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

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• 作者：Nag S. Kumar^a ; Edie M. Dullaghan^b ; B. Brett Finlay^c ; ^d ; Huansheng Gong^d ; Neil E. Reiner^d ; ^e ; J. Jon Paul Selvam^a ; Lisa M. Thorson^d ; Sara Campbell^b ; Nicholas Vitko^f ; Anthony R. Richardson^f ; Roya Zoraghi^d ; Robert N. Young^a ; ^{robert_young@sfu.ca" class="auth_mail}
• 关键词：BHI ; brain&ndash ; heart infusion broth ; MRSA ; methicillin-resistant Staphylococcus aureus ; PK ; pyruvate kinase ; MIC ; minimal inhibitory concentration ; TSA ; tryptic soy agar ; TSB ; tryptic soy broth
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：1 March, 2014
• 年：2014
• 卷：22
• 期：5
• 页码：1708-1725
• 全文大小：2849 K

文摘

A novel series of bis-indoles derived from naturally occurring marine alkaloid 4 were synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK is not only critical for bacterial survival which would make it a target for development of novel antibiotics, but it is reported to be one of the most highly connected 鈥榟ub proteins鈥?in MRSA, and thus should be very sensitive to mutations and making it difficult for the bacteria to develop resistance. From the co-crystal structure of cis-3-4-dihydrohamacanthin B (4) bound to S. aureus PK we were able to identify the pharmacophore needed for activity. Consequently, we prepared simple direct linked bis-indoles such as 10b that have similar anti-MRSA activity as compound 4. Structure-activity relationship (SAR) studies were carried out on 10b and led us to discover more potent compounds such as 10c, 10d, 10k and 10m with enzyme inhibiting activities in the low nanomolar range that effectively inhibited the bacteria growth in culture with minimum inhibitory concentrations (MIC) for MRSA as low as 0.5 渭g/ml. Some potent PK inhibitors, such as 10b, exhibited attenuated antibacterial activity and were found to be substrates for an efflux mechanism in S. aureus. Studies comparing a wild type S. aureus with a construct (S. aureus LAC 螖pyk::Erm^R) that lacks PK activity confirmed that bactericidal activity of 10d was PK-dependant.