Antimicrobial Activity of Gallium Protoporphyrin IX against Acinetobacter baumannii Strains Displaying Different Antibiotic Resistance Phenotypes

• Published in: Antimicrobial agents and chemotherapy 2015-12, Vol.59 (12), p.7657-7665
• Main Authors: Arivett, Brock A, Fiester, Steven E, Ohneck, Emily J, Penwell, William F, Kaufman, Cynthia M, Relich, Ryan F, Actis, Luis A
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii; Acinetobacter baumannii - drug effects; Acinetobacter baumannii - growth & development; Acinetobacter baumannii - metabolism; Acinetobacter Infections - drug therapy; Acinetobacter Infections - microbiology; Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Cell Line, Tumor; Coordination Complexes; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Drug Resistance, Multiple, Bacterial; Drug Resistance, Multiple, Bacterial - drug effects; Epithelial Cells - drug effects; Epithelial Cells - microbiology; Experimental Therapeutics; Galleria mellonella; Gallium; Gallium - chemistry; Gallium - pharmacology; Humans; Iron - metabolism; Larva - drug effects; Larva - microbiology; Microbial Sensitivity Tests; Microbial Viability - drug effects; Moths - drug effects; Moths - microbiology; Phenotype; Protoporphyrins; Protoporphyrins - chemistry; Protoporphyrins - pharmacology; Survival Analysis
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01472-15

A paucity of effective, currently available antibiotics and a lull in antibiotic development pose significant challenges for treatment of patients with multidrug-resistant (MDR) Acinetobacter baumannii infections. Thus, novel therapeutic strategies must be evaluated to meet the demands of treatment of these often life-threatening infections. Accordingly, we examined the antibiotic activity of gallium protoporphyrin IX (Ga-PPIX) against a collection of A. baumannii strains, including nonmilitary and military strains and strains representing different clonal lineages and isolates classified as susceptible or MDR. Susceptibility testing demonstrated that Ga-PPIX inhibits the growth of all tested strains when cultured in cation-adjusted Mueller-Hinton broth, with a MIC of 20 μg/ml. This concentration significantly reduced bacterial viability, while 40 μg/ml killed all cells of the A. baumannii ATCC 19606(T) and ACICU MDR isolate after 24-h incubation. Recovery of ATCC 19606(T) and ACICU strains from infected A549 human alveolar epithelial monolayers was also decreased when the medium was supplemented with Ga-PPIX, particularly at a 40-μg/ml concentration. Similarly, the coinjection of bacteria with Ga-PPIX increased the survival of Galleria mellonella larvae infected with ATCC 19606(T) or ACICU. Ga-PPIX was cytotoxic only when monolayers or larvae were exposed to concentrations 16-fold and 1,250-fold higher than those showing antibacterial activity, respectively. These results indicate that Ga-PPIX could be a viable therapeutic option for treatment of recalcitrant A. baumannii infections regardless of the resistance phenotype, clone lineage, time and site of isolation of strains causing these infections and their iron uptake phenotypes or the iron content of the media.