Abstract
Pseudomonas aeruginosa is one of the main causative agents of nosocomial infections and the spread of multidrug-resistant strains is rising. Therefore, novel strategies for therapy are urgently required. The outer membrane composition of Gram-negative pathogens and especially of Pa restricts the efficacy of antibiotic entry into the cell and determines virulence. For efficient outer membrane protein biogenesis, the β-barrel assembly machinery (BAM) complex in the outer membrane and periplasmic chaperones like Skp and SurA are crucial. Previous studies indicated that the importance of individual proteins involved in outer membrane protein biogenesis may vary between different Gram-negative species. In addition, since multidrug-resistant Pa strains pose a serious global threat, the interference with both virulence and antibiotic resistance by disturbing outer membrane protein biogenesis might be a new strategy to cope with this challenge. Therefore, deletion mutants of the non-essential BAM complex components bamB and bamC, of the skp homolog hlpA as well as a conditional mutant of surA were investigated. The most profound effects for both traits were associated with reduced levels of SurA, characterized by increased membrane permeability, enhanced sensitivity to antibiotic treatment and attenuation of virulence in a Galleria mellonella infection model. Strikingly, the depletion of SurA in a multidrug-resistant clinical bloodstream isolate re-sensitized the strain to antibiotic treatment. From our data we conclude that SurA of Pa serves as a promising target for developing a drug that shows antiinfective activity and re-sensitizes multidrug-resistant strains to antibiotics.
Highlights
The widespread use of antibiotics is causative for the rapid development of multidrug-resistant strains
To identify potential targets in order to possibly develop new strategies to treat especially infections caused by multidrugresistant Pseudomonas aeruginosa (Pa), we investigated the role of components involved in the assembly of proteins into the outer membrane (OM) by deletion of the non-essential barrel assembly machinery (BAM) complex components BamB and a BamC homolog as well as the periplasmic shuttle proteins SurA and HlpA in Pa PA14
Because of the clinical importance and increasing numbers of multidrug-resistant strains we addressed the role of Pa BamB (PA14_14910), BamC (PA14_51260), the Skp-like protein HlpA (PA14_17170), and SurA (PA14_07760) for fitness and virulence of Pa in order to determine which factors might be the best targets for drug development
Summary
The widespread use of antibiotics is causative for the rapid development of multidrug-resistant strains. For the insertion of these β-barrel proteins, Gram-negative bacteria employ a conserved transport system consisting of the periplasmic chaperones SurA, Skp, and DegP, which protect and guide newly synthesized proteins from the Sec translocon in the inner membrane to the OM and the β-barrel assembly machinery (BAM) complex (Sklar et al, 2007; Tashiro et al, 2009; Goemans et al, 2014; Li et al, 2018). Both SurA and Skp act as chaperones and are thought to form a partially redundant network. In Neisseria mengitidis, Skp is more important for shaping the OMP composition than SurA, indicating species-specific differences (Tamae et al, 2008)
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