title: Gallium-Protoporphyrin IX InhibitsPseudomonas aeruginosaGrowth by Targeting Cytochromes.
abstract: Pseudomonas aeruginosais a challenging pathogen due to both innate and acquired resistance to antibiotics. It is capable of causing a variety of infections, including chronic lung infection in cystic fibrosis (CF) patients. Given the importance of iron in bacterial physiology and pathogenicity, iron-uptake and metabolism have become attractive targets for the development of new antibacterial compounds.P. aeruginosacan acquire iron from a variety of sources to fulfill its nutritional requirements both in the environment and in the infected host. The adaptation ofP. aeruginosato heme iron acquisition in the CF lung makes heme utilization pathways a promising target for the development of new anti-Pseudomonasdrugs. Gallium [Ga(III)] is an iron mimetic metal which inhibitsP. aeruginosagrowth by interfering with iron-dependent metabolism. The Ga(III) complex of the heme precursor protoporphyrin IX (GaPPIX) showed enhanced antibacterial activity against several bacterial species, although no inhibitory effect has been reported onP. aeruginosa. Here, we demonstrate that GaPPIX is indeed capable of inhibiting the growth of clinicalP. aeruginosastrains under iron-deplete conditions, as those encountered by bacteria during infection, and that GaPPIX inhibition is reversed by iron. UsingP. aeruginosaPAO1 as model organism, we show that GaPPIX enters cells through both the heme-uptake systemshasandphu, primarilyviathe PhuR receptor which plays a crucial role inP. aeruginosaadaptation to the CF lung. We also demonstrate that intracellular GaPPIX inhibits the aerobic growth ofP. aeruginosaby targeting cytochromes, thus interfering with cellular respiration.
authors.affiliation: Department of Science, Roma Tre University Rome, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hijazi
authors.affiliation: Department of Science, Roma Tre University Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Visca
authors.affiliation: Department of Science, Roma Tre University Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Frangipani
mesh_terms: D000332:Aerobiosis; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003580:Cytochromes / Q000037:antagonists & inhibitors*; D004579:Electron Transport / Q000187:drug effects; D005708:Gallium / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011524:Protoporphyrins / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D003580:Cytochromes; D011524:Protoporphyrins; C028025:protoporphyrin IX; D005708:Gallium
keywords: aerobic respiration; antibacterial; cystic fibrosis; gallium; heme; infection; iron-uptake; terminal oxidases