Anaerobic metabolism and quorum sensing by Pseudomonas aeruginosa biofilms in chronically infected cystic fibrosis airways: rethinking antibiotic treatment strategies and drug targets

Hassett, Daniel J.; Cuppoletti, John; Trapnell, Bruce C.; Lymar, Sergei V.; Rowe, John J.; Yoon, Sang Sun; Hilliard, George M.; Parvatiyar, Michelle S.; Kamani, Moneesha C.; Wozniak, Daniel J.; Hwang, Sung Hei; McDermott, Timothy R.; Ochsner, Urs A.

doi:10.1016/s0169-409x(02)00152-7

Cited by 279 publications

(298 citation statements)

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“…In general, little is known about the mechanisms of regulation of LasR by different environmental factors and how the effects are transmitted to other parts of the cellular machinery through LasR, which is embedded in a large and complex regulatory network. On the other hand, many genes are involved in iron and O 2 regulation (Vasil & Ochsner, 1999;Hassett et al, 2002). The interplays of LasR, QS and the regulatory components related to iron and oxygen deserve further study.…”

Section: Discussionmentioning

confidence: 99%

Expression of the quorum-sensing regulatory protein LasR is strongly affected by iron and oxygen concentrations in cultures of Pseudomonas aeruginosa irrespective of cell density

et al. 2005

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Expression of the quorum-sensing regulatory protein LasR is strongly affected by iron and oxygen concentrations in cultures of Pseudomonas aeruginosa irrespective of cell density The expression of the transcriptional regulatory protein LasR, a main component of the quorum-sensing (QS) system in Pseudomonas aeruginosa, was recently found to be sensitive to several environmental factors in addition to its dependency on cell density. However, the inherent effects of the different factors have seldom been separately demonstrated due to concurrent changes of culture conditions in typical experimental settings. Furthermore, the interplays of the different factors are unknown. In this work, the effects and interplay of iron concentration and dissolved oxygen tension (pO 2 ) on the expression of lasR in P. aeruginosa were studied in defined growth media with varied iron concentration and pO 2 values in computer-controlled batch and continuous cultures. b-Galactosidase activity in a recombinant P. aeruginosa PAO1 (NCCB 2452) strain with a lasRp-lacZ fusion was used as a reporter for lasR expression. In batch culture with a constant pO 2 <10 % air saturation, a strong correlation between the exhaustion of iron and the increase of lasR expression was observed. In continuous culture with nearly constant cell density but varied pO 2 values, lasR expression generally increased with increasing oxidative stress with the exception of growth under O 2 -limited conditions (pO 2 <0 %). Under O 2 limitation, the expression of lasR strongly depended on the concentration of iron. It showed a nearly twofold increase in cells grown under iron deprivation in comparison with cells grown in iron-replete conditions and reached the expression level seen at high oxidative stress. A preliminary proteomic analysis was carried out for extracellular proteins in samples from batch cultures grown under different iron concentrations. Several of the extracellular proteins (e.g. AprA, LasB, PrpL) which were up-regulated under iron-limited conditions were found to be QS regulated proteins. Thus, this study clearly shows the links between QS and genes involved in iron and oxygen regulation in P. aeruginosa. INTRODUCTIONPseudomonas aeruginosa, a Gram-negative opportunistic human pathogen, is often found in nosocomial infections. In particular, it can cause chronic pulmonary infection of cystic fibrosis patients, leading to a high mortality rate due to the formation of virulence factors and the inappropriate host response (Hybiske et al., 2004;Wolfgang et al., 2004;Lyczak et al., 2002). In P. aeruginosa, the formation of numerous virulence factors is controlled to a large extent by a mechanism called quorum sensing (QS) (Fuqua & Greenberg, 1998;Wagner et al., 2003;Schuster et al., 2003;Hentzer et al., 2003;Juhas et al., 2004). Two major genetic components of QS, the las and rhl systems, have been identified in P. aeruginosa. The las system consists of LasR, a transcriptional regulatory protein, and LasI, the autoinducer synthase that controls the producti...

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Section: Discussionmentioning

confidence: 99%

Expression of the quorum-sensing regulatory protein LasR is strongly affected by iron and oxygen concentrations in cultures of Pseudomonas aeruginosa irrespective of cell density

et al. 2005

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“…When used in trials for patients with CF with chronic B. cepacia complex infection, however, inhaled aztreonam did not result in any statistically significant improvement in FEV 1 or decreases in sputum bacterial density compared with placebo (70). The ability of b-lactam antibiotics to function in the CF lung could be limited by the slow, anaerobic biofilm growth of organisms (71). In vitro studies of biofilm growth of P. aeruginosa on CF airway cells have demonstrated little additional benefit of aztreonam in combination with tobramycin, likely due to bacterial exopolysaccharide production causing tolerance to aztreonam (72).…”

Section: Ats Seminarsmentioning

confidence: 93%

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

et al. 2014

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Despite significant advances in treatment strategies targeting the underlying defect in cystic fibrosis (CF), airway infection remains an important cause of lung disease. In this two-part series, we review recent evidence related to the complexity of CF airway infection, explore data suggesting the relevance of individual microbial species, and discuss current and future treatment options. In Part I, the evidence with respect to the spectrum of bacteria present in the CF airway, known as the lung microbiome is discussed. Subsequently, the current approach to treat methicillin-resistant Staphylococcus aureus, gram-negative bacteria, as well as multiple coinfections is reviewed. Newer molecular techniques have demonstrated that the airway microbiome consists of a large number of microbes, and the balance between microbes, rather than the mere presence of a single species, may be relevant for disease pathophysiology. A better understanding of this complex environment could help define optimal treatment regimens that target pathogens without affecting others. Although relevance of these organisms is unclear, the pathologic consequences of methicillin-resistant S. aureus infection in patients with CF have been recently determined. New strategies for eradication and treatment of both acute and chronic infections are discussed. Pseudomonas aeruginosa plays a prominent role in CF lung disease, but many other nonfermenting gram-negative bacteria are also found in the CF airway. Many new inhaled antibiotics specifically targeting P. aeruginosa have become available with the hope that they will improve the quality of life for patients. Part I concludes with a discussion of how best to treat patients with multiple coinfections.

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“…In the CF airway, P. aeruginosa is growing either in or behind mucus plugs that create an anaerobic environment. Additionally, these organisms are thought to be in a biofilm growth mode [17]. The aminoglycoside, tobramycin, is typically one of the most active antimicrobials when tested by MIC or agar-based techniques [18].…”

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confidence: 99%

“…Our understanding of the pathogenesis of CF lung disease due to mucoid P. aeruginosa has advanced greatly over the past 10 years [1,2,17]. Unfortunately, practices in the clinical microbiology laboratory have not kept pace, as evidenced by close to half of the laboratories performing P. aeruginosa susceptibility testing using methods associated with very major errors [13,16].…”

Section: For Reprint Orders Please Contact: Reprints@future-drugscommentioning

confidence: 99%

Is there value in susceptibility testing ofPseudomonas aeruginosacausing chronic infection in patients with cystic fibrosis?

Gilligan

2006

Expert Review of Anti-infective Therapy

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Anaerobic metabolism and quorum sensing by Pseudomonas aeruginosa biofilms in chronically infected cystic fibrosis airways: rethinking antibiotic treatment strategies and drug targets

Cited by 279 publications

References 64 publications

Expression of the quorum-sensing regulatory protein LasR is strongly affected by iron and oxygen concentrations in cultures of Pseudomonas aeruginosa irrespective of cell density

Expression of the quorum-sensing regulatory protein LasR is strongly affected by iron and oxygen concentrations in cultures of Pseudomonas aeruginosa irrespective of cell density

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

Is there value in susceptibility testing ofPseudomonas aeruginosacausing chronic infection in patients with cystic fibrosis?

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