Host defense antimicrobial peptides as antibiotics: design and application strategies

Mishra, Biswajit; Reiling, Scott; Zarena, D.; Wang, Guangshun

doi:10.1016/j.cbpa.2017.03.014

Cited by 258 publications

(238 citation statements)

References 96 publications

(100 reference statements)

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“…A host of physicochemical techniques and membrane models has been applied to their characterization . However, notwithstanding the very promising properties of HDPs, there has been no real breakthrough in their clinical application, although several peptides are now in clinical trials . In our opinion, one of the reasons for this lack of success is that several very basic aspects of their function are still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

From liposomes to cells: Filling the gap between physicochemical and microbiological studies of the activity and selectivity of host‐defense peptides

et al. 2018

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Host‐defense peptides (HPDs) are bactericidal and immunomodulatory molecules, part of the innate immune system of many organisms, including man. They kill bacteria mostly by perturbing their membranes, and for this reason they are a promising class of molecules to fight drug‐resistant microbes. However, their success towards clinical application is still limited, partly due to many unanswered questions on their activity and function. Our current understanding of HDPs has been reached by two parallel, but largely independent, approaches: microbiological studies on HDP effects on cells, and physicochemical investigations on model membranes. All current models for the mechanisms of HDP membrane perturbation and cell selectivity were derived from the latter kind of studies, but their relevance for real cells still had to be demonstrated. In the last few years, several studies led to quantitative insights into HDP behavior directly in cells: membrane‐binding and peptide‐induced pores in bacteria and liposomes were compared; the number of cell‐bound peptide molecules needed to kill a bacterium was determined; the variation of peptide activity and toxicity with the density of cells was characterized; selectivity was examined in a mixture of target and host cells; the sequence of events leading to bacterial death was observed in real time by microscopy on single cells. Overall, these approaches led to a new understanding of HDPs that will be helpful for their development into effective antibiotic drugs.

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Section: Introductionmentioning

confidence: 99%

From liposomes to cells: Filling the gap between physicochemical and microbiological studies of the activity and selectivity of host‐defense peptides

et al. 2018

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“…The promising anti‐ Candida effect of many AMPs has spurred further investigations into the development of compounds that are more druglike than the natural AMPs. Studies on smaller synthetic derivatives of AMPs are thus emerging to address the general hurdles of using peptides as drugs such as high production costs, peptide antigenicity, short systemic half‐lives, and low oral bioavailability . One such synthetic example is the synthetic kaxin family developed by Burrows et al These peptides displayed superior antifungal properties compared with magainin II and cecropin P1 but were 1 order of magnitude less potent than fluconazole .…”

Section: Introductionmentioning

confidence: 99%

Development and evaluation of cationic amphiphilic antimicrobial 2,5‐diketopiperazines

Labriere

Kondori

Caous

et al. 2018

Journal of Peptide Science

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Both pathogenic bacteria and fungi are developing resistance to common antimicrobial treatment at an alarming rate. To counteract this development, it is of essence to develop new classes of antimicrobial agents. One such class is antimicrobial peptides, most of which are derived from the innate immune system. In this study, a series of novel 2,5‐diketopiperazines were designed, synthesized, and evaluated for their antimicrobial abilities. The compounds were designed to probe the pharmacophore dictated for short linear mimics of antimicrobial cationic peptides, and as such, the compounds contain a range of cationic and hydrophobic functionalities. Several of the prepared compounds displayed high antimicrobial activities toward bacteria and also against human pathogenic fungi. Of particular interest was the high activity toward fungal strains with an inherent increased resistance toward conventional antifungal agents. The most effective compounds displayed inhibition of Candida glabrata and Candida krusei growth at concentrations between 4 and 8 μg/mL, which is comparable to commercial antifungal agents in use. Structure activity relationship studies revealed a similar dependence on cationic charge and the volume of the hydrophobic bulk as for linear cationic antimicrobial peptides. Finally, the hemolytic activity of selected compounds was evaluated, which revealed a potential to produce active compounds with attenuation of unwanted hemolysis. The findings highlight the potential of cyclic cationic amphiphilic peptidomimetics as a class of promising compounds for the treatment of infections caused by microorganisms with an increased resistance to conventional antimicrobial agents.

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“…It should be emphasized that besides displaying antimicrobial activities, AMPs are also endowed with immunomodulatory properties, for example wound‐healing activity, which may speed up the recovery process from an infectious agent by restoring the integrity of the damaged tissue . This makes AMPs even more attractive molecules over classical antibiotics …”

Section: Discussionmentioning

confidence: 99%

Esculentin‐1a derived peptides kill Pseudomonas aeruginosa biofilm on soft contact lenses and retain antibacterial activity upon immobilization to the lens surface

et al. 2018

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Contact lens (CL) wear is a risk factor for development of microbial keratitis, a vision threatening infection of the eye. Adverse events associated with colonization of lenses, especially by the multi-drug resistant and biofilm forming bacterium Pseudomonas aeruginosa remain a major safety issue. Therefore, novel strategies and compounds to reduce the onset of CL-associated ocular infections are needed. Recently, the activity of the frog skin-derived antimicrobial peptide Esc(1-21) and its diastereomer Esc(1-21)-1c was evaluated against both planktonic and sessile forms of this pathogen. Furthermore, Esc(1-21) was found to significantly reduce the severity of P. aeruginosa keratitis in a mouse model and preserve antipseudomonal activity in the presence of human basal tears. Here, we have analyzed the activity of the peptides on P. aeruginosa biofilm formed on soft CLs. Microbiological assays and scanning electron microscopy analysis indicated that the peptides were able to disrupt the bacterial biofilm, with the diastereomer having the greater efficacy (up to 85% killing vs no killing at 4 μM for some strains). Furthermore, upon covalent immobilization to the CL, the two peptides were found to cause more than four log reduction in the number of bacterial cells within 20 minutes and to reduce bacterial adhesion to the CL surface (77%-97% reduction) in 24 hours. Importantly, peptide immobilization was not toxic to mammalian cells and did not affect the lens characteristics. Overall, our data suggest that both peptides have great potential to be developed as novel pharmaceuticals for prevention and treatment of CL-associated P. aeruginosa keratitis.

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Host defense antimicrobial peptides as antibiotics: design and application strategies

Cited by 258 publications

References 96 publications

From liposomes to cells: Filling the gap between physicochemical and microbiological studies of the activity and selectivity of host‐defense peptides

From liposomes to cells: Filling the gap between physicochemical and microbiological studies of the activity and selectivity of host‐defense peptides

Development and evaluation of cationic amphiphilic antimicrobial 2,5‐diketopiperazines

Esculentin‐1a derived peptides kill Pseudomonas aeruginosa biofilm on soft contact lenses and retain antibacterial activity upon immobilization to the lens surface

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