Carolyn L. Cannon
University of Texas Southwestern Medical Center
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Clinical Microbiology Reviews | 2002
Jeffrey B. Lyczak; Carolyn L. Cannon; Gerald B. Pier
SUMMARY While originally characterized as a collection of related syndromes, cystic fibrosis (CF) is now recognized as a single disease whose diverse symptoms stem from the wide tissue distribution of the gene product that is defective in CF, the ion channel and regulator, cystic fibrosis transmembrane conductance regulator (CFTR). Defective CFTR protein impacts the function of the pancreas and alters the consistency of mucosal secretions. The latter of these effects probably plays an important role in the defective resistance of CF patients to many pathogens. As the modalities of CF research have changed over the decades from empirical histological studies to include biophysical measurements of CFTR function, the clinical management of this disease has similarly evolved to effectively address the ever-changing spectrum of CF-related infectious diseases. These factors have led to the successful management of many CF-related infections with the notable exception of chronic lung infection with the gram-negative bacterium Pseudomonas aeruginosa. The virulence of P. aeruginosa stems from multiple bacterial attributes, including antibiotic resistance, the ability to utilize quorum-sensing signals to form biofilms, the destructive potential of a multitude of its microbial toxins, and the ability to acquire a mucoid phenotype, which renders this microbe resistant to both the innate and acquired immunologic defenses of the host.
Microbes and Infection | 2000
Jeffrey B. Lyczak; Carolyn L. Cannon; Gerald B. Pier
Pseudomonas aeruginosa is an ubiquitous pathogen capable of infecting virtually all tissues. A large variety of virulence factors contribute to its importance in burn wounds, lung infection and eye infection. Prominent factors include pili, flagella, lipopolysaccharide, proteases, quorum sensing, exotoxin A and exoenzymes secreted by the type III secretion system.
Chemical Reviews | 2009
Khadijah M. Hindi; Matthew J. Panzner; Claire A. Tessier; Carolyn L. Cannon; Wiley J. Youngs
Ofele and Wanzlick reported the synthesis of the first N-heterocyclic carbene (NHC) metal complexes in 1968.1,2 The isolation of the first free carbene by Arduengo in 1991 set the scene for an ever-growing interest and advancement in the field of N-heterocyclic carbene chemistry.3 Shortly thereafter, the use of these ligands in organometallic chemistry, particularly in catalysis dramatically increased.4,5 N-heterocyclic carbenes are neutral 2-electron donors, with an ability to bond to both hard and soft metals making them more versatile ligands than phosphines.6 As an added advantage, not only are NHCs easier to synthesize and functionalize than phosphines but they also form a stronger bond to metals and therefore form more stable metal complexes than metal phosphine complexes.7,8 The N-heterocyclic carbene ligands interact with metal centers primarily through strong σ-donation and to a lesser degree through π-backdonation (Figure 1).9,10 Figure 1 Orbital diagram of NHC bonding to metal center. Ghosh and coworkers11,12,13,14,15,16 as well as others17,18,19 took special interest in the exceptional stability of several metal-NHC complexes and conducted in depth analyses in order to gain better insights into the structure and bonding. In particular, the metal-ligand donor-acceptor interactions were inspected using the charge decomposition analysis (CDA). CDA is a tool used to quantitatively estimate the degree of NHC → metal σ-donation, designated by d, and NHC ← metal π-back donation, designated by b.20,21 Thus a higher d/b ratio emphasizes the ability of NHC to function as an effective σ-donor, whereas a lower d/b ratio highlights the greater NHC ← metal π-back donation. Interestingly, in the studies conducted by Ghosh, greater NHC ← metal π-back donation was observed in Pd-NHC complexes exhibiting lower d/b ratios ranging between 2.59 – 3.9913,14 and Au-NHC complexes with d/b ratios ranging between 5.23 – 5.8815,16 as compared to the Ag-NHC complexes with d/b ratios ranging between 7.8 – 12.6811,12,16. This observation could attest to why silver-NHC complexes are particularly better transmetallating agents. The newly emerging interest in the medicinal applications of stable metal NHCs led us to examine the few accounts available in the literature dealing with this area of research. This review will discuss in detail the medicinal applications of various transition metal-NHC complexes including silver, gold, rhodium, ruthenium, and palladium. The antimicrobial, antitumor, and resistance properties, along with proposed mechanisms of action to suppress the bacterial growth or proliferation of tumor cells will be discussed.
Chest | 2008
Arnon Elizur; Carolyn L. Cannon; Thomas W. Ferkol
Patients with cystic fibrosis (CF) experience declining pulmonary function related to chronic airway inflammation, which results from epithelial and immune cell secretion of proinflammatory mediators that promote neutrophil influx into the airways. This inflammatory response may be disproportionate to the inciting infectious stimulus, resulting in an overly exuberant influx of neutrophils. The neutrophils release proteases, including neutrophil elastase, that eventually overwhelm the antiprotease capacity of the lung and cleave structural proteins, leading to bronchiectasis. This deleterious inflammatory process in patients with CF has become a potential therapeutic target, though the development of effective antiinflammatory therapies has been limited by the lack of sensitive outcome measures. Historically, indirect measures of lung disease, such as spirometry, have been used to assess the effect of antiinflammatory drugs. BAL remains the primary method of interrogating the inflammatory status of the airway, but the procedure is invasive and may eventually be supplanted by induced sputum. Anatomic imaging with high-resolution CT scanning is used clinically, but has unknown utility, and functional imaging, using positron emission tomography, appears promising but is still investigational. Despite the paucity of outcome measures, clinical trials of antiinflammatory agents, including corticosteroids and ibuprofen, have demonstrated benefits, though their use has been limited by adverse effects. Azithromycin is increasingly used as an immunomodulatory agent, although its mechanism of action remains unclear. Strategies for modulating the airway inflammation in patients with CF are currently under development and may offer new therapeutic options for these patients.
Journal of Medicinal Chemistry | 2008
Khadijah M. Hindi; Tammy J. Siciliano; Semih Durmus; Matthew J. Panzner; Doug A. Medvetz; D. Venkat Reddy; Lisa A. Hogue; Christine E. Hovis; Julia K. Hilliard; Rebekah J. Mallet; Claire A. Tessier; Carolyn L. Cannon; Wiley J. Youngs
A series of methylated imidazolium salts with varying substituents on the 4 and 5 positions of the imidazole ring were synthesized. These salts were reacted with silver acetate to afford their corresponding silver N-heterocyclic carbene (NHC) complexes. These complexes were then evaluated for their stability in water as well as for their antimicrobial efficacy against a variety of bacterial strains associated with cystic fibrosis and chronic lung infections.
Proceedings of the National Academy of Sciences of the United States of America | 2002
Torsten H. Schroeder; Martin M. Lee; Patrick W. Yacono; Carolyn L. Cannon; A. Alev Gerçeker; David E. Golan; Gerald B. Pier
Immune cells are activated during cellular responses to antigen by two described mechanisms: (i) direct uptake of antigen and (ii) extraction and internalization of membrane components from antigen-presenting cells. Although endocytosis of microbial antigens by pattern recognition molecules (PRM) also activates innate immunity, it is not known whether this involves extraction and internalization of microbial surface components. Epithelial cells on mucosal surfaces use a variety of receptors that are distinct from the classical endocytic PRM to bind and internalize intact microorganisms. Nonclassical receptor molecules theoretically could act as a type of endocytic PRM if these molecules could recognize, bind, extract, and internalize a pathogen-associated molecule and initiate cell signaling. We report here that the interaction between the cystic fibrosis transmembrane conductance regulator (CFTR) and the outer core oligosaccharide of the lipopolysaccharide (LPS) in the outer membrane of Pseudomonas aeruginosa satisfies all of these conditions. P. aeruginosa LPS was specifically recognized and bound by CFTR, extracted from the organisms surface, and endocytosed by epithelial cells, leading to a rapid (5- to 15-min) and dynamic translocation of nuclear transcription factor NF-κB. Inhibition of epithelial cell internalization of P. aeruginosa LPS prevented NF-κB activation. Cellular activation depended on expression of wild-type CFTR, because both cultured ΔF508 CFTR human airway epithelial cells and lung epithelial cells of transgenic-CF mice failed to endocytose LPS and translocate NF-κB. CFTR serves as a critical endocytic PRM in the lung epithelium, coordinating the effective innate immune response to P. aeruginosa infection.
Biomaterials | 2009
Khadijah M. Hindi; Andrew J. Ditto; Matthew J. Panzner; Douglas A. Medvetz; Daniel S. Han; Christine E. Hovis; Julia K. Hilliard; Jane B. Taylor; Yang H. Yun; Carolyn L. Cannon; Wiley J. Youngs
The pressing need to treat multi-drug resistant bacteria in the chronically infected lungs of cystic fibrosis (CF) patients has given rise to novel nebulized antimicrobials. We have synthesized a silver-carbene complex (SCC10) active against a variety of bacterial strains associated with CF and chronic lung infections. Our studies have demonstrated that SCC10-loaded into L-tyrosine polyphosphate nanoparticles (LTP NPs) exhibits excellent antimicrobial activity in vitro and in vivo against the CF relevant bacteria Pseudomonas aeruginosa. Encapsulation of SCC10 in LTP NPs provides sustained release of the antimicrobial over the course of several days translating into efficacious results in vivo with only two administered doses over a 72 h period.
Proceedings of the National Academy of Sciences of the United States of America | 2003
Fadie T. Coleman; Simone Mueschenborn; Gloria Meluleni; Christopher Ray; Vincent J. Carey; Sara O. Vargas; Carolyn L. Cannon; Frederick M. Ausubel; Gerald B. Pier
No transgenic cystic fibrosis (CF) mouse model developed to date mimics the major clinical phenotype found in humans with CF, chronic Pseudomonas aeruginosa lung infection. In a transgenic CF transmembrane conductance regulator (cftr) mouse colony, we found WT, heterozygous, and homozygous CF mice housed in the same cage became chronically colonized in the oropharynx with environmental P. aeruginosa when the bacterium was present in drinking water. Elimination of P. aeruginosa from drinking water resulted in clearance in most WT and CF heterozygous, but not homozygous mice. For experimental evaluation, a combination of specific animal husbandry techniques and an oral infection route showed cftr−/− mice but not WT mice can be chronically colonized by P. aeruginosa with subsequent lung translocation, yielding a pathologic picture indicative of chronic lung infection. In some instances, mucoid isolates of P. aeruginosa were recovered from lungs, indicating conditions were present for conversion to mucoidy. Overexpression of human CFTR in the lungs of WT mice markedly accelerated the clearance rate of P. aeruginosa, demonstrating that lung levels of CFTR play an important role in defense against infection. P. aeruginosa mutants unable to express the surface polysaccharide alginate or the global regulator GacA were deficient in their ability to colonize the mice. CF mice made potent immune responses to P. aeruginosa outer membrane antigens. Overall, we found that under the proper conditions, transgenic CF mice are hypersusceptible to P. aeruginosa colonization and infection and can be used for evaluations of lung pathophysiology, bacterial virulence, and development of therapies aimed at treating CF lung disease.
Journal of Antimicrobial Chemotherapy | 2012
Jeff G. Leid; Andrew J. Ditto; Amanda R. Knapp; Parth N. Shah; Brian D. Wright; Robyn Blust; Lanette Christensen; C. B. Clemons; J. P. Wilber; G. W. Young; Ae Gyeong Kang; Matthew J. Panzner; Carolyn L. Cannon; Yang H. Yun; Wiley J. Youngs; Nicole M. Seckinger; Emily K. Cope
OBJECTIVES Silver carbenes may represent novel, broad-spectrum antimicrobial agents that have low toxicity while providing varying chemistry for targeted applications. Here, the bactericidal activity of four silver carbene complexes (SCCs) with different formulations, including nanoparticles (NPs) and micelles, was tested against a panel of clinical strains of bacteria and fungi that are the causative agents of many skin and soft tissue, respiratory, wound, blood, and nosocomial infections. METHODS MIC, MBC and multidose experiments were conducted against a broad range of bacteria and fungi. Time-release and cytotoxicity studies of the compounds were also carried out. Free SCCs and SCC NPs were tested against a panel of medically important pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Acinetobacter baumannii (MRAB), Pseudomonas aeruginosa, Burkholderia cepacia and Klebsiella pneumoniae. RESULTS All four SCCs demonstrated strong efficacy in concentration ranges of 0.5-90 mg/L. Clinical bacterial isolates with high inherent resistance to purified compounds were more effectively treated either with an NP formulation of these compounds or by repeated dosing. Overall, the compounds were active against highly resistant bacterial strains, such as MRSA and MRAB, and were active against the biodefence pathogens Bacillus anthracis and Yersinia pestis. All of the medically important bacterial strains tested play a role in many different infectious diseases. CONCLUSIONS The four SCCs described here, including their development as NP therapies, show great promise for treating a wide variety of bacterial and fungal pathogens that are not easily killed by routine antimicrobial agents.
American Journal of Physiology-cell Physiology | 1998
Carolyn L. Cannon; Srisaila Basavappa; Kevin Strange
Cell swelling activates an outwardly rectifying anion channel termed VSOAC (volume-sensitive organic osmolyte/anion channel). Regulation of VSOAC by intracellular electrolytes was characterized in Chinese hamster ovary cells by whole cell patch clamp. Elevation of intracellular CsCl concentration from 40 to 180 mM resulted in a concentration-dependent decrease in channel activation. Activation of VSOAC was insensitive to the salt gradient across the plasma membrane, the intracellular concentration of specific anions or cations, and the total intracellular concentration of cations, anions, or electrolytes. Comparison of cells dialyzed with either CsCl or Na2SO4solutions demonstrated directly that VSOAC activation is modulated by intracellular ionic strength (μi). The relative cell volume at which VSOAC current activation was triggered, termed the channel volume set point, decreased with decreasing ionic strength. At μi = 0.04, VSOAC activation occurred spontaneously in shrunken cells. The rate of VSOAC activation was nearly 50-fold higher in cells with μi = 0.04 vs. those with μi = 0.18. We propose that μi modulates the volume sensor responsible for channel activation.