The GDP-Mannose Dehydrogenase of <i>Pseudomonas aeruginosa</i>: An Old and New Target to Fight against Antibiotics Resistance of Mucoid Strains

• Main Author: Christian Hulen (Author)
• Format: Book
• Published: MDPI AG, 2023-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Alginates play an important role in the resistance of mucoid strains of <i>Pseudomonas aeruginosa</i> to antibiotics, as well as their persistence by escaping the immune defense system. GDP-mannose dehydrogenase (GMD) is the key enzyme in alginate biosynthesis by catalyzing the irreversible double oxidation of GDP-mannose to GDP-mannuronate. GDP-mannose dehydrogenase purified from mucoid strains exhibits strong negative cooperativity for its substrate, the GDP-mannose, with a K_M of 13 µM for the site of strong affinity and 3 mM for this weak of a binding. The presence of a nucleotide strongly associated with the enzyme was detected, confirming the fact that the substrate oxidation reaction takes place in two distinct steps, with the substrate blocked on the enzyme in a half-oxidation state in the form of a hemiacetal. As the GMD polypeptide has only one site for substrate binding, our results tend to confirm the fact that the enzyme functions in a dimer form. The GDP-mannose dehydrogenase inhibition strategy that we developed a few years ago, based on the synthesis of substrate analogs, has shown its effectiveness. The addition of an alkynyl radical on carbon 6 of the mannose grafted to an amino-sulfonyl-guanosine allows, at a concentration of 0.5 mM, to inhibit GMD by 90%. As we had previously shown the effectiveness of these analogs on the sensitivity of mucoid strains of <i>Pseudomonas aeruginosa</i> to aminoglycosides, this revives the interest in the synthesis of new inhibitors of GDP-mannose dehydrogenase.

Item Description

10.3390/antibiotics12121649
2079-6382