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

authors

  • EL-HALFAWY, OMAR M.
  • KLETT ARROYO, JAVIER
  • INGRAM, REBECCA J.
  • LOUTET, SLADE A.
  • MURPHY, MICHAEL E. P.
  • MARTIN SANTAMAR√ćA, SONSOLES
  • VALVANO, MIGUEL A.

published in

publication date

  • May 2017

start page

  • 1

end page

  • 15

issue

  • 2

volume

  • 8

International Standard Serial Number (ISSN)

  • 2161-2129

Electronic International Standard Serial Number (EISSN)

  • 2150-7511

abstract

  • 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.

subjects

  • Biology and Biomedicine
  • Chemistry

keywords

  • ceftazidime; ciprofloxacin gentamicin; lipocalin; lipocalin bcna; lipocalin bcnb; norfloxacin; rifampicin; unclassified drug; vitamin; antiinfective agent; lipocalin adult; animal experiment; antibiotic capture; antibiotic resistance; antibiotic therapy; bacterium isolate; burkholderia; cenocepacia controlled study; extracellular space; female; in vitro study; in vivo study; limit of quantitation methicillin resistant;staphylococcus; aureus; mouse; mycobacterium tuberculosis nonhuman; protein secretion;pseudomonas; aeruginosa; drug effects; gene expression; genetics; metabolism; anti-bacterial agents; burkholderia; cenocepacia; drug resistance; bacterial gene expression lipocalins; methicillin-resistant; staphylococcus aureus mycobacterium; tuberculosis; pseudomonas aeruginosa