title: The complex interplay of iron, biofilm formation, and mucoidy affecting antimicrobial resistance of Pseudomonas aeruginosa.
abstract: Pseudomonas aeruginosa is a Gram-negative opportunistic bacterial pathogen that is refractory to a variety of current antimicrobial therapeutic regimens. Complicating treatment for such infections is the ability of P. aeruginosa to form biofilms, as well as several innate and acquired resistance mechanisms. Previous studies suggest iron plays a role in resistance to antimicrobial therapy, including the efficacy of an FDA-approved iron chelator, deferasirox (DSX), or Gallium, an iron analog, in potentiating antibiotic-dependent killing of P. aeruginosa biofilms. Here, we show that iron-replete conditions enhance resistance of P. aeruginosa nonbiofilm growth against tobramycin and tigecycline. Interestingly, the mechanism of iron-enhanced resistance to each of these antibiotics is distinct. Whereas pyoverdine-mediated iron uptake is important for optimal resistance to tigecycline, it does not enhance tobramycin resistance. In contrast, heme supplementation results in increased tobramycin resistance, while having no significant effect on tigecycline resistance. Thus, nonsiderophore bound iron plays an important role in resistance to tobramycin, while pyoverdine increases the ability of P. aeruginosa to resist tigecycline treatment. Lastly, we show that iron increases the minimal concentration of tobramycin, but not tigecycline, required to eradicate P. aeruginosa biofilms. Moreover, iron depletion blocks the previous observed induction of biofilm formation by subinhibitory concentrations of tobramycin, suggesting iron and tobramycin signal through overlapping regulatory pathways to affect biofilm formation. These data further support the role of iron in P. aeruginosa antibiotic resistance, providing yet another compelling case for targeting iron acquisition for future antimicrobial drug development.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA; Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, MD, USA.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Oglesby-Sherrouse
authors.forename: Louise
authors.initials: L
authors.lastname: Djapgne
authors.forename: Angela T
authors.initials: AT
authors.lastname: Nguyen
authors.forename: Adriana I
authors.initials: AI
authors.lastname: Vasil
authors.forename: Michael L
authors.initials: ML
authors.lastname: Vasil
mesh_terms: D000693:Anaerobiosis; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000254:growth & development*; D027682:Cation Transport Proteins / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D006418:Heme / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008911:Minocycline / Q000031:analogs & derivatives / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000502:physiology*; D017262:Siderophores / Q000378:metabolism; D000078304:Tigecycline; D014031:Tobramycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D027682:Cation Transport Proteins; D007502:Iron Chelating Agents; D017262:Siderophores; D006418:Heme; D000078304:Tigecycline; D007501:Iron; D008911:Minocycline; D014031:Tobramycin
keywords: Pseudomonas aeruginosa; antibiotic resistance; biofilms; iron; tigecyclin; tobramycin