Overcoming Drug Resistance with Alginate Oligosaccharides Able To Potentiate the Action of Selected Antibiotics

Khan, Saira; Tøndervik, Anne; Sletta, Håvard; Klinkenberg, Geir; Emanuel, Charlotte; Onsøyen, E.; Myrvold, Rolf; Howe, Robin; Walsh, Timothy R.; Hill, Katja E.; Thomas, David W.

doi:10.1128/aac.00525-12

Cited by 146 publications

(180 citation statements)

References 33 publications

(31 reference statements)

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…In the in vivo lung infection model, a single treatment of OligoG CF-5/20 by tracheal instillation significantly reduced the mucoid P. aeruginosa biofilm from the lungs of immunocompetent mice compared to that for saline controls. These findings support pre-vious in vitro studies demonstrating the biofilm disruption effects (10,11,12).…”

Section: Discussionsupporting

confidence: 79%

See 1 more Smart Citation

OligoG CF-5/20 Disruption of Mucoid Pseudomonas aeruginosa Biofilm in a Murine Lung Infection Model

Wang

Song

Ciofu

et al. 2016

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Biofilm growth is a universal survival strategy for bacteria, providing an effective and resilient approach for survival in an otherwise hostile environment. In the context of an infection, a biofilm provides resistance and tolerance to host immune defenses and antibiotics, allowing the biofilm population to survive and thrive under conditions that would destroy their planktonic counterparts. Therefore, the disruption of the biofilm is a key step in eradicating persistent bacterial infections, as seen in many types of chronic disease. In these studies, we used both in vitro minimum biofilm eradication concentration (MBEC) assays and an in vivo model of chronic biofilm infection to demonstrate the biofilm-disrupting effects of an alginate oligomer, OligoG CF-5/20. Biofilm infections were established in mice by tracheal instillation of a mucoid clinical isolate of Pseudomonas aeruginosa embedded in alginate polymer beads. The disruption of the biofilm by OligoG CF-5/20 was observed in a dose-dependent manner over 24 h, with up to a 2.5-log reduction in CFU in the infected mouse lungs. Furthermore, in vitro assays showed that 5% OligoG CF-5/20 significantly reduced the MBEC for colistin from 512 g/ml to 4 g/ml after 8 h. These findings support the potential for OligoG CF-5/20 as a biofilm disruption agent which may have clinical value in reducing the microbial burden in chronic biofilm infections. It has been suggested that biofilms are present in more than 65% of all bacterial infections (1). Biofilm-associated bacteria show an innate resistance to antibiotics, disinfectants, and host defense mechanisms (2, 3) and are thought to contribute to survival in chronic lung infections. Several in vitro studies have demonstrated that bacteria growing in a biofilm can become 10 to 1,000 times more resistant to the effects of antimicrobial agents than planktonic-growing bacteria of the same strain (4, 5). Patients with cystic fibrosis (CF) are highly susceptible to lung infections. As the disease progresses their lungs become chronically infected by P. aeruginosa as a biofilm infection (6), contributing to the destructive cycle of inflammation and fibrosis (7). Clinically, the presence of mucoid variants is associated with poor prognosis, deterioration of lung function, and increased tissue damage (2, 8). Therefore, the disruption of the biofilm is a key step in eradicating persistent bacterial infections, as is seen in many types of chronic disease.The novel alginate oligomer OligoG CF-5/20 is a low-molecular-weight oligosaccharide enriched from sodium alginate polysaccharides. It is an oligomer composed of ␣-L-guluronic acid (Ͼ85%) and ␤-D-mannuronic acid (Ͻ15%) (Fig. 1). OligoG CF-5/20 is currently in phase 2b clinical trials in CF patients. Previous in vitro studies have shown the ability of OligoG CF-5/20 to perturb biofilm formation, thereby reducing tolerance to antibiotic treatment (9-12).High-molecular-weight polymeric alginate is one of the components produced by P. aeruginosa in the formation of biofilms in the a...

show abstract

Section: Discussionsupporting

confidence: 79%

“…OligoG CF-5/20 is currently in phase 2b clinical trials in CF patients. Previous in vitro studies have shown the ability of OligoG CF-5/20 to perturb biofilm formation, thereby reducing tolerance to antibiotic treatment (9)(10)(11)(12).…”

mentioning

confidence: 99%

OligoG CF-5/20 Disruption of Mucoid Pseudomonas aeruginosa Biofilm in a Murine Lung Infection Model

Wang

Song

Ciofu

et al. 2016

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…The results clearly show that OligoG CF-5/20 reduce the growth of the test strains in a dose dependent manner. This is in line with previously reported data on human pathogens associated with respiratory infections in CF and COPD [6] and for fungal strains [5]. The mechanism for the bacteriostatic effect of OligoG CF-5/20 is not yet elucidated, however several properties of OligoG CF-5/20 might contribute to the overall observed effects.…”

Section: Oligog Cf-5/20 Is Able To Potentiate the Effect Of Antibiotisupporting

confidence: 80%

“…Robotic high throughput MIC assays were performed mainly as described previously [5,6]. Antibiotics were dissolved in MH broth with the highest concentration being 200 μg/ml for each.…”

Section: Determination Of Minimum Inhibitory Concentration (Mic) For mentioning

confidence: 99%

“…OligoG CF-5/20 has been shown to modulate the properties of mucus in human cystic fibrosis (CF) sputum [1] and intestinal mucus of CF mice [1,2]. It has also been shown to disrupt established Pseudomonas aeruginosa biofilms [3,4], and to potentiate the action of antibiotics from several classes against a wide range bacteria and fungi [5,6]. Alginate oligomers are currently being investigated in the treatment of chronic respiratory diseases like CF and chronic obstructive pulmonary disease (COPD).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Alginate Oligomers Inhibit Growth of Bacteria Causing Bovine Mastitis and Potentiate the Activity of Antibiotics Commonly Used For Treatment of the Disease

Tøndervik¹,

Klinkenberg²,

Aune³

et al. 2017

J Adv Dairy Res

Self Cite

View full text Add to dashboard Cite

Alginate oligomers have been shown to disrupt microbial biofilms and reduce minimum inhibitory concentrations (MIC) for many clinically relevant antibiotics to a range of human pathogens. The antibiofilm and potentiating effects of alginate oligomers has previously been focused on bacterial and fungal strains that play significant roles in chronic human infections. This study on the effects of an alginate oligomer (OligoG CF-5/20) on bacteria that cause bovine mastitis is the first report that investigates a significant disease in animal health. The effect of OligoG CF-5/20 on the inhibitory concentrations of ampicillin, erythromycin, cephalothin and lincomycin to a test panel of nine bacterial strains associated with bovine mastitis were investigated. Two different media were used for cultivation, the standard Mueller-Hinton normally used for bacterial MIC determination, and a skimmed milk medium to mimic the native growth conditions for mastitis bacteria. OligoG CF-5/20 was shown to inhibit growth of all strains tested, and demonstrated a 2 to 8 fold reduction in MICs for erythromycin, cephalothin and lincomycin. The data highlights a potential role for alginate oligomers in potentiating the efficacy of antibiotics, and thereby potentially reducing antibiotic use, in the treatment of mastitis in dairy cattle.

show abstract

Substitution of one calcium‐binding amino acid strengthens substrate binding in a thermophilic alginate lyase

Wang

et al. 2018

FEBS Letters

View full text Add to dashboard Cite

Ligand binding is sensitive to temperatures since noncovalent bonds between the binding site and ligand could be broken by heat. How metal ion-binding amino acids in alginate lyase evolve to achieve tight substrate binding in a hostile environment remains unknown. An endolytic alginate lyase AlgAT0 specifically cleaved the M-G glycosidic bond and released disaccharides as the main end product. Four conserved calcium-binding sites were predicted and the supplement of Ca led to enhanced substrate binding and protein stability. Among the four conserved calcium-binding sites, one substitution of aspartate for glutamate in AlgAT0 was proved to stimulate Ca affinity. This study suggested that substrate affinity of polysaccharide lyases could be improved by tight binding to Ca via one amino acid substitution.

show abstract

Overcoming Drug Resistance with Alginate Oligosaccharides Able To Potentiate the Action of Selected Antibiotics

Cited by 146 publications

References 33 publications

OligoG CF-5/20 Disruption of Mucoid Pseudomonas aeruginosa Biofilm in a Murine Lung Infection Model

OligoG CF-5/20 Disruption of Mucoid Pseudomonas aeruginosa Biofilm in a Murine Lung Infection Model

Alginate Oligomers Inhibit Growth of Bacteria Causing Bovine Mastitis and Potentiate the Activity of Antibiotics Commonly Used For Treatment of the Disease

Substitution of one calcium‐binding amino acid strengthens substrate binding in a thermophilic alginate lyase

Contact Info

Product

Resources

About