Antibiotics with novel and polypharmacological mechanisms of action are urgently needed. To this end, the total synthesis of mindapyrroles A and B was completed via a Friedel-Crafts alkylation. The antibacterial activity of these compounds was investigated against a panel of gram-positive and gram-negative pathogens, and their mechanism of action was determined to be different from their monomer pyoluteorin.

Abstract

In the search for antibacterial compounds that can overcome drug resistant species, molecules that enact novel or polypharmacological mechanisms of action (MoA) are needed. As a preliminary foray into molecules of this background, the total synthesis of mindapyrroles A and B was undertaken leveraging a biomimetic approach. Following their synthesis, they and their monomer pyoluteorin were tested against a range of pathogenic bacteria in minimum inhibitory concentration assays to confirm their activity. These molecules were then tested for their ability to disrupt membrane potential in S. aureus. Our findings indicate that pyoluteorin acts as a protonophore but the mindapyrroles do not. This work encapsulates the first total synthesis of mindapyrrole B and the second total synthesis of mindapyrrole A in 11 % and 30 % overall yields, respectively. It also provides insights into the antibacterial properties and different MoAs between the monomer and dimers.