Therapeutics for Drug-Resistant Bacteria: Pseudouridimycins

DESCRIPTION (provided by applicant): We have discovered the first nucleoside-analog inhibitor (NAI) that selectively inhibits bacterial RNA polymerase (RNAP): pseudouridimycin (PUM). PUM is produced by Streptomyces sp. NAI38640 and comprises a guanidinylated, N-hydroxylated Gly-Gln dipeptide conjugated to 5'-amino-pseudoridine. PUM inhibits bacterial RNAP--but not mammalian RNAP--in vitro, inhibits bacterial growth in culture, and potently clears infection in a mouse model of Group A Streptococcus infection (ED50 = 10 mg/kg). The compound exhibits antibacterial activity against a broad spectrum of drug-sensitive and drug-resistant bacterial pathogens, including drug-sensitive, penicillin-resistant, macrolide-resistant, and multi-drug-resistant Streptococci, drug-sensitive, methicillin-resistant, and multi-drug-resistant Staphylococci, Neisseria sp., Haemophilus sp., and Moraxella sp. The compound exhibits no cross-resistance with rifampin, the RNAP inhibitor in current use in broad-spectrum antibacterial therapy, and exhibits a spontaneous resistance frequency