Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in Acinetobacter baumannii and Escherichia coli

被引:2
|
作者
Peng, Yutian [1 ]
Moffat, John G. [2 ]
DuPai, Cory [3 ]
Kofoed, Eric M. [1 ]
Skippington, Elizabeth [3 ]
Modrusan, Zora [4 ]
Gloor, Susan L. [2 ]
Clark, Kevin [2 ]
Xu, Yiming [2 ]
Li, Shuxuan [5 ]
Chen, Liuxi [5 ]
Liu, Xingrong [5 ]
Wu, Ping [6 ]
Harris, Seth F. [6 ]
Wang, Shumei [7 ]
Crawford, Terry D. [7 ]
Li, Chun Sing [8 ]
Liu, Zhiguo [8 ]
Wai, John [8 ]
Tan, Man-Wah [1 ]
机构
[1] Genentech Inc, Dept Infect Dis, South San Francisco, CA 94080 USA
[2] Genentech Inc, Dept Biochem & Cellular Pharmacol, South San Francisco, CA USA
[3] Genentech Inc, Dept Bioinformat, South San Francisco, CA USA
[4] Genentech Inc, Dept Prote & Genom Technol, South San Francisco, CA USA
[5] Genentech Inc, Dept Drug Metab & Pharmacokinet, South San Francisco, CA 94080 USA
[6] Genentech Inc, Dept Struct Biol, South San Francisco, CA USA
[7] Genentech Inc, Dept Discovery Chem, South San Francisco, CA USA
[8] WuXi AppTec Co Ltd, Waigaoqiao Free Trade Zone, Shanghai, Peoples R China
关键词
inosine monophosphate dehydrogenase; GuaB; Acinetobacter baumannii; Escherichia coli; de novo guanine biosynthesis; antibacterial; DNA-DAMAGE; BACTERIAL; IDENTIFICATION; PATHOGEN; BIOSYNTHESIS; ENTEROBACTIN; ORGANIZATION; MECHANISM; PATHWAYS; REGULON;
D O I
10.1128/jb.00102-24
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Inosine 5 '-monophosphate dehydrogenase (IMPDH), known as GuaB in bacteria, catalyzes the rate-limiting step in de novo guanine biosynthesis and is conserved from humans to bacteria. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here, we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important Gram-negative pathogens: Acinetobacter baumannii and Escherichia coli. Specifically, the GuaB inhibitor G6 rapidly kills A. baumannii but only kills E. coli after 24 h. After exposure to G6, the expression of genes involved in purine biosynthesis and stress responses change in opposite directions while siderophore biosynthesis is downregulated in both species. Our results suggest that different species respond to GuaB inhibition using distinct regulatory programs and possibly explain the different bactericidal kinetics upon GuaB inhibition. The comparison highlights opportunities for developing GuaB inhibitors as novel antibiotics.
引用
收藏
页数:20
相关论文
共 50 条
  • [1] Inhibition of inosine monophosphate dehydrogenase (IMPDH) Preface
    Pankiewicz, KW
    CURRENT MEDICINAL CHEMISTRY, 1999, 6 (07) : U2 - U2
  • [2] Effects of Inosine-5′-monophosphate Dehydrogenase (IMPDH/GuaB) Inhibitors on Borrelia burgdorferi Growth in Standard and Modified Culture Conditions
    Siegel, Eric L.
    Rich, Connor
    Saravanan, Sanchana
    Pearson, Patrick
    Xu, Guang
    Rich, Stephen M.
    MICROORGANISMS, 2024, 12 (10)
  • [3] Inhibition of inosine monophosphate dehydrogenase (IMPDH) by the antiviral compound, 2-vinylinosine monophosphate
    Pal, S
    Bera, B
    Nair, V
    BIOORGANIC & MEDICINAL CHEMISTRY, 2002, 10 (11) : 3615 - 3618
  • [4] Novel inhibitors of inosine monophosphate dehydrogenase (IMPDH)
    Clark, JL
    Patterson, SE
    Mason, JC
    Otto, MJ
    Schinazi, RF
    Watanabe, KA
    Risal, D
    Goldstein, BM
    Pankiewicz, KW
    CHEMISTRY OF NUCLEIC ACID COMPONENTS, 2002, 5 : 256 - 260
  • [5] Inhibition of inosine monophosphate dehydrogenase (IMPDH) by 2-[2-(Z)-fluorovinyl]inosine 5′-monophosphate
    Nair, V
    Kamboj, RC
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (04) : 645 - 647
  • [6] Inhibition of inosine monophosphate dehydrogenase (IMPDH) as a therapeutic approach for hepatitis B.
    Hamatake, R
    Minimo, L
    Lau, JY
    Raney, A
    HEPATOLOGY, 2001, 34 (04) : 633A - 633A
  • [7] Inosine monophosphate dehydrogenase (IMPDH) as a target in drug discovery
    Shu, Qingning
    Nair, Vasu
    MEDICINAL RESEARCH REVIEWS, 2008, 28 (02) : 219 - 232
  • [8] Synthesis of the inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors
    Cholewinski, Grzegorz
    Iwaszkiewicz-Grzes, Dorota
    Prejs, Michal
    Glowacka, Agnieszka
    Dzierzbicka, Krystyna
    JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2015, 30 (04) : 550 - 563
  • [9] Rapid synthesis of novel inosine monophosphate dehydrogenase (IMPDH) inhibitors
    Guo, JQ
    Pitts, WJ
    Dhar, TGM
    Liu, CJ
    Shen, ZQ
    Gu, HH
    Watterson, SH
    Carlsen, M
    Iwanowicz, EJ
    Barrish, J
    Fleener, CA
    Rouleau, K
    Sherbina, NZ
    Hollenbaugh, D
    Bassolino, D
    Cheney, D
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2002, 223 : B134 - B134
  • [10] The chemistry of nucleoside and dinucleotide inhibitors of inosine monophosphate dehydrogenase (IMPDH)
    Pankiewicz, KW
    Goldstein, BM
    RECENT ADVANCES IN NUCLEOSIDES: CHEMISTRY AND CHEMOTHERAPY, 2002, : 71 - 90