Controlled Release of LL‐37‐Derived Synthetic Antimicrobial and Anti‐Biofilm Peptides SAAP‐145 and SAAP‐276 Prevents Experimental Biomaterial‐Associated <i>Staphylococcus aureus</i> Infection

Riool, Martijn; Breij, Anna de; Boer, Leonie de; Kwakman, Paulus H. S.; Cordfunke, Robert A.; Cohen, Or; Malanovic, Nermina; Emanuel, Noam; Lohner, Karl; Drijfhout, Jan W.; Nibbering, Peter H.; Zaat, Sebastian A. J.

doi:10.1002/adfm.201606623

Cited by 54 publications

(48 citation statements)

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“…These challenges can be overcome through the use of tailored drug delivery systems such as nanoparticles for encapsulation and controlled release (39)(40)(41). Our recent report that SAAP-145 and SAAP-276 incorporated in a controlled-release coating were highly effective against biomaterial-associated infections in vivo (26) demonstrates the potency of SAAPs in tissues.…”

Section: Discussionmentioning

confidence: 99%

The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms

et al. 2018

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Development of novel antimicrobial agents is a top priority in the fight against multidrug-resistant (MDR) and persistent bacteria. We developed a panel of synthetic antimicrobial and antibiofilm peptides (SAAPs) with enhanced antimicrobial activities compared to the parent peptide, human antimicrobial peptide LL-37. Our lead peptide SAAP-148 was more efficient in killing bacteria under physiological conditions in vitro than many known preclinical- and clinical-phase antimicrobial peptides. SAAP-148 killed MDR pathogens without inducing resistance, prevented biofilm formation, and eliminated established biofilms and persister cells. A single 4-hour treatment with hypromellose ointment containing SAAP-148 completely eradicated acute and established, biofilm-associated infections with methicillin-resistant and MDR from wounded ex vivo human skin and murine skin in vivo. Together, these data demonstrate that SAAP-148 is a promising drug candidate in the battle against antibiotic-resistant bacteria that pose a great threat to human health.

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Section: Discussionmentioning

confidence: 99%

The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms

et al. 2018

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“…In vivo studies showed that S. epidermidis applied on the surface of titanium implants, both as adherent cells and as a pregrown biofilm, rapidly relocated from the implants to the surrounding tissue (Riool et al, 2014 ). Similarly, large numbers of S. aureus were cultured from mouse tissues around infected titanium (Riool et al, 2017a , b ) and silicon elastomer implants (de Breij et al, 2016 ). In a murine model of chronic osteomyelitis, S. aureus was found in osteoblasts and osteocytes, as well as in canaliculi of live cortical bone (de Mesy Bentley et al, 2017 ).…”

Section: Biomaterial-associated Infectionsmentioning

confidence: 99%

Antimicrobial Peptides in Biomedical Device Manufacturing

et al. 2017

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Over the past decades the use of medical devices, such as catheters, artificial heart valves, prosthetic joints, and other implants, has grown significantly. Despite continuous improvements in device design, surgical procedures, and wound care, biomaterial-associated infections (BAI) are still a major problem in modern medicine. Conventional antibiotic treatment often fails due to the low levels of antibiotic at the site of infection. The presence of biofilms on the biomaterial and/or the multidrug-resistant phenotype of the bacteria further impair the efficacy of antibiotic treatment. Removal of the biomaterial is then the last option to control the infection. Clearly, there is a pressing need for alternative strategies to prevent and treat BAI. Synthetic antimicrobial peptides (AMPs) are considered promising candidates as they are active against a broad spectrum of (antibiotic-resistant) planktonic bacteria and biofilms. Moreover, bacteria are less likely to develop resistance to these rapidly-acting peptides. In this review we highlight the four main strategies, three of which applying AMPs, in biomedical device manufacturing to prevent BAI. The first involves modification of the physicochemical characteristics of the surface of implants. Immobilization of AMPs on surfaces of medical devices with a variety of chemical techniques is essential in the second strategy. The main disadvantage of these two strategies relates to the limited antibacterial effect in the tissue surrounding the implant. This limitation is addressed by the third strategy that releases AMPs from a coating in a controlled fashion. Lastly, AMPs can be integrated in the design and manufacturing of additively manufactured/3D-printed implants, owing to the physicochemical characteristics of the implant material and the versatile manufacturing technologies compatible with antimicrobials incorporation. These novel technologies utilizing AMPs will contribute to development of novel and safe antimicrobial medical devices, reducing complications and associated costs of device infection.

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“…Whereas a thin hydroxyapatite (HA) film on Ti implants can already provide the electrostatic interaction with cationic HDPs to delay their burst release, [240,241] HDPs must be incorporated within a CaP coating for more sustained release profiles. [242][243][244] This has for example yielded 7 day steady release of the HDPs Tet213 and HHC-36 from CaP-coated metal implants. [244,245] Incorporation of HDPs in polymer-based coatings can enhance the in vivo stability of HDPs, [246] considering their susceptibility to proteolytic degradation or binding to plasma components.…”

Section: Strategies For Hdp Biofunctionalization Of Biomaterialsmentioning

confidence: 99%

“…To realize even longer lasting drug release, multilayer polyelectrolyte assemblies can be applied to release HDP over a period of weeks. [243,248,249] For instance, Riool et al produced implants coated with a polymer-lipid encapsulation matrix (PLEX) containing the LL-37-derived anti-biofilm peptides SAAP-145 and SAAP-276. The self-assembly of multiple alternating layers of polymer and phospholipid in the PLEX provided zero-order release kinetics of the SAAP peptides stretching over a period of one month, and was more potent than an antibiotic-based doxycycline-PLEX coating in reducing the bacterial numbers.…”

Section: Strategies For Hdp Biofunctionalization Of Biomaterialsmentioning

confidence: 99%

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Combating Implant Infections: Shifting Focus from Bacteria to Host

et al. 2020

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commensal skin bacteria, Staphylococci, and in particular Staphylococcus aureus, have a strong tendency to colonize foreign bodies and cause IAI. [3,4] Important for the underlying pathophysiology, Staphylococci are highly competent at producing biofilms on implant surfaces, which encapsulate the bacterial niche from the outside environment, [5,6] thereby protecting the bacteria from host defense systems and antibiotics. [7] Antibiotics are administered as a routine procedure. [8] However, as a consequence of widespread antibiotics usage, bacteria are exposed to subinhibitory concentrations of antibiotics at a larger scale, driving their development toward antibiotic resistance, [9] as illustrated by the emergence of methicillin-resistant S. aureus (MRSA). [10,11] As an improvement over current clinically applied local antibiotics delivery systems, [12] the recent developments in implant surface engineering approaches allow better antimicrobial functionalities to be incorporated to allow for more tunable and controlled drug release. [13-15] The "race to the surface" model is popular among biomaterials researchers to predict the biomaterials fate, resulting from the competition between eukaryotic cells and bacteria at the material surface. [16] Using this template, implant antibacterial properties are being stemmed from direct contact killing mechanisms due to implant surface modifications [17,18] or firm immobilization of drugs, [19,20] as they both "shield" the implant from bacterial adhesion. The current anti-infective biomaterials strategies being explored can be categorized as: 1) implant functionalization with antibiotics or antibacterial drugs such as host defense peptides (HDPs), inorganic materials (e.g., chitosan and derivatives), and inorganics (e.g., silver, copper, and zinc metal nanoparticles (NPs)), 2) anti-biofilm surface modification (e.g., coating with antifouling polymers or quorum sensor inhibitors), or 3) physical surface changes for direct contact-killing properties (e.g., nanotubes, nanopillars, and metal implantation). [15,21] Emerging as a serious alternative or adjuvant therapy to antibiotics, bacteriophage (phage) therapy uses viruses responsible for the lysis of specific bacterial strains. [22,23] As a natural predator of bacteria, phages employ different killing mechanisms, making multidrug resistant bacteria susceptible for phages. [24] Moreover, phages are highly specific for pathogenic cells, which can eliminate disastrous off-target effects in the host. [25] As a limitation, the use of phage cocktails is needed for therapeutic efficacy, [26] while there is currently is no conclusive data on possible long-term side effects of phage therapy in The widespread use of biomaterials to support or replace body parts is increasingly threatened by the risk of implant-associated infections. In the quest for finding novel anti-infective biomaterials, there generally has been a one-sided focus on biomaterials with direct antibacterial properties, which leads to excessive use of antibacterial ag...

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Controlled Release of LL‐37‐Derived Synthetic Antimicrobial and Anti‐Biofilm Peptides SAAP‐145 and SAAP‐276 Prevents Experimental Biomaterial‐Associated Staphylococcus aureus Infection

Cited by 54 publications

References 56 publications

The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms

The antimicrobial peptide SAAP-148 combats drug-resistant bacteria and biofilms

Antimicrobial Peptides in Biomedical Device Manufacturing

Combating Implant Infections: Shifting Focus from Bacteria to Host

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