title: Gallium Compounds Exhibit Potential as New Therapeutic Agents against Mycobacterium abscessus.
abstract: The rapidly growing nontuberculous mycobacterial species Mycobacterium abscessus has recently emerged as an important pathogen in patients with cystic fibrosis (CF). Treatment options are limited because of the organism's innate resistance to standard antituberculous antibiotics, as well as other currently available antibiotics. New antibiotic approaches to the treatment of M. abscessus are urgently needed. The goal of the present study was to assess the growth-inhibitory activity of different Ga compounds against an American Type Culture Collection (ATCC) strain and clinical isolates of M. abscessus obtained from CF and other patients. In our results, using Ga(NO3)3 and all of the other Ga compounds tested inhibited the growth of ATCC 19977 and clinical isolates of M. abscessus. Inhibition was mediated by disrupting iron uptake, as the addition of exogenous iron (Fe) restored basal growth. There were modest differences in inhibition among the isolates for the same Ga chelates, and for most Ga chelates there was only a slight difference in potency from Ga(NO3)3. In contrast, Ga-protoporphyrin completely and significantly inhibited the ATCC strain and clinical isolates of M. abscessus at much lower concentrations than Ga(NO3)3. In in vitro broth culture, Ga-protoporphyrin was more potent than Ga(NO3)3. When M. abscessus growth inside the human macrophage THP-1 cell line was assessed, Ga-protoporphyrin was >20 times more active than Ga(NO3)3. The present work suggests that Ga exhibits potent growth-inhibitory capacity against the ATCC strain, as well as against antibiotic-resistant clinical isolates of M. abscessus, including the highly antibiotic-resistant strain MC2638. Ga-based therapy offers the potential for further development as a novel therapy against M. abscessus.
authors.affiliation: Research Service, VAMC-Nebraska/Western Iowa, Omaha, Nebraska, USA Department of Pathology and Microbiology, University of Nebraska Medical Center College of Medicine, Omaha, Nebraska, USA.
authors.forename: Maher Y
authors.initials: MY
authors.lastname: Abdalla
authors.affiliation: Research Service, VAMC-Nebraska/Western Iowa, Omaha, Nebraska, USA Department of Internal Medicine, University of Nebraska Medical Center College of Medicine, Omaha, Nebraska, USA.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Switzer
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Goss
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Moira L
authors.initials: ML
authors.lastname: Aitken
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Research Service, VAMC-Nebraska/Western Iowa, Omaha, Nebraska, USA Department of Internal Medicine, University of Nebraska Medical Center College of Medicine, Omaha, Nebraska, USA Department of Pathology and Microbiology, University of Nebraska Medical Center College of Medicine, Omaha, Nebraska, USA bradley.britigan@unmc.edu.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Britigan
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000382:microbiology; D005708:Gallium / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D009165:Mycobacterium Infections, Nontuberculous / Q000188:drug therapy; D009170:Nontuberculous Mycobacteria / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D005708:Gallium