQ)) were used for functional assays, including antibiotic susceptibility, physiology (swimming motility and secreted protease activity), stress adaptation (oxidative, envelope, and iron-depletion stresses), and virulence to Caenorhabditis elegans. KJΔPhoPQ totally lost swimming motility, had enhanced secreted protease activity, increased susceptibility to antibiotics (β-lactam, quinolone, aminoglycoside, macrolide, chloramphenicol, and sulfamethoxazole/ trimethoprim), menadione, H2O2, SDS, and 2,2′-dipyridyl, as well as attenuated virulence to C. elegans. Trans-complementation of KJΔPhoPQ with phoPQ reverted these altered phenotypes to the wild-type levels. Conclusions Given the critical and global roles of PhoPQ TCS in antibiotic susceptibility, physiology, stress adaptation, and virulence, PhoPQ is a potential target for the design of drugs or adjuvants.

Structural and functional comparison of magnesium transporters throughout evolution

“…Expression of the mgtA and mgtCB loci is modulated by the PhoQ/P two-component system, a phosphorylation relay that regulates virulence, pH, osmolality-induced stress, and Mg 2+ deficiency (Fig. 1) [59][60][61]. The membrane receptor PhoQ phosphorylates the transcription factor PhoP when extracellular Mg 2+ concentrations decrease.…”

Network-based analysis of virulence factors for uncovering Aeromonas veronii pathogenesis

“…Except CpxA which is a histidine kinase, the other 8 proteins are response regulators in two-component regulatory systems. It has been reported that many twocomponent regulatory systems, such as PhoP/PhoQ and EnvZ/OmpR, play important roles in virulence [36][37][38][39]. Thus, the 9 proteins could be potential drug targets.…”

Network-Based Analysis of Virulence Factors for Uncovering Aeromonas Veronii Pathogenesis

“…Except for CpxA that is a histidine kinase, the other 8 proteins are response regulators in two-component regulatory systems. It has been reported that many two-component regulatory systems, such as PhoP/PhoQ and EnvZ/OmpR, play important roles in virulence [32][33][34][35]. Thus, the 9 proteins could be potential drug targets.…”