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Antimicrob Agents Chemother. 2017 Nov 22;61(12). pii: e00987-17. doi: 10.1128/AAC.00987-17. Print 2017 Dec.

An Antipersister Strategy for Treatment of Chronic Pseudomonas aeruginosa Infections.

Author information

1
EnBiotix, Inc., Cambridge, Massachusetts, USA.
2
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
3
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
4
Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA.
5
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
7
EnBiotix, Inc., Cambridge, Massachusetts, USA diane.j-m@enbiotix.com.

Abstract

Bacterial persisters are a quasidormant subpopulation of cells that are tolerant to antibiotic treatment. The combination of the aminoglycoside tobramycin with fumarate as an antibacterial potentiator utilizes an antipersister strategy that is aimed at reducing recurrent Pseudomonas aeruginosa infections by enhancing the killing of P. aeruginosa persisters. Stationary-phase cultures of P. aeruginosa were used to generate persister cells. A range of tobramycin concentrations was tested with a range of metabolite concentrations to determine the potentiation effect of the metabolite under a variety of conditions, including a range of pH values and in the presence of azithromycin or cystic fibrosis (CF) patient sputum. In addition, 96-well dish biofilm and colony biofilm assays were performed, and the cytotoxicity of the tobramycin-fumarate combination was determined utilizing a lactate dehydrogenase (LDH) assay. Enhanced killing of up to 6 orders of magnitude of P. aeruginosa persisters over a range of CF isolates, including mucoid and nonmucoid strains, was observed for the tobramycin-fumarate combination compared to killing with tobramycin alone. Furthermore, significant fumarate-mediated potentiation was seen in the presence of azithromycin or CF patient sputum. Fumarate also reduced the cytotoxicity of tobramycin-treated P. aeruginosa to human epithelial airway cells. Finally, in mucoid and nonmucoid CF isolates, complete eradication of P. aeruginosa biofilm was observed in the colony biofilm assay due to fumarate potentiation. These data suggest that a combination of tobramycin with fumarate as an antibacterial potentiator may be an attractive therapeutic for eliminating recurrent P. aeruginosa infections in CF patients through the eradication of bacterial persisters.

KEYWORDS:

Pseudomonas aeruginosa; aminoglycoside; bacterial metabolite; bacterial persistence; cystic fibrosis; fumarate; persistent infection; persisters; potentiator; tobramycin

PMID:
28923873
PMCID:
PMC5700368
DOI:
10.1128/AAC.00987-17
[Indexed for MEDLINE]
Free PMC Article

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