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Antibiotic capture by bacterial lipocalins uncovers an extracellular mechanism of intrinsic antibiotic resistance

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2017-05-03
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American Society for Microbiology
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The potential for microbes to overcome antibiotics of different classes before they reach bacterial cells is largely unexplored. Here we show that a soluble bacterial lipocalin produced by Burkholderia cenocepacia upon exposure to sublethal antibiotic concentrations increases resistance to diverse antibiotics in vitro and in vivo. These phenotypes were recapitulated by heterologous expression in B. cenocepacia of lipocalin genes from Pseudomonas aeruginosa, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus. Purified lipocalin bound different classes of bactericidal antibiotics and contributed to bacterial survival in vivo. Experimental and X-ray crystal structure-guided computational studies revealed that lipocalins counteract antibiotic action by capturing antibiotics in the extracellular space. We also demonstrated that fat-soluble vitamins prevent antibiotic capture by binding bacterial lipocalin with higher affinity than antibiotics. Therefore, bacterial lipocalins contribute to antimicrobial resistance by capturing diverse antibiotics in the extracellular space at the site of infection, which can be counteracted by known vitamins.
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Ceftazidime, Lipocalin, Norfloxacin, Rifampicin, Vitamin, Burkholderia, Female, Staphylococcus, Aureus, Mouse, Pseudomonas, Aeruginosa, Genetics, Metabolism, Burkholderia, Cenocepacia, Tuberculosis, Ciprofloxacin gentamicin, Lipocalin bcna, Lipocalin bcnb, Unclassified drug, Antiinfective agent, Lipocalin adult, Animal experiment, Antibiotic capture, Antibiotic resistance, Antibiotic therapy, Bacterium isolate, Cenocepacia controlled study, Gene expression, Drug effects, Extracellular space, Anti-bacterial agents, Drug resistance, In vitro study, In vivo study, Limit of quantitation methicillin resistant, Mycobacterium tuberculosis nonhuman, Protein secretion, Bacterial gene expression lipocalins, Methicillin-resistant, Pseudomonas aeruginosa, Staphylococcus aureus mycobacterium
Bibliographic citation
El-Halfawy, O. M., Klett, J., Ingram, R. J., Loutet, S. A., Murphy, M., Martín‐Santamaría, S., & Valvano, M. A. (2017). Antibiotic capture by bacterial lipocalins uncovers an extracellular mechanism of intrinsic antibiotic resistance. MBio, 8(2).