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B4: Strukturbiologische Charakterisierung eines diagnostischen monoklonalen Antikörpers bei Pseudomonas aeruginosa-Infektionen

Keywords: LPS; P. aeruginosa; core structure; structural analysis; cross-reactive monoclonal antibodies

Pseudomonas aeruginosa belongs to a group of Gram-negative bacteria, which play a major role in secondary, especially nosocomial infections. In particular immuno compromised patients and, especially, individuals suffering from severe burns or Cystic Fibrosis (CF) are infected. Its increasing and outstanding resistance against antibiotics, has rendered P. aeruginosa to one of the most important Gram-negative bacteria provoking nosocomial infections.

One of those factors mediating pathogenicity of P. aeruginosa is predominantly lipopolysaccharide (LPS, endotoxin). LPS represents the main antigen of pseudomonads. It is structurally composed of three parts: the O-antigen (O-specific chain), the core region (inner and outer core) and its endotoxically active lipid A component. The core region of P. aeruginosa LPS and its lipid A have recently attracted increasing interest by the biosciences. As a moderately conserved region, the core plays an outstanding role during the elimination and clearance of pseudomonads from the surface of endothelial cells (which is hampered in CF patients). Moreover, this core region is considered to be a suitable epitope for broadly cross-reactive monoclonal antibodies.

In the past two periods of funding (1997 - 2003), we succeeded in determining the primary structure of the core oligosaccharide of P. aeruginosa LPS. We could define a structurally conserved domain, which, together with Pseudomonas-typical functional (charged) groups (phosphate, pyrophosphate, triphosphate, L?alanine, O-acetyl and carbamoyl) represent the characteristic substituents in all pseudomonads of the Palleroni group I ('true pseudomonads'). This structure, therefore, represents a suitable common epitope for broadly cross-reactive monoclonal antibodies against this very defined region of the endotoxin. Besides the chemical analysis, in the serological part of the project we generated several monoclonal antibodies (mAbs) of which two expressed cross-reactive properties against different Pseudomonas species (P. fluorescens, P. alcaligenes).

Our aim o in the third funding period will be to continue the chemical and intensify the serological and biological analyses of the core structure in P. aeruginosa and selected mAbs directed against it. Based on the knowledge of the primary structure with putative reactive core epitopes (functional groups) we will select suitable mAbs expressing broad cross-reactive properties for diagnosis of P. aeruginosa infections. In the future, our strategy will be to test whether these mAbs express cross-protective properties of potential use for anti-inflammatory therapy against pseudomonad infections.


Prof. Dr. Ulrich Zähringer

Forschungszentrum Borstel
Zentrum für Medizin und Biowissenschaften
Parkallee 22
23845 Borstel

Telefon: 04537-188-462
Telefax: 04537-188-612

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