Type II fatty acid synthesis is not a suitable antibiotic target for Gram-positive pathogens
| Autor: | Claire Poyart, Sophie Brinster, Gilles Lamberet, Alexandra Gruss, Bart Staels, Patrick Trieu-Cuot |
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| Přispěvatelé: | Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Bactéries Lactiques et Pathogènes Opportunistes ( UBLO ), Institut National de la Recherche Agronomique ( INRA ), Récepteurs nucléaires, lipoprotéines et athérosclérose, Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Biologie des Bactéries Pathogènes à Gram-positif, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Centre national de Référence des Streptocoques (CNR), Assistance publique - Hôpitaux de Paris (AP-HP), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bactéries Lactiques et Pathogènes Opportunistes (UBLO), Institut National de la Recherche Agronomique (INRA), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP) |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Serum
medicine.drug_class Gram-positive bacteria Platensimycin Antibiotics Microbial Sensitivity Tests Gram-Positive Bacteria Streptococcus agalactiae Substrate Specificity Microbiology Rats Sprague-Dawley Mice 03 medical and health sciences chemistry.chemical_compound [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology Sepsis Streptococcal Infections Drug Resistance Bacterial medicine Animals Humans Pathogen Fatty acid synthesis 030304 developmental biology Antibacterial agent 0303 health sciences Multidisciplinary Virulence biology 030306 microbiology Fatty Acids Reproducibility of Results Gene Expression Regulation Bacterial biology.organism_classification Antimicrobial Anti-Bacterial Agents Rats 3. Good health Mice Inbred C57BL [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology chemistry Biochemistry Genes Bacterial Bacteria |
| Zdroj: | Nature Nature, Nature Publishing Group, 2009, 458 (7234), pp.83-6. 〈10.1038/nature07772〉 Nature, 2009, 458 (7234), pp.83-6. ⟨10.1038/nature07772⟩ Nature, Nature Publishing Group, 2009, 458 (7234), pp.83-6. ⟨10.1038/nature07772⟩ |
| ISSN: | 0028-0836 1476-4679 1476-4687 |
| DOI: | 10.1038/nature07772〉 |
| Popis: | The type II fatty acid synthesis (FASII) pathway has been suggested to be a promising antimicrobial target, and the antibiotics platensimycin and platencin that target this pathway are claimed to be potentially effective against multiresistant Gram-positive bacteria. But a new study casts doubt on the value of this approach. Clinical isolates of a series of Gram-positive pathogens, including staphylococci, streptococci, pneumococci, and enterococci, are shown to overcome drug-induced blockade of FASII pathway inhibition when supplied with exogenous fatty acids either in laboratory growth medium or when infecting animals. Importantly, human serum is a highly effective source of fatty acids. The type II fatty acid biosynthesis pathway has been suggested to be a promising antimicrobial target. It is shown that major Gram-positive pathogen groups may circumvent the action of these antimicrobials by using host derived fatty acids instead, leaving these antibiotics ineffective. Antimicrobial drugs targeting the reportedly essential type II fatty acid synthesis (FASII) pathway1,2,3,4,5 have been recently acclaimed for their efficacy against infections caused by multiresistant Gram-positive bacteria6,7,8. Our findings show that the strategy for antibiotic development based on FASII pathway targets is fundamentally flawed by the fact that exogenous fatty acids fully bypass inhibition of this pathway in both in vitro and in vivo conditions. We demonstrate that major Gram-positive pathogens—such as streptococci, pneumococci, enterococci and staphylococci—overcome drug-induced FASII pathway inhibition when supplied with exogenous fatty acids, and human serum proves to be a highly effective source of fatty acids. For opportunist pathogen Streptococcus agalactiae, growth in serum leads to an overall decrease of FASII gene expression. No antibiotic inhibitor could have a stronger effect than the inactivation of the target gene, so we challenged the role of FASII using deletion mutants. Our results unequivocally show that the FASII target enzymes are dispensable in vivo during S. agalactiae infection. The results of this study largely compromise the use of FASII-based antimicrobials for treating sepsis caused by Gram-positive pathogens. |
| Databáze: | OpenAIRE |
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