Abstract
Pseudomonas aeruginosa is 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. aeruginosa can acquire iron from a variety of sources to fulfill its nutritional requirements both in the environment and in the infected host. The adaptation of P. aeruginosa to heme iron acquisition in the CF lung makes heme utilization pathways a promising target for the development of new anti-Pseudomonas drugs. Gallium [Ga(III)] is an iron mimetic metal which inhibits P. aeruginosa growth 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 on P. aeruginosa. Here, we demonstrate that GaPPIX is indeed capable of inhibiting the growth of clinical P. aeruginosa strains under iron-deplete conditions, as those encountered by bacteria during infection, and that GaPPIX inhibition is reversed by iron. Using P. aeruginosa PAO1 as model organism, we show that GaPPIX enters cells through both the heme-uptake systems has and phu, primarily via the PhuR receptor which plays a crucial role in P. aeruginosa adaptation to the CF lung. We also demonstrate that intracellular GaPPIX inhibits the aerobic growth of P. aeruginosa by targeting cytochromes, thus interfering with cellular respiration.
Highlights
Pseudomonas aeruginosa is a challenging bacterial pathogen due to both innate and acquired resistance to several antibiotics (Moore and Flaws, 2011)
The ability of pathogenic bacteria to colonize the host and cause infections is dependent on their capability to acquire iron and generate energy to sustain in vivo growth (Ratledge and Dover, 2000; Alvarez-Ortega and Harwood, 2007; Hammer et al, 2013)
The success of P. aeruginosa as a pathogen relies on the presence of several iron-uptake systems, as well as on a multiplicity of terminal oxidases which allow bacterial respiration in vivo
Summary
Pseudomonas aeruginosa is a challenging bacterial pathogen due to both innate and acquired resistance to several antibiotics (Moore and Flaws, 2011). Aerobic respiration in P. aeruginosa relies on five terminal oxidases (Matsushita et al, 1982, 1983; Fujiwara et al, 1992; Cunningham and Williams, 1995; Cunningham et al, 1997; Stover et al, 2000; Comolli and Donohue, 2002, 2004) Three of these enzymes, the aa terminal oxidase (Cox), the cbb (Cco-1), and the cbb (Cco-2) are cytochrome c-type oxidases, while the other two, i.e., the cyanide-insensitive oxidase (Cio) and the bo oxidase (Cyo), are quinol oxidases (Figure 1). Only nitrite reductase (Nir) and nitric oxide reductase (Nor) contain heme as a cofactor (Figure 1)
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