Browsing by Author "Boshoff, Helena I. M."
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Item Expanding Benzoxazole-Based Inosine 5?-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents(Journal of Medicinal Chemistry, 2018-05) Chacko, Shibin; Boshoff, Helena I. M.; Singh, Vinayak; Ferraris, Davide M.; Gollapalli, Deviprasad R.; Zhang, Minjia; Lawson, Ann P.; Pepi, Michael J.; Joachimiak, Andrzej; Rizzi, Menico; Mizrahi, Valerie; Cuny, Gregory D.; Hedstrom, LizbethNew drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. Mycobacterium tuberculosis (Mtb) inosine 5?-monophosphate dehydrogenase 2 (MtbIMPDH2) is a promising yet controversial potential target. The inhibition of MtbIMPDH2 blocks the biosynthesis of guanine nucleotides, but high concentrations of guanine can potentially rescue the bacteria. Herein we describe an expansion of the structure–activity relationship (SAR) for the benzoxazole series of MtbIMPDH2 inhibitors and demonstrate that minimum inhibitory concentrations (MIC) of ?1 ?M can be achieved. The antibacterial activity of the most promising compound, 17b (Q151), is derived from the inhibition of MtbIMPDH2 as demonstrated by conditional knockdown and resistant strains. Importantly, guanine does not change the MIC of 17b, alleviating the concern that guanine salvage can protect Mtb in vivo. These findings suggest that MtbIMPDH2 is a vulnerable target for tuberculosis.Item Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds(PLoS Biology, 2015-10) Grzyska, Magdalena M.; Kim, Youngchang; Gorla, Suresh K.; Wei, Yang; Mandapati, Kavitha; Zhang, Minjia; Maltseva, Natalia; Modi, Gyan; Boshoff, Helena I. M.; Gu, Minyi; Aldrich, Courtney; Cuny, Gregory D.; Hedstrom, Lizbeth; Joachimiak, AndrzejTuberculosis (TB) remains a worldwide problem and the need for new drugs is increasingly more urgent with the emergence of multidrug- and extensively-drug resistant TB. Inosine 5’-monophosphate dehydrogenase 2 (IMPDH2) from Mycobacterium tuberculosis (Mtb) is an attractive drug target. The enzyme catalyzes the conversion of inosine 5’-monophosphate into xanthosine 5’-monophosphate with the concomitant reduction of NAD+ to NADH. This reaction controls flux into the guanine nucleotide pool. We report seventeen selective IMPDH inhibitors with antitubercular activity. The crystal structures of a deletion mutant of MtbIMPDH2 in the apo form and in complex with the product XMP and substrate NAD+ are determined. We also report the structures of complexes with IMP and three structurally distinct inhibitors, including two with antitubercular activity. These structures will greatly facilitate the development of MtbIMPDH2-targeted antibiotics.