Combination of hypothiocyanite and lactoferrin (ALX-109) enhances the ability of tobramycin and aztreonam to eliminate Pseudomonas aeruginosa biofilms growing on cystic fibrosis airway epithelial cells

Moreau‐Marquis, Sophie; Coutermarsh, Bonita; Stanton, Bruce A.

doi:10.1093/jac/dku357

Cited by 53 publications

(58 citation statements)

References 48 publications

(58 reference statements)

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“…A major example of the medical potential of lactoferrin is the development of ALX-109 by Alaxia, which is a combination of the protein and hypothiocyanite for the treatment of CF [160]. This drug combination has been granted orphan drug status by American and European licensing agencies and has been shown to enhance the ability of conventional antibiotics to eliminate biofilms of P. aeruginosa growing on CF airway epithelial cells [284]. Derivatives of lactoferrin, have also shown the potential for therapeutic development such as hLF(1-11), which was developed by AM Pharma, and in clinical trials the peptide was safely injected into neutropenic stem cell transplantation patients [160].…”

Section: Potential Applications Of Ph Dependent Antimicrobial Peptmentioning

confidence: 99%

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

et al. 2016

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Antimicrobial peptides (AMPs) are potent antibiotics of the innate immune system that have been extensively investigated as a potential solution to the global problem of infectious diseases caused by pathogenic microbes. A group of AMPs that are increasingly being reported are those that utilise pH dependent antimicrobial mechanisms, and here we review research into this area. This review shows that these antimicrobial molecules are produced by a diverse spectrum of creatures, including vertebrates and invertebrates, and are primarily cationic, although a number of anionic examples are known. Some of these molecules exhibit high pH optima for their antimicrobial activity but in most cases, these AMPs show activity against microbes that present low pH optima, which reflects the acidic pH generally found at their sites of action, particularly the skin. The modes of action used by these molecules are based on a number of major structure/function relationships, which include metal ion binding, changes to net charge and conformational plasticity, and primarily involve the protonation of histidine, aspartic acid and glutamic acid residues at low pH. The pH dependent activity of pore forming antimicrobial proteins involves mechanisms that generally differ fundamentally to those used by pH dependent AMPs, which can be described by the carpet, toroidal pore and barrel-stave pore models of membrane interaction. A number of pH dependent AMPs and antimicrobial proteins have been developed for medical purposes and have successfully completed clinical trials, including kappacins, LL-37, histatins and lactoferrin, along with a number of their derivatives. Major examples of the therapeutic application of these antimicrobial molecules include wound healing as well as the treatment of multiple cancers and infections due to viruses, bacteria and fungi. In general, these applications involve topical administration, such as the use of mouth washes, cream formulations and hydrogel delivery systems. Nonetheless, many pH dependent AMPs and antimicrobial proteins have yet to be fully characterized and these molecules, as a whole, represent an untapped source of novel biologically active agents that could aid fulfillment of the urgent need for alternatives to conventional antibiotics, helping to avert a return to the pre-antibiotic era.

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Section: Potential Applications Of Ph Dependent Antimicrobial Peptmentioning

confidence: 99%

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

et al. 2016

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“…Moreau-Marquis et al (2008) demonstrated reduced P. aeruginosa biofilm growth on epithelial cells treated with an iron chelator and subsequently demonstrated (Moreau-Marquis et al, 2009) tobramycin in combination with iron chelators can eliminate P. aeruginosa biofilms. In a recent study, the same group have shown that a combination of hypocyanite and lactoferrin enhances the ability of tobramycin and aztreonam to eliminate P. aeruginosa biofilms on lung epithelial cells (Moreau-Marquis et al, 2015). Data from Reid et al (2009) indicate that iron chelation enhances the efficacy of tobramycin therapy in a low oxygen environment, such as that which pertains in areas of the CF lung.…”

Section: Novel Therapeutic Strategies Targeting Iron Acquisition In Cmentioning

confidence: 99%

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

Tyrrell¹,

Callaghan²

2016

Microbiology

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Iron acquisition is vital to microbial survival and is implicated in the virulence of many of the pathogens that reside in the cystic fibrosis (CF) lung. The multifaceted nature of iron acquisition by both bacterial and fungal pathogens encompasses a range of conserved and speciesspecific mechanisms, including secretion of iron-binding siderophores, utilization of siderophores from other species, release of iron from host iron-binding proteins and haemoproteins, and ferrous iron uptake. Pathogens adapt and deploy specific systems depending on iron availability, bioavailability of the iron pool, stage of infection and presence of competing pathogens. Understanding the dynamics of pathogen iron acquisition has the potential to unveil new avenues for therapeutic intervention to treat both acute and chronic CF infections. Here, we examine the range of strategies utilized by the primary CF pathogens to acquire iron and discuss the different approaches to targeting iron acquisition systems as an antimicrobial strategy.

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“…The combination of ALX-109 and tobramycin or aztreonam reduced biofilm formation and disrupted established biofilms on CF airway epithelial cells. Importantly, ALX-109 reduced the concentration of tobramycin required to eradicate P. aeruginosa biofilms by 5-fold (119).…”

Section: Inhaled Antibiotic Admixturesmentioning

confidence: 99%

Inhaled Antibiotics for Gram-Negative Respiratory Infections

et al. 2016

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SUMMARYGram-negative organisms comprise a large portion of the pathogens responsible for lower respiratory tract infections, especially those that are nosocomially acquired, and the rate of antibiotic resistance among these organisms continues to rise. Systemically administered antibiotics used to treat these infections often have poor penetration into the lung parenchyma and narrow therapeutic windows between efficacy and toxicity. The use of inhaled antibiotics allows for maximization of target site concentrations and optimization of pharmacokinetic/pharmacodynamic indices while minimizing systemic exposure and toxicity. This review is a comprehensive discussion of formulation and drug delivery aspects,in vitroand microbiological considerations, pharmacokinetics, and clinical outcomes with inhaled antibiotics as they apply to disease states other than cystic fibrosis. In reviewing the literature surrounding the use of inhaled antibiotics, we also highlight the complexities related to this route of administration and the shortcomings in the available evidence. The lack of novel anti-Gram-negative antibiotics in the developmental pipeline will encourage the innovative use of our existing agents, and the inhaled route is one that deserves to be further studied and adopted in the clinical arena.

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Combination of hypothiocyanite and lactoferrin (ALX-109) enhances the ability of tobramycin and aztreonam to eliminate Pseudomonas aeruginosa biofilms growing on cystic fibrosis airway epithelial cells

Abstract: Inhalation therapy combining hypothiocyanite and lactoferrin with TOBI(®) (tobramycin) or Cayston(®) (aztreonam) may be beneficial to CF patients by decreasing the airway bacterial burden of P. aeruginosa.

Cited by 53 publications

References 48 publications

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

pH Dependent Antimicrobial Peptides and Proteins, Their Mechanisms of Action and Potential as Therapeutic Agents

Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies

Inhaled Antibiotics for Gram-Negative Respiratory Infections

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