Recent advances in therapeutic targets identification and development of treatment strategies towards Pseudomonas aeruginosa infections

Abstract

The opportunistic human pathogen Pseudomonas aeruginosa is the causal agent of a wide variety of infections. This non-fermentative Gram-negative bacillus can colonize zones where the skin barrier is weakened, such as wounds or burns. It also causes infections of the urinary tract, respiratory system or bloodstream. P. aeruginosa infections are common in hospitalized patients for which multidrug-resistant, respectively extensively drug-resistant isolates can be a strong contributor to a high rate of in-hospital mortality. Moreover, chronic respiratory system infections of cystic fibrosis patients are especially concerning, since very tedious to treat. P. aeruginosa exploits diverse cell-associated and secreted virulence factors, which play essential roles in its pathogenesis. Those factors encompass carbohydrate-binding proteins, quorum sensing that monitor the production of extracellular products, genes conferring extensive drug resistance, and a secretion system to deliver effectors to kill competitors or subvert host essential functions. In this article, we highlight recent advances in the understanding of P. aeruginosa pathogenicity and virulence as well as efforts for the identification of new drug targets and the development of new therapeutic strategies against P. aeruginosa infections. These recent advances provide innovative and promising strategies to circumvent infection caused by this important human pathogen.

Minimalist Tetrazine N-Acetyl Muramic Acid Probes for Rapid and Efficient Labeling of Commensal and Pathogenic Peptidoglycans in Living Bacterial Culture and During Macrophage Invasion

“…aeruginosa infection, including biofilm formation cell-secreted factors, as well as several anatomical structures, including pili, flagella, and LPS . These factors all serve as potential drug targets for improved treatment modalities where new antibiotics are desperately needed to combat these bacteria in the clinic. − It is well known that these bacteria, like others, are able to shed and remodel their PG structures; however, few studies have been able to distinguish PG as a definitive virulence factor during infection. − Additionally, current investigations examining the dynamic changes in PG topology and architecture during infection involve the use of denaturing methods to isolate PG for downstream assaying. − Here, we sought to utilize our fast and robust minimal tetrazine probe to execute dynamic in situ labeling of the PG anatomy in live bacteria to serve as a platform for many potential downstream applications. Previous attempts to label these species resulted in either low incorporation, high background, or unusual morphology and nonspecific labeling when labeled with SPAAC. , Use of the new HTz-NAM and aTCO-SiR labeling strategy resulted in markedly improved labeling and notably less background in the NAM-treated sample in P. putida (Figure A, SI Figures 33 and 34).…”

Optimization of the Synthesis and Conjugation of the Methyl Rhamnan Tip of Pseudomonas aeruginosa A-Band Polysaccharide and Immunogenicity Evaluation for the Continued Development of a Potential Glycoconjugate Vaccine

“…This antimicrobial resistance (AMR) has prompted the World Health Organization and others to state that priorities include preventing infections by developing novel vaccines against AMR bacteria such as Pa due to the high mortality risk and the economic cost of these infections. , Antibiotic-resistant Pa is often respirator-acquired and affects especially patients afflicted with cystic fibrosis, causing pneumonia and also a range of acute infections that can lead to sepsis . There is currently no vaccine on the market against Pa ; however, a range of vaccines are being developed. , …”

“…4 There is currently no vaccine on the market against Pa; however, a range of vaccines are being developed. 5,6 Glycoconjugate vaccines are historically robust, safe, and efficient in preventing infections. 4,7−9 When developing a glycoconjugate vaccine against a bacteria, a range of carbohydrates on the surface of the bacteria can be targeted, such as the capsule and lipopolysaccharides.…”

“…C NMR (150 MHz, CD 3 OD): δ 103.2 (C1‴′), 103.1 (C1‴), 103.0 (2C, C1″, C1′), 101.7 (C1), 83.1 (3C, C3′, C3″, C3‴), 82.8 (C3), 82.0 (C3‴′), 79.4 (C4‴), 79.3 (C4), 79.2 (2C, C4′, C4″), 72.6 (C4‴′), 70.5 (C5‴′), 69.1 (3C, C5′, C5″, C5‴), 68.7 (C5), 68.4 (C2′), 67.9 (3C, C2″, C2‴, C2‴′), 67 5. (C2), 64.6 (OCH 2 CH 2 NH), 57.3 (OCH 3 ), 56.7 (OCH 3 ), 56.6 (3C, OCH 3 ), 40.4 (OCH 2 CH 2 NH), 18.7 (C6), 18.6 (3C, C6′, C6″, C6‴), 17.9 (C6‴′).…”

“… 4 There is currently no vaccine on the market against Pa ; however, a range of vaccines are being developed. 5 , 6 …”