A novel antimicrobial target—expanded and revisited mode of action of pantothenamides

Pantothenamides are analogs of pantothenic acid (vitamin B5), which is a natural precursor of coenzyme A (CoA). It has been shown that these compounds, predominantly N-substituted pantothenamides, possess antimicrobial activity against various pathogenic bacteria such as E. coli and S. aureus. It is widely accepted that these compounds act through combined inhibition of coenzyme A and fatty acid synthesis. However, the precise mechanism of action remains unrevealed. Here is reported the identification of a novel target of pantothenamides, never considered before. Molecular dynamics simulations together with free energy calculations reveal that the hydrophobic pocket of the acyl carrier protein (ACP) binds N-pentylpantothenamide. Consequently, the sequestration of the acyl chain attached to the Ppant prosthetic arm is defunct since the inhibitor occupies the hydrophobic core of the ACP. Thus, the acyl chain remains solvent-exposed and susceptible to hydrolysis. Moreover, the ACP with N-pentylpantothenamide bound could change its chain-flipping ability as well as its interaction propensity towards downstream enzyme partners of the fatty acid synthesis pathway, which could result in the suppression of the fatty acid synthesis rate.