The Kdo Biosynthetic Pathway Toward OM Biogenesis as Target in Antibacterial Drug Design and Development

Laura      Cipolla; Alessandra      Polissi; Cristina      Airoldi; Paolo      Galliani; Paola      Sperandeo; Francesco      Nicotra

Abstract

Despite important advances made in the last century, infectious diseases caused by pathogenic microrganisms are still a major threat to human health. This is worsened by the occurrence of new forms of bacterial resistance against antibiotics, that are the main remedy against infectious diseases, and their rapid spreading across bacterial species, pose additional threats to our health. Thus, the necessity to develop new weapons against pathogenic bacteria is widely recognized as a major challenge for modern drug research. Traditional antibiotic discovery procedures have so far focused on inhibiting the main processes of the bacterial cell (replication, transcription, translation, and peptidoglycan synthesis). This review will give an overview of the therapeutic strategies to cure infectious diseases caused by Gram-negative bacteria through the development of inhibitors of Kdo biosynthesis. Kdo is a monsaccharide essential for OM biogenesis, OM being an essential cellular structure shared by all Gram-negative bacteria. Hence, inhibitors of its biosynthesis can have a broad-spectrum antibacterial activity.

Keywords: LPS, enzyme inhibitors, Kdo, Lipid A, Gram-negative bacteria, antibiotics, enzyme structure