Potentiation of aminoglycoside lethality by C4-dicarboxylates requires RpoN in antibiotic tolerant Pseudomonas aeruginosa.

Potentiation of aminoglycoside lethality by C4-dicarboxylates requires RpoN in antibiotic tolerant Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2019 Aug 05;: Authors: Hall CW, Farkas E, Zhang L, Mah TF Abstract Antibiotic tolerance contributes to the inability of standard antimicrobial therapies to clear the chronic Pseudomonas aeruginosa lung infections that often afflict patients with cystic fibrosis (CF). Metabolic potentiation of bactericidal antibiotics with carbon sources has emerged as a promising strategy to re-sensitise tolerant bacteria to antibiotic killing. Fumarate (FUM), a C4-dicarboxylate, has been recently shown to re-sensitise tolerant P. aeruginosa to killing by tobramycin (TOB), an aminoglycoside antibiotic, when used in combination (TOB+FUM). Fumarate and other C4-dicarboxylates are taken up intracellularly by transporters regulated by the alternative sigma factor, RpoN. Once in the cell, FUM is metabolised, leading to enhanced electron transport chain activity, regeneration of the proton motive force, and increased TOB uptake. In this work, we demonstrate that a ΔrpoN mutant displays impaired FUM uptake and, consequently, non-susceptibility to TOB+FUM treatment. RpoN was also found to be essential for susceptibility to other aminoglycoside and C4-dicarboxylate combinations. Importantly, RpoN loss-of-function mutations have been documented to evolve in the CF lung, and these loss-of-function alleles can also result in TO...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research

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The U.S. Food and Drug Administration approved Vertex Pharmaceuticals Inc's combination treatment for a rare condition called cystic fibrosis, the agency said on Monday.
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Boston-based Vertex Pharmaceuticals Inc. has achieved one of the biggest feats to date for cystic fibrosis patients — a treatment that could benefit 90 percent of patients with the rare lung disease. The FDA approved a combination of three drugs Monday called Trikafta, which targets a mutation in the F508del gene. That genetic error is found in approximately 90 percent of patients with the rare lung disease. "If you think about it, we went from being able to treat no patients to being able to…
Source: bizjournals.com Health Care:Biotechnology headlines - Category: Biotechnology Authors: Source Type: news
BOSTON--(BUSINESS WIRE)--Oct. 21, 2019-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced the U.S. Food and Drug Administration (FDA) has approved Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor) for the treatment of...
Source: Drugs.com - New Drug Approvals - Category: Drugs & Pharmacology Source Type: news
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Source: Clinics - Category: General Medicine Source Type: research
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Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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Source: The Journal of Heart and Lung Transplantation - Category: Transplant Surgery Authors: Tags: Case Anecdotes, Comments and Opinions Source Type: research
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Source: Expert Review of Respiratory Medicine - Category: Respiratory Medicine Tags: Expert Rev Respir Med Source Type: research
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