Serious human infections caused by Pseudomonas aeruginosa and other intrinsically antibiotic-resistant pathogens are frequent occurrences. Clinicians increasingly depend on alternative antibiotics like polymyxin (Pm) to treat such infections. Binding of Pm to lipid A, a component of the bacterial cell wall, is key to its antimicrobial mechanism of action. Recently, highly Pm-resistant (PmR) strains of P. aeruginosa have been cultured from European cystic fibrosis (CF) patients who were failing treatment with inhaled Pm. These strains have modified lipid A. Data show that in the US, ~20% of CF adults with chronic P. aeruginosa airway infection were treated with inhaled Pm during 2003-2005, most of them receiving this treatment routinely. Moreover, ~5% of CF isolates identified in US clinical microbiology labs as multidrug-resistant P. aeruginosa in the past 6 years represent PmR strains. The goal of the proposed interdisciplinary project is to define resistance mechanisms in PmR CF strains of P. aeruginosa as potential targets for drug development.
The specific aims of the project are to: (1) optimize the reliability of Pm susceptibility testing for PmR strains of P. aeruginosa;(2) define the dependence of CF strain Pm resistance on specific lipid A structures and PmrAB-regulated genetic loci;and (3) define additional genetic loci required for CF strain Pm resistance.
These aims will be accomplished by using the tools of analytical chemistry, mass spectrometry, bacterial genetics, and DNA sequencing to define resistance phenotypes and lipid A structures of an international collection of PmR CF strains, identify novel Pm resistance genes in these strains, and determine the dependence of resistance phenotypes on known and novel Pm resistance genes. Relevance: Because of antibiotic-resistant infections such as those caused by Pseudomonas, doctors are using alternative antibiotics like polymyxin more often. Polymyxin-resistant Pseudomonas has now been found in European cystic fibrosis patients for whom polymyxin treatment was not working, and similar bacteria have been found in cystic fibrosis patients in the US. An interdisciplinary study of polymyxin resistant Pseudomonas from patients with cystic fibrosis is proposed to pinpoint the bacterial genes responsible for this resistance, so that management strategies may be devised to overcome it.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067653-05
Application #
7817031
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Taylor, Christopher E,
Project Start
2007-05-15
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$683,379
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Brackett, Christopher M; Furlani, Robert E; Anderson, Ryan G et al. (2016) Second Generation Modifiers of Colistin Resistance Show Enhanced Activity and Lower Inherent Toxicity. Tetrahedron 72:3549-3553
Thaipisuttikul, Iyarit; Hittle, Lauren E; Chandra, Ramesh et al. (2014) A divergent Pseudomonas aeruginosa palmitoyltransferase essential for cystic fibrosis-specific lipid A. Mol Microbiol 91:158-74
Zemke, Anna C; Shiva, Sruti; Burns, Jane L et al. (2014) Nitrite modulates bacterial antibiotic susceptibility and biofilm formation in association with airway epithelial cells. Free Radic Biol Med 77:307-16
Wurst, Jacqueline M; Drake, Eric J; Theriault, Jimmy R et al. (2014) Identification of inhibitors of PvdQ, an enzyme involved in the synthesis of the siderophore pyoverdine. ACS Chem Biol 9:1536-44
Gutu, Alina D; Sgambati, Nicole; Strasbourger, Pnina et al. (2013) Polymyxin resistance of Pseudomonas aeruginosa phoQ mutants is dependent on additional two-component regulatory systems. Antimicrob Agents Chemother 57:2204-15
Rada, Balázs; Jendrysik, Meghan A; Pang, Lan et al. (2013) Pyocyanin-enhanced neutrophil extracellular trap formation requires the NADPH oxidase. PLoS One 8:e54205
Nichols, David P; Caceres, Silvia; Caverly, Lindsay et al. (2013) Effects of azithromycin in Pseudomonas aeruginosa burn wound infection. J Surg Res 183:767-76
Moskowitz, Samuel M; Brannon, Mark K; Dasgupta, Nandini et al. (2012) PmrB mutations promote polymyxin resistance of Pseudomonas aeruginosa isolated from colistin-treated cystic fibrosis patients. Antimicrob Agents Chemother 56:1019-30
Miller, Amanda K; Brannon, Mark K; Stevens, Laurel et al. (2011) PhoQ mutations promote lipid A modification and polymyxin resistance of Pseudomonas aeruginosa found in colistin-treated cystic fibrosis patients. Antimicrob Agents Chemother 55:5761-9
Moskowitz, Samuel M; Ernst, Robert K (2010) The role of Pseudomonas lipopolysaccharide in cystic fibrosis airway infection. Subcell Biochem 53:241-53

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