Abstract
In the current scenario of high antibiotic resistance, the search for therapeutic options against Pseudomonas aeruginosa must be approached from different perspectives: cell-wall biology as source of bacterial weak points and our immune system as source of weapons. Our recent study suggests that once the permeability barrier has been overcome, the activity of our cell-wall-targeting immune proteins is notably enhanced, more in mutants with impaired peptidoglycan recycling. The present work aims at analyzing the activity of these proteins [lysozyme and Peptidoglycan-Recognition-Proteins (PGLYRPs)], alone or with a permeabilizer (subinhibitory colistin) in clinical strains, along with other features related to the cell-wall. We compared the most relevant and complementary scenarios: acute (bacteremia) and chronic infections [early/late isolates from lungs of cystic fibrosis (CF) patients]. Although a low activity of lysozyme/PGLYRPs per se (except punctual highly susceptible strains) was found, the colistin addition significantly increased their activity regardless of the strains’ colistin resistance levels. Our results show increased susceptibility in late CF isolates, suggesting that CF adaptation renders P. aeruginosa more vulnerable to proteins targeting the cell-wall. Thus, our work suggests that attacking some P. aeruginosa cell-wall biology-related elements to increase the activity of our innate weapons could be a promising therapeutic strategy.
Highlights
The present work aims at analyzing the activity of these proteins [lysozyme and Peptidoglycan-RecognitionProteins (PGLYRPs)], alone or with a permeabilizer in clinical strains, along with other features related to the cell-wall
It is well known that P. aeruginosa accumulates multiple adaptive mutations, such as those leading to virulence attenuation or antimicrobial resistance, that promote persistence in the cystic fibrosis (CF) lung niche, where bacteria are notably protected against the diffusion of certain immune elements mainly thanks to the mucus and biofilm lifestyle[16,17,18]
The encouraging results we show here enforce the idea that attacking some of the P. aeruginosa cell-wall biology-related elements to increase the activity of our innate humoral weapons targeting the PGN or being the adjuvant for the use of exogenous lysozyme/PGLYRPs to be administered as a combined treatment, could be a very promising therapeutic strategy
Summary
The present work aims at analyzing the activity of these proteins [lysozyme and Peptidoglycan-RecognitionProteins (PGLYRPs)], alone or with a permeabilizer (subinhibitory colistin) in clinical strains, along with other features related to the cell-wall. It is well known that P. aeruginosa accumulates multiple adaptive mutations, such as those leading to virulence attenuation or antimicrobial resistance, that promote persistence in the CF lung niche, where bacteria are notably protected against the diffusion of certain immune elements mainly thanks to the mucus and biofilm lifestyle[16,17,18] This scenario is completely different to that the bloodstream demands for infection development, in which acute virulence is determinant[19]. Our results draw a complex scenario revealing the participation of many actors defining the phenotypes of the clinical strains in terms of their susceptibility to the studied innate weapons, which opens a new horizon in the search for targets to habilitate these elements as future antipseudomonal resources
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