دورية أكاديمية
أعرض في EDS

Substrate Analogues Entering the Lipoic Acid Salvage Pathway via Lipoate-Protein Ligase 2 Interfere with Staphylococcus aureus Virulence.

التفاصيل البيبلوغرافية
العنوان: Substrate Analogues Entering the Lipoic Acid Salvage Pathway via Lipoate-Protein Ligase 2 Interfere with Staphylococcus aureus Virulence.
المؤلفون: Scattolini A; Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas, Ocampo y Esmeralda, S2000FHQ Rosario, Argentina.; Departamento de Microbiología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, 2000 Rosario, Argentina., Grammatoglou K; Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia., Nikitjuka A; Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia., Jirgensons A; Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia., Mansilla MC; Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas, Ocampo y Esmeralda, S2000FHQ Rosario, Argentina.; Departamento de Microbiología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, 2000 Rosario, Argentina., Windshügel B; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, Schnackenburgallee 114, 22525 Hamburg, Germany.; School of Science, Constructor University, Campus Ring 1, 28759 Bremen, Germany.
المصدر: ACS infectious diseases [ACS Infect Dis] 2024 Jun 14; Vol. 10 (6), pp. 2172-2182. Date of Electronic Publication: 2024 May 09.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: ACS Publications Country of Publication: United States NLM ID: 101654580 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2373-8227 (Electronic) Linking ISSN: 23738227 NLM ISO Abbreviation: ACS Infect Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : ACS Publications, [2015]-
مواضيع طبية MeSH: Thioctic Acid*/pharmacology , Thioctic Acid*/analogs & derivatives , Staphylococcus aureus*/drug effects , Staphylococcus aureus*/enzymology , Staphylococcus aureus*/genetics , Anti-Bacterial Agents*/pharmacology , Anti-Bacterial Agents*/chemistry, Virulence ; Animals ; Peptide Synthases/metabolism ; Peptide Synthases/genetics ; Caenorhabditis elegans ; Bacterial Proteins/metabolism ; Bacterial Proteins/genetics ; Staphylococcal Infections/microbiology ; Staphylococcal Infections/drug therapy
مستخلص: Lipoic acid (LA) is an essential cofactor in prokaryotic and eukaryotic organisms, required for the function of several multienzyme complexes such as oxoacid dehydrogenases. Prokaryotes either synthesize LA or salvage it from the environment. The salvage pathway in Staphylococcus aureus includes two lipoate-protein ligases, LplA1 and LplA2, as well as the amidotransferase LipL. In this study, we intended to hijack the salvage pathway by LA analogues that are transferred via LplA2 and LipL to the E2 subunits of various dehydrogenases, thereby resulting in nonfunctional enzymes that eventually impair viability of the bacterium. Initially, a virtual screening campaign was carried out to identify potential LA analogues that bind to LplA2. Three selected compounds affected S. aureus USA300 growth in minimal medium at concentrations ranging from 2.5 to 10 μg/mL. Further analysis of the most potent compound ( Lpl-004 ) revealed its transfer to E2 subunits of dehydrogenase complexes and a negative impact on its functionality. Growth impairment caused by Lpl-004 treatment was restored by adding products of the lipoate-dependent enzyme complexes. In addition, Caenorhabditis elegans infected with LpL-004 -treated USA300 demonstrated a significantly expanded lifespan compared to worms infected with untreated bacteria. Our results provide evidence that LA analogues exploiting the LA salvage pathway represent an innovative strategy for the development of novel antimicrobial substances.
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فهرسة مساهمة: Keywords: LplA2; Staphylococcus aureus; infection model; lipoic acid; salvage pathway; virtual screening
المشرفين على المادة: 73Y7P0K73Y (Thioctic Acid)
EC 6.3.2.- (lipoate-protein ligase)
0 (Anti-Bacterial Agents)
EC 6.3.2.- (Peptide Synthases)
0 (Bacterial Proteins)
تواريخ الأحداث: Date Created: 20240509 Date Completed: 20240614 Latest Revision: 20240620
رمز التحديث: 20240620
مُعرف محوري في PubMed: PMC11184557
DOI: 10.1021/acsinfecdis.4c00148
PMID: 38724014
قاعدة البيانات: MEDLINE
الوصف
تدمد:2373-8227
DOI:10.1021/acsinfecdis.4c00148