title: Indirect resistance to several classes of antibiotics in cocultures with resistant bacteria expressing antibiotic-modifying or -degrading enzymes.
abstract: OBJECTIVE
  Indirect resistance (IR), the ability of an antibiotic-resistant population of bacteria to protect a susceptible population, has been previously observed for β-lactamase-producing bacteria and associated with antimicrobial treatment failures. Here, we determined whether other resistance determinants could cause IR in the presence of five other classes of antibiotics.
  
  
  METHODS
  A test was designed to detect IR and 14 antibiotic resistance genes were tested in the presence of 13 antibiotics from six classes. A bioassay was used to measure the ability of resistance-causing enzymes to decrease the concentration of active antibiotics in the medium.
  
  
  RESULTS
  We confirmed IR in the presence of β-lactam antibiotics (ampicillin and mecillinam) when TEM-1A was expressed. We found that bacteria expressing antibiotic-modifying or -degrading enzymes Ere(A), Tet(X2) or CatA1 caused IR in the presence of macrolides (erythromycin and clarithromycin), tetracyclines (tetracycline and tigecycline) and chloramphenicol, respectively. IR was not observed with resistance determinants that did not modify or destroy antibiotics or with enzymes modifying aminoglycosides or degrading fosfomycin. IR was dependent on the resistance enzymes decreasing the concentration of active antibiotics in the medium, hence allowing nearby susceptible bacteria to resume growth once the antibiotic concentration fell below their MIC.
  
  
  CONCLUSIONS
  IR was not limited to β-lactamase-producing bacteria, but was also caused by resistant bacteria carrying cytoplasmic antibiotic-modifying or -degrading enzymes that catalyse energy-consuming reactions requiring complex cellular cofactors. Our results suggest that IR is common and further emphasizes that coinfecting agents and the human microflora can have a negative impact during antimicrobial therapy.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Hervé
authors.initials: H
authors.lastname: Nicoloff
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden dan.andersson@imbim.uu.se.
authors.forename: Dan I
authors.initials: DI
authors.lastname: Andersson
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000378:metabolism*; D001711:Biotransformation; D003470:Culture Media / Q000737:chemistry; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D059013:Microbial Consortia; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D003470:Culture Media; D004798:Enzymes