The development of novel narrow-spectrum antibiotics represents one viable strategy towards the ever-worsening threat of antibiotic resistance. Promysalin, a secondary metabolite isolated from Pseudomonas putida, is a particularly interesting example due to its potent species-specific inhibition of P. aeruginosa, an opportunistic Gram-negative pathogen commonly encountered in clinical settings. However, promysalin’s structural instability in vitro renders the molecule currently unsuitable for clinical use. Recent computational modeling of promysalin’s binding mode with its enzyme target, succinate dehydrogenase, suggest the potential to overcome these liabilities through slight structural modification. As such, a novel series of rationally-designed analogues was synthesized. Preliminary biological analysis of these compounds was then performed to test their inhibitory activity, revealing a new potential lead compound for further derivatization.

Computationally-guided design of promysalin analogues to overcome resistance in P. aeruginosa

ACS Fall 2021

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