The serious challenge posed by multidrug-resistant bacterial infections with concomitant treatment failure and high mortality rates presents an urgent threat to the global health. We herein report the discovery of potent first-in-class antimicrobial compounds that are highly effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The compounds were synthesized employing a cascade of Groebke–Blackburn–Bienaymé and aza-Michael addition reactions. The best hits were fast-acting at eradicating exponentially growing MRSA, with killing achieved after 30 minutes of exposure to the compounds. They were also able to kill MRSA persister cells which are tolerant to most available medications. Microscopic analyses using fluorescence microscope and atomic force microscope demonstrated that these compounds permeabilize and disrupt bacterial cell membranes. Most notably, bacterial resistance toward these lead drug candidates was not observed after 20 serial passages in stark contrast to the significant resistance developed rapidly upon exposure to a clinically relevant antibiotic. Furthermore, the compounds did not induce significant hemolysis to human red blood cells. Safety studies revealed a compound with an excellent safety profile in mice (Figure 1). These small molecules hold a promise for further studies and development as new antibacterial agents against MRSA infections.

Discovery of a novel class of small molecules which rapidly eradicate methicillin-resistant Staphylococcus aureus (MRSA) persisters without detectable resistance or toxicity

ACS Spring 2022

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