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A Metabolic Dependency for Host Isoprenoids in the Obligate Intracellular Pathogen Rickettsia parkeri Underlies a Sensitivity to the Statin Class of Host-Targeted Therapeutics.

التفاصيل البيبلوغرافية
العنوان: A Metabolic Dependency for Host Isoprenoids in the Obligate Intracellular Pathogen Rickettsia parkeri Underlies a Sensitivity to the Statin Class of Host-Targeted Therapeutics.
المؤلفون: Ahyong V; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA., Berdan CA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California, USA., Burke TP; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA., Nomura DK; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California, USA., Welch MD; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA welch@berkeley.edu.
المصدر: MSphere [mSphere] 2019 Nov 13; Vol. 4 (6). Date of Electronic Publication: 2019 Nov 13.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101674533 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-5042 (Electronic) Linking ISSN: 23795042 NLM ISO Abbreviation: mSphere Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Society for Microbiology, [2015]-
مواضيع طبية MeSH: Host-Pathogen Interactions*, Cytoplasm/*microbiology , Rickettsia/*growth & development , Rickettsia/*metabolism , Terpenes/*metabolism, Animals ; Anticholesteremic Agents/metabolism ; Chlorocebus aethiops ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism ; Terpenes/antagonists & inhibitors ; Vero Cells
مستخلص: Gram-negative bacteria in the order Rickettsiales have an obligate intracellular growth requirement, and some species cause human diseases such as typhus and spotted fever. The bacteria have evolved a dependence on essential nutrients and metabolites from the host cell as a consequence of extensive genome reduction. However, it remains largely unknown which nutrients they acquire and whether their metabolic dependency can be exploited therapeutically. Here, we describe a genetic rewiring of bacterial isoprenoid biosynthetic pathways in the Rickettsiales that has resulted from reductive genome evolution. Furthermore, we investigated whether the spotted fever group Rickettsia species Rickettsia parkeri scavenges isoprenoid precursors directly from the host. Using targeted mass spectrometry, we found that infection caused decreases in host isoprenoid products and concomitant increases in bacterial isoprenoid metabolites. Additionally, we report that treatment of infected cells with statins, which inhibit host isoprenoid synthesis, prohibited bacterial growth. We show that growth inhibition correlates with changes in bacterial size and shape that mimic those caused by antibiotics that inhibit peptidoglycan biosynthesis, suggesting that statins lead to an inhibition of cell wall synthesis. Altogether, our results describe a potential Achilles' heel of obligate intracellular pathogens that can potentially be exploited with host-targeted therapeutics that interfere with metabolic pathways required for bacterial growth. IMPORTANCE Obligate intracellular pathogens, which include viruses as well as certain bacteria and eukaryotes, are a subset of infectious microbes that are metabolically dependent on and unable to grow outside an infected host cell because they have lost or lack essential biosynthetic pathways. In this study, we describe a metabolic dependency of the bacterial pathogen Rickettsia parkeri on host isoprenoid molecules that are used in the biosynthesis of downstream products, including cholesterol, steroid hormones, and heme. Bacteria make products from isoprenoids, such as an essential lipid carrier for making the bacterial cell wall. We show that bacterial metabolic dependency can represent a potential Achilles' heel and that inhibiting host isoprenoid biosynthesis with the FDA-approved statin class of drugs inhibits bacterial growth by interfering with the integrity of the cell wall. This work supports the potential to treat infections by obligate intracellular pathogens through inhibition of host biosynthetic pathways that are susceptible to parasitism.
(Copyright © 2019 Ahyong et al.)
التعليقات: Erratum in: mSphere. 2019 Nov 27;4(6):. (PMID: 31776245)
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معلومات مُعتمدة: S10 RR027696 United States RR NCRR NIH HHS; R01 AI109044 United States AI NIAID NIH HHS; R01 CA172667 United States CA NCI NIH HHS; F32 AI133912 United States AI NIAID NIH HHS; R21 AI109270 United States AI NIAID NIH HHS
فهرسة مساهمة: Keywords: Rickettsia; isoprenoids; metabolic parasitism
المشرفين على المادة: 0 (Anticholesteremic Agents)
0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
0 (Terpenes)
SCR Organism: Rickettsia parkeri
تواريخ الأحداث: Date Created: 20191115 Date Completed: 20200605 Latest Revision: 20200702
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6854040
DOI: 10.1128/mSphere.00536-19
PMID: 31722991
قاعدة البيانات: MEDLINE
الوصف
تدمد:2379-5042
DOI:10.1128/mSphere.00536-19