Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa

N. Srinivas et al., Science 327, 1010 (2010).

Speaker: Shu-Sheng Chen (陳沭勝)                                     Time: 15:00~16:00, Mar. 2, 2011

Commentator: Chun-Keung Yu, Ph.D. (余俊強博士)         Place: Room 601

Abstract:

Pseudomonas aeruginosa, an important Gram-negative nosocomial pathogen, causes severe infections in bloodstream, urinary tract, gastrointestinal tract, skin and soft tissues and lung, especially in patients with cystic fibrosis. Antipseudomonal antibiotics, including cephalosporins, carbapenems, aminoglycosides and fluoroquinolones, are extensively used in Pseudomonas infection. However, in recent decades antibiotic resistance becomes a serious problem to treat with P. aeruginosa infection. It is emergent to develop new antibiotics to combat drug-resistant strain of P. aeruginosa. In previous studies, the authors generated antimicrobial peptide protegrin I (PG-I); nevertheless, this peptide possessed hemolytic activity. In this study, the authors synthesized a family of peptidomimetic antibiotics based on the structure of PG-I and further measured the antimicrobial activities by broth microdilution method. The results showed that the peptidomimetics had specific antimicrobial effects on Pseudomonas spp., but not against other Gram-positive and Gram-negative bacteria. Moreover, membrane integrity of protein and nucleic acids biogenesis of P. aeruginosawere evaluated and revealed that the peptidomimetics did not kill P. aeruginosa by disrupting the membrane integrity or blocking biogenesis of DNA, RNA, and protein. An alternative approach to investigate the antimicrobial mechanisms of the peptidomimetics was to create a mutant library. They demonstrated that protein LptD, functions in outer-membrane biogenesis, is the target of peptidomimetics. A mouse septicemia model was used and confirmed that the peptidomimetics provided the protection ability against P. aeruginosa infection. Taken together, this family of peptidomimetic antibiotics may have therapeutic application against drug-resistant P. aeruginosa.

References:

1.      N. Srinivas et al., Org. Biomol. Chem. 5, 3100 (2007).

2.      A. Bragonzi, Sci. Transl. Med. 2, 21ps9 (2010).

3.      R. Haarmann et al, J. phys.: Condens. Matter. 22, 454124 (2010).