Bacterial phospholipases (PLs) are a ubiquitous group of enzymes that catalyze the hydrolysis of cell membrane glycerophospholipids and/or sphingomyelin into fatty acids and other lipophilic biologically relevant substances. Of these, the Clostridium perfringens PLC (also known as alpha toxin) is the most well studied and is the major lethal factor in clostridial gas gangrene (myonecrosis). Targeting the alpha toxin has proved highly beneficial in experimental models of C. perfringens myonecrosis, yet no anti-alpha toxin strategies exist for human use. Other clostridial species associated with myonecrosis include C. novyii, C. absonum and C. bifermentans and each produces highly homologous PLC enzymes. Other clinically important pathogens that produce extracellular PLCs include Listeria monocytogenes, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus cereus [1]. Using the C. perfringens PLC as a model enzyme, this study will use a medicinal chemistry approach to develop novel inhibitors targeting the pathobiological activities of C. perfringens alpha toxin. C. perfringens alpha toxin possesses sphingomyelinase activity [1,2]. A substrate based analog design is employed in targeting sphingomyelinase activity of C. perfringens [3,4]. A non-radioactive fluorescent assay is employed in developing probes targeting spingomyelinase activity of C. perfringens.

Strategies towards inhibition of virulent bacterial phospholipases.

ACS Fall 2021

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