Activity of Cysteamine against the Cystic Fibrosis Pathogen Burkholderia cepacia Complex

Fraser-Pitt, D.; Mercer, Derry K.; Lovie, Emma; Robertson, Jennifer; O’Neil, Deborah A.

doi:10.1128/aac.01198-16

Cited by 17 publications

(18 citation statements)

References 30 publications

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“…Cysteamine has direct antimicrobial properties against common CF pathogens with a range of minimal inhibitory concentrations (MIC) [ 19 , 20 ]. We sought to extend this finding using antibiotic-resistant clinical isolates of 4 common CF pathogens.…”

Section: Resultsmentioning

confidence: 99%

Cysteamine-mediated clearance of antibiotic-resistant pathogens in human cystic fibrosis macrophages

et al. 2017

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Members of the Burkholderia cepacia complex are virulent, multi-drug resistant pathogens that survive and replicate intracellularly in patients with cystic fibrosis (CF). We have discovered that B. cenocepacia cannot be cleared from CF macrophages due to defective autophagy, causing continued systemic inflammation and infection. Defective autophagy in CF is mediated through constitutive reactive oxygen species (ROS) activation of transglutaminase-2 (TG2), which causes the sequestration (accumulation) of essential autophagy initiating proteins. Cysteamine is a TG2 inhibitor and proteostasis regulator with the potential to restore autophagy. Therefore, we sought to examine the impact of cysteamine on CF macrophage autophagy and bacterial killing. Human peripheral blood monocyte-derived macrophages (MDMs) and alveolar macrophages were isolated from CF and non-CF donors. Macrophages were infected with clinical isolates of relevant CF pathogens. Cysteamine caused direct bacterial growth killing of live B. cenocepacia, B. multivorans, P. aeruginosa and MRSA in the absence of cells. Additionally, B. cenocepacia, B. multivorans, and P. aeruginosa invasion were significantly decreased in CF MDMs treated with cysteamine. Finally, cysteamine decreased TG2, p62, and beclin-1 accumulation in CF, leading to increased Burkholderia uptake into autophagosomes, increased macrophage CFTR expression, and decreased ROS and IL-1β production. Cysteamine has direct anti-bacterial growth killing and improves human CF macrophage autophagy resulting in increased macrophage-mediated bacterial clearance, decreased inflammation, and reduced constitutive ROS production. Thus, cysteamine may be an effective adjunct to antibiotic regimens in CF.

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Section: Resultsmentioning

confidence: 99%

Cysteamine-mediated clearance of antibiotic-resistant pathogens in human cystic fibrosis macrophages

et al. 2017

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“…Cys also prevents the formation of, and disrupts already established, Pseudomonas aeruginosa and Enterococcus faecalis biofilms (45,48). NAC and Cys show antimicrobial activity against Gram-positive and Gram-negative pathogens, with MICs usually falling in the range of 500 to 5,000 g/ml (45,46,(49)(50)(51), although lower values have been reported for some bacteria (46,52). It is generally recognized that the mechanisms underlying the therapeutic and clinical applications of NAC (and Cys) are still unclear and, possibly, more complex than previously envisaged (53).…”

Section: Discussionmentioning

confidence: 99%

N -Acetyl- l -Cysteine and Cysteamine as New Strategies against Mixed Biofilms of Nonencapsulated Streptococcus pneumoniae and Nontypeable Haemophilus influenzae

Domenech

Garcı́a

2017

Antimicrob Agents Chemother

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Acute otitis media, a polymicrobial disease of the middle ear cavity of children, is a significant public health problem worldwide. It is most frequently caused by encapsulated Streptococcus pneumoniae and nontypeable Haemophilus influenzae, although the widespread use of pneumococcal conjugate vaccines is apparently producing an increase in the carriage of nonencapsulated S. pneumoniae. Frequently, pneumococci and H. influenzae live together in the human nasopharynx, forming a self-produced biofilm. Biofilms present a global medical challenge since the inherent antibiotic resistance of their producers demands the use of large doses of antibiotics over prolonged periods. Frequently, these therapeutic measures fail, contributing to bacterial persistence. Here, we describe the development of an in vitro nonencapsulated S. pneumoniae-nontypeable H. influenzae biofilm system with polystyrene or glass-bottom plates. Confocal laser scanning microscopy and specific fluorescent labeling of pneumococcal cells with Helix pomatia agglutinin revealed an even distribution of both species within the biofilm. This simple and robust protocol of mixed biofilms was used to test the antimicrobial properties of two well-known antioxidants that are widely used in the clinical setting, i.e., N-acetyl-L-cysteine and cysteamine. This repurposing approach showed the high potency of N-acetyl-Lcysteine and cysteamine against mixed biofilms of nonencapsulated S. pneumoniae and nontypeable H. influenzae. Decades of clinical use mean that these compounds are safe to use, which may accelerate their evaluation in humans. KEYWORDS Haemophilus influenzae, Streptococcus pneumoniae, antioxidants, biofilmsA cute otitis media (AOM) is defined as the presence of inflammation in the middle ear accompanied by the rapid onset of signs and symptoms of an ear infection. Frequent suppurative complications of AOM are mastoiditis, hearing loss, and meningitis. AOM is a significant public health problem worldwide (incidence rate, ϳ11%) (1). Indeed, Ͼ80% of children suffer at least one episode of AOM by their third birthday and 40% will suffer six or more recurrences by the age of 7 years (2). Pediatric AOM, which is often treated with antibiotics (56 to 95% of cases, depending on the country) (3), represents a significant health care burden, annually accounting for some $2.88 billion in medical costs in the United States (4). A polymicrobial disease, AOM is typically caused by colonization of the middle ear space by opportunistic bacteria that normally form part of the nasopharyngeal microbiota. The most frequently involved bacterial pathogens are Streptococcus pneumoniae, nontypeable (nonencapsulated) Haemophilus influenzae (NT H. influenzae), and, to a lesser extent, Moraxella catarrhalis and other species (5). Several respiratory viruses may also cause AOM (6).

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“…This molecule is already approved for other diseases and its safety profile is known since 1994 ( Gahl et al, 2007 ). Moreover, cysteamine showed antimicrobial activity against P. aeruginosa , so recently Fraser-Pitt et al (2016) showed its effect in combination with antimicrobial agents used for the treatment of Burkholderia . In particular, they found that cysteamine was able to enhance the antimicrobial activity of tobramycin (even reversing resistance/insensitivity in 17 out of 36 strains), ciprofloxacin (reversing resistance/insensitivity in 10 strains), trimethoprim-sulfamethoxazole, but not ceftazidime.…”

Section: Molecules In Clinical Use For Other Diseasesmentioning

confidence: 99%

“…In particular, they found that cysteamine was able to enhance the antimicrobial activity of tobramycin (even reversing resistance/insensitivity in 17 out of 36 strains), ciprofloxacin (reversing resistance/insensitivity in 10 strains), trimethoprim-sulfamethoxazole, but not ceftazidime. Furthermore, inhibition of bacterial biofilm was observed in presence of sub-inhibitory concentrations of cysteamine ( Fraser-Pitt et al, 2016 ).…”

Section: Molecules In Clinical Use For Other Diseasesmentioning

confidence: 99%

Burkholderia cenocepacia Infections in Cystic Fibrosis Patients: Drug Resistance and Therapeutic Approaches

et al. 2017

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Burkholderia cenocepacia is an opportunistic pathogen particularly dangerous for cystic fibrosis (CF) patients. It can cause a severe decline in CF lung function possibly developing into a life-threatening systemic infection known as cepacia syndrome. Antibiotic resistance and presence of numerous virulence determinants in the genome make B. cenocepacia extremely difficult to treat. Better understanding of its resistance profiles and mechanisms is crucial to improve management of these infections. Here, we present the clinical distribution of B. cenocepacia described in the last 6 years and methods for identification and classification of epidemic strains. We also detail new antibiotics, clinical trials, and alternative approaches reported in the literature in the last 5 years to tackle B. cenocepacia resistance issue. All together these findings point out the urgent need of new and alternative therapies to improve CF patients’ life expectancy.

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Activity of Cysteamine against the Cystic Fibrosis Pathogen Burkholderia cepacia Complex

Cited by 17 publications

References 30 publications

Cysteamine-mediated clearance of antibiotic-resistant pathogens in human cystic fibrosis macrophages

Cysteamine-mediated clearance of antibiotic-resistant pathogens in human cystic fibrosis macrophages

N -Acetyl- l -Cysteine and Cysteamine as New Strategies against Mixed Biofilms of Nonencapsulated Streptococcus pneumoniae and Nontypeable Haemophilus influenzae

Burkholderia cenocepacia Infections in Cystic Fibrosis Patients: Drug Resistance and Therapeutic Approaches

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