个人简介
Adaptive stress responses as determinants of antibiotic resistance in Pseudomonas aeruginosa and how to counter them
研究领域
General interest
Bacterial stress responses as determinants of antibiotic resistance and targets for therapeutic intervention
Specific interest
Oxidative stress-promoted antibiotic resistance in Pseudomonas aeruginosa causing chronic lung infections
Background
P. aeruginosa is a Gram-negative opportunistic human pathogen associated with debilitating infections of immunocompromised individuals including those with HIV/AIDS cancer and severe burns, although it also causes less severe infections of healthy individuals (e.g., swimmers ear and hot tub folliculitis). A common nosocomial (i.e., hospital-acquired) pathogen linked to infections of the blood, lungs and urinary tract, particularly in very sick individuals (e.g., those in the ICU), P. aeruginosa is a major pulmonary pathogen in patients with cystic fibrosis and chronic obstructive pulmonary disease and a major cause of ventilator-associated pneumonias. Infections caused by P. aeruginosa have a high mortality rate, in part attributable to the organism’s intrinsically high resistance to many antimicrobials and the increased incidence of multidrug-resistant isolates in health care settings, both of which complicate antipseudomonal chemotherapy.
Patients with cystic fibrosis (CF) are susceptible to pulmonary infections caused by many microorganisms, particularly Pseudomonas aeruginosa, which infects 80% of CF patients. Such infections typically become chronic and lead to death, making P. aeruginosa lung infection the leading cause of mortality in CF. Historically, CF patients colonized with P. aeruginosa have been treated with a combination of antibiotics, bronchodilators and chest physiotherapy. β-lactams and/or aminoglycosides have been the antibiotics of choice though in recent years these have been augmented by the fluoroquinolones. Despite earlier concerns with toxicity, colistin is gaining favour, particularly in the treatment of multidrug-resistant P. aeruginosa infections. Still, aminoglycosides remain the most significant class of antibiotic used in the treatment of CF lung infections. Unfortunately, the need for ongoing and/or recurring treatment of chronic lung infections in CF patients contributes to the rise of antibiotic resistance in P. aeruginosa in the CF lung.
Primary objective
To characterize the stress adaptive mutations driving antibiotic resistance development in chronic lung infections of Pseudomonas aeruginosa in order to development suitable anti-resistance approaches to managing these infections.
Overview
Chronic pulmonary infections in cystic fibrosis and bronchiectasis patients caused by P. aeruginosa are major causes of human morbidity and mortality. Unfortunately, treatment of these infections is complicated by the increase in antibiotic resistance that develops during long-term colonization of the lung by this organism. Recent evidence suggests that this resistance derives, not from the usual acquired resistance mechanisms but from the accumulation of a unique set of adaptive mutations that are primarily intended to enhance the organism’s fitness at the site of infection but which also promote resistance. A hallmark of chronic P. aeruginosa lung infection is dysregulated pulmonary inflammation leading to release of reactive oxygen species (ROS) and, ultimately, chronic lung oxidative (O2) stress. In the case of chronic infections of the lungs of cystic fibrosis (CF) patients, this appears to be a driving force for the development of resistance to the aminoglycosides (AGs), an important class of anti-pseudomonal agent, with many AG resistance-promoting mutations having demonstrable links to O2 stress. Chronic P. aeruginosa infection in bronchiectasis patients is also associated with ongoing inflammation and chronic O2 stress, with AG resistance also a problem in these isolates. Thus, ROS/lung inflammation may be a driving force for AG resistance in these isolates as well and, thus, in P. aeruginosa causing chronic lung infections generally. The goals of my work are to define the contributions of these O2 stress-adaptive mutations to AG resistance in CF and bronchiectasis isolates of P. aeruginosa and to identify the resistance mechanisms involved, with an eye to targetting these latter therapeutically in an effort to maintain AG efficacy in managing chronic P. aeruginosa lung infections.
Sponsors
Canadian Institutes of Health Research and Cystic Fibrosis Canada
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Fruci, M, and K. Poole. 2016. Bacterial stress responses as determinants of antimicrobial resistance, pp. 115-136. In Stress and environmental control of gene expression in bacteria, F.J. de Bruijn (ed), Wiley-Blackwell Publishers, New York, NY, USA., in press.
Poole, K., and M. Fruci. 2016. Antimicrobial efflux systems as components of bacterial stress responses. In Efflux-mediated drug resistance in bacteria: mechanisms, regulation and clinical implications, X.-Z. Li, C. Elkins and H. Zgurskaya (eds), Springer Publishing, New York, NY, USA., in press.
Poole, K., C. Gilmour, M.A. Farha, E. Mullen, C.H.-F. Lau, and E.D. Brown. 2016. Potentiation of aminoglycoside activity in Pseudomonas aeruginosa by targeting the AmgRS envelope stress-responsive two-component system. Antimicrob. Agents Chemother. 60:3509-3518.
Poole, K., C.H.-F. Lau, C. Gilmour, Y. Hao, and J.S. Lam. 2015. Polymyxin susceptibility in Pseudomonas aeruginosa linked to the MexXY-OprM multidrug efflux system. Antimicrob. Agents Chemother. 59:7276-7289.
Purssell, A., M. Fruci, A. Mikalauskas, C. Gilmour, and K. Poole. 2015. EsrC, an envelope stress-regulated repressor of the mexCD-oprJ multidrug efflux operon in Pseudomonas aeruginosa. Environ. Microbiol. 17:186-198.
Lau, C. H.-F., C. Gilmour, E. Mullen, and K. Poole. 2015. AmgRS-mediated envelope stress-inducible expression of the mexXY multidrug efflux operon of Pseudomonas aeruginosa. MicrobiologyOpen 4:121-135.
Lau, C.H.-F., D. Hughes, and K. Poole. 2014. MexY-promoted aminoglycoside resistance in Pseudomonas aeruginosa: involvement of a putative proximal binding pocket in aminoglycoside recognition. mBio 5:e01068.
Poole, K. 2013. Pseudomonas efflux pumps, pp. 175-206. In Microbial efflux pumps, E. Yu, Q. Zhang, and M.H. Brown (eds), Caister Academic Press, Norfolk, UK (invited book chapter).
Purssell, A. and K. Poole. 2013. Functional characterization of the NfxB repressor of the mexCD-oprJ multidrug efflux operon of Pseudomonas aeruginosa. Microbiology 159:2058-2073.
Hay, T., S. Fraud, C.H.F. Lau, C. Gilmour and K. Poole. 2013. Antibiotic inducibility of the mexXY multidrug efflux operon of Pseudomonas aeruginosa: involvement of the MexZ anti-reperssor ArmZ. PLoS ONE 8: e56858.
Lau, C. H.-F., S. Fraud, M. Jones, S. N. Peterson, and K. Poole. 2013. Mutational activation of the AmgRS two-component system in pan-aminoglycoside-resistant Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 57:2243-2251.
Poole, K. 2012. Stress responses as determinants of antimicrobial resistance in Gram-negative bacteria. Trends in Microbiol. 20: 227-234. (invited review)
Starr, L.M., Fruci, M.J., and K. Poole. 2012. Pentachlorophenol induction of the Pseudomonas aeruginosa mexAB-oprM efflux operon: involvement of the NalC and MexR repressors and the MexR anti-repressor ArmR. PLoS ONE 7:e32684.
Lau, C. H.-F., S. Fraud, M. Jones, S. N. Peterson, and K. Poole. 2012. Reduced expression of the rplU-rpmA ribosomal protein operon in mexXY expressing pan-aminoglycoside-resistant Pseudomnonas aeruginosa. Antimicrob. Agents Chemother. 56: 5171-5179.
Krahn,T., C. Gilmour, J. Tilak, S. Fraud, N. Kerr, C.H.F. Lau, and K. Poole. 2012. Determinants of intrinsic aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 56:5591-5602.
Poole, K. 2011. Pseudomonas aeruginosa: resistance to the max. Front. Microbiol. doi: 10.3389/fcmi.2011.00065.
Fetar, H., C. Gilmour, R. Klinoski, D.M. Daigle, C.R. Dean and K. Poole. 2011. The mexEF-oprN multidrug efflux operon of P. aeruginosa: regulation by the MexT activator in response to nitrosative stress and chloramphenicol. Antimicrob. Agents Chemother. 55:508-514
Fraud, S. and K. Poole. 2011. Oxidative stress induction of the MexXY multidrug efflux genes and promotion of aminoglycoside resistance development in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 55:1068-1074
Morita Y, C Gilmour, D Metcalf, and K Poole. 2009. Translational control of the antibiotic inducibility of the PA5471 gene required for mexXY multidrug efflux gene expression in Pseudomonas aeruginosa. J. Bacteriol. 191:4966-4975.
Fraud S, A Campigotto, Z Chen, and K Poole. 2008. The MexCD-OprJ multidrug efflux system in Pseudomonas aeruginosa: involvement in chlorhexidine resistance and induction by membrane damaging agents dependent upon the AlgU stress-response sigma factor. Antimicrob. Agents Chemother. 52:4478-4482.
Wilke MS, M Heller, L Creagh, C Haynes, LP McIntosh, K Poole and NCJ Strynadka. 2008. The crystal structure of MexR from Pseudomonas aeruginosa in complex with its anti-repressor ArmR. Proc. Natl. Acad. Sci., 105:14832-14837.
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