Tailored anti-biofilm activity – Liposomal delivery for mimic of small antimicrobial peptide (original) (raw)
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Wound infections are a common complication of combat-related injuries that significantly increase morbidity and mortality. Multi-drug resistant (MDR) organisms and their associated biofilms play a significant role in the pathogenicity and chronicity of wound infections. A critical barrier to progress in the treatment of traumatic wounds is the need for broad spectrum antimicrobials that are effective against biofilms and compatible with topical delivery. In this study, we present the in vitro efficacy of two de novo designed cationic, antimicrobial peptides and related topical formulations against single species and polymicrobial biofilms of MDR bacteria. Minimum biofilm eradication concentrations for peptides ranged from 0.7 μM for Staphylococcus aureus to 13.2 μM for Pseudomonas aeruginosa. Varying pH did not adversely impact peptide activity, however, in the presence of albumin, minimum biofilm eradication concentrations generally increased. When formulated into gels or dressings, both peptides eradicated mono-and polymicrobial biofilms of MDR pathogens. The biocompatibility index (BI) was found to be greater than one for both ASP-1 and ASP-2, with a slightly greater (more favorable) BI for ASP-2. The BIs for both peptides were greater than BIs previously reported for commonly used topical antimicrobial agents. The antimicrobial peptides and related formulations presented provide a promising platform for treatment of wound biofilms to improve outcomes for those injured in combat.
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Drug delivery via nanovehicles is successfully employed in several clinical settings, yet bacterial infections, forming microbial communities in the form of biofilms, present a strong challenge to therapeutic treatment due to resistance to conventional antimicrobial therapies. Liposomes can provide a versatile drug-vector strategy for biofilm treatment, but are limited by the need to balance colloidal stability with biofilm penetration. We have discovered a liposomic functionalization strategy, using membrane-embedded moieties of poly[2-(methacryloyloxy)ethyl phosphorylcholine], pMPC, that overcomes this limitation. Such pMPCylation results in liposomic stability equivalent to current functionalization strategies (mostly PEGylation, the present gold-standard), but with strikingly improved cellular uptake and cargo conveyance. Fluorimetry, cryo-electron, and fluorescence microscopies reveal a far-enhanced antibiotic delivery to model Pseudomonas aeruginosa biofilms by pMPC-liposomes, followed by faster cytosolic cargo release, resulting in significantly greater biofilm eradication than either PEGylation or free drug. Moreover, this combination of techniques uncovers the molecular mechanism underlying the enhanced interaction with bacteria, indicating it arises from bridging by divalent ions of the zwitterionic groups on the pMPC moieties to the negatively charged lipopolysaccharide chains emanating from the bacterial membranes. Our results point to pMPCylation as a transformative strategy for liposomal functionalization, leading to next-generation delivery systems for biofilm treatment.
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Staphylococcus aureus biofilm-associated infections are a major public health concern. Current therapies are hampered by reduced penetration of antibiotics through biofilm and low accumulation levels at infected sites, requiring prolonged usage. To overcome these, repurposing antibiotics in combination with nanotechnological platforms is one of the most appealing fast-track and cost-effective approaches. In the present work, we assessed the potential therapeutic benefit of three antibiotics, vancomycin, levofloxacin and rifabutin (RFB), through their incorporation in liposomes. Free RFB displayed the utmost antibacterial effect with MIC and MBIC50 below 0.006 µg/mL towards a methicillin susceptible S. aureus (MSSA). RFB was selected for further in vitro studies and the influence of different lipid compositions on bacterial biofilm interactions was evaluated. Although positively charged RFB liposomes displayed the highest interaction with MSSA biofilms, RFB incorporated in negatively...
Novel Treatment Strategies for Biofilm-Based Infections
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Biofilm-growing cells show an enhanced antimicrobial tolerance with respect to the same cells growing in a free-floating way. This is due to physical or chemical diffusion barriers and increased transfer of resistance markers. Thus, tissue-and medical device-related biofilms can be considered among the leading sources of antibiotic treatment failure, causing many of the deadliest chronic infections afflicting humans nowadays. To find a satisfying way to counteract this major health threat, a great effort has been made in recent years to develop safe, effective and fast-acting anti-biofilm strategies. In this review, we summarise and evaluate the most promising tools and molecules that have demonstrated their ability to modulate steps involved in biofilm formation or to disperse pre-formed biofilms, without conferring evolutionary pressure to microorganisms.
Therapeutic Strategies against Biofilm Infections
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A biofilm is an aggregation of surface-associated microbial cells that is confined in an extracellular polymeric substance (EPS) matrix. Infections caused by microbes that form biofilms are linked to a variety of animals, including insects and humans. Antibiotics and other antimicrobials can be used to remove or eradicate biofilms in order to treat infections. However, due to biofilm resistance to antibiotics and antimicrobials, clinical observations and experimental research clearly demonstrates that antibiotic and antimicrobial therapies alone are frequently insufficient to completely eradicate biofilm infections. Therefore, it becomes crucial and urgent for clinicians to properly treat biofilm infections with currently available antimicrobials and analyze the results. Numerous biofilm-fighting strategies have been developed as a result of advancements in nanoparticle synthesis with an emphasis on metal oxide np. This review focuses on several therapeutic strategies that are curre...
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Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), typified by the pulse-field type USA300, is an emerging endemic pathogen that is spreading rapidly among healthy people. CA-MRSA causes skin and soft tissue infections, life-threatening necrotizing pneumonia and sepsis, and is remarkably resistant to many antibiotics. Here we show that engineered liposomes composed of naturally occurring sphingomyelin were able to sequester cytolytic toxins secreted by USA300 and prevent necrosis of human erythrocytes, peripheral blood mononuclear cells and bronchial epithelial cells. Mass spectrometric analysis revealed the capture by liposomes of phenol-soluble modulins, α-hemolysin and other toxins. Sphingomyelin liposomes prevented hemolysis induced by pure phenol-soluble modulin-α3, one of the main cytolytic components in the USA300 secretome. In contrast, sphingomyelin liposomes harboring a high cholesterol content (66 mol/%) were unable to protect human cells from phenol-soluble modulin-α3-induced lysis, however these liposomes efficiently sequestered the potent staphylococcal toxin α-hemolysin. In a murine cutaneous abscess model, a single dose of either type of liposomes was sufficient to significantly decrease tissue dermonecrosis. Our results provide further insights into the promising potential of tailored liposomal therapy in the battle against infectious diseases.
Beyond conventional antibiotics — New directions for combination products to combat biofilm
Advanced Drug Delivery Reviews, 2017
Medical device related infections are a significant and growing source of morbidity and mortality. Biofilm formation is a common feature of medical device infections that is not effectively prevented or treated by systemic antibiotics. Antimicrobial medical device combination products provide a pathway for local delivery of antimicrobial therapeutics with the ability to achieve high local concentrations while minimizing systemic side effects. In this review, we present considerations for the design of local antimicrobial delivery systems, which can be facilitated by modeling local pharmacokinetics in the context of the target device application. In addition to the need for local delivery, a critical barrier to progress in the field is the need to incorporate agents effective against biofilm. This article aims to review key properties of antimicrobial peptides that make them well suited to meet the demands of the next generation of antimicrobial medical devices, including broad spectrum activity, rapid and biocidal mechanisms of action, and efficacy against biofilm.
Biofilms: Novel Strategies Based on Antimicrobial Peptides
Pharmaceutics, 2019
The problem of drug resistance is very worrying and ever increasing. Resistance is due not only to the reckless use of antibiotics but also to the fact that pathogens are able to adapt to different conditions and develop self-defense mechanisms such as living in biofilms; altogether these issues make the search for alternative drugs a real challenge. Antimicrobial peptides appear as promising alternatives but they have disadvantages that do not make them easily applicable in the medical field; thus many researches look for solutions to overcome the disadvantages and ensure that the advantages can be exploited. This review describes the biofilm characteristics and identifies the key features that antimicrobial peptides should have. Recalcitrant bacterial infections caused by the most obstinate bacterial species should be treated with a strategy to combine conventional peptides functionalized with nano-tools. This approach could effectively disrupt high density infections caused by bi...