Discovery and optimization of a new class of pyruvate kinase inhibitors as potential therapeutics for the treatment of methicillin-resistant Staphylococcus aureus infections

A novel series of 2,2′-bridged bis-indoles has been designed and synthesized as potent and selective allosteric inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). Based on examination of the X-ray structure of the 3,3′-bridged bis-indole natural product cis-3-4-dihydrohamacanthin B (4) bound to MSRA PK (IC50 = 16 nM and MIC = 12.5 μg/ml), a 2,2′-bridged bis-indole series was envisaged and was optimized for enzyme and cell growth inhibition activity to identify compounds such a 10d with low nanomolar potency (IC50 = 2.0 nM) for inhibition of MRSA PK, high selectivity over human PK isoforms, low mammalian cell toxicity and excellent antibacterial activity against MRSA (MIC = 0.5 μg/ml).