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Enhanced Clearing of Wound-Related Pathogenic Bacterial Biofilms Using Protease-Functionalized Antibiotic Nanocarriers.
ACS Appl Mater Interfaces. 2019 Nov 27; 11(47):43902-43919.AA

Abstract

Biofilms are prevalent in chronic wounds and once formed are very hard to remove, which is associated with poor outcomes and high mortality rates. Biofilms are comprised of surface-attached bacteria embedded in an extracellular polymeric substance (EPS) matrix, which confers increased antibiotic resistance and host immune evasion. Therefore, disruption of this matrix is essential to tackle the biofilm-embedded bacteria. Here, we propose a novel nanotechnology to do this, based on protease-functionalized nanogel carriers of antibiotics. Such active antibiotic nanocarriers, surface coated with the protease Alcalase 2.4 L FG, "digest" their way through the biofilm EPS matrix, reach the buried bacteria, and deliver a high dose of antibiotic directly on their cell walls, which overwhelms their defenses. We demonstrated their effectiveness against six wound biofilm-forming bacteria, Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis, Klebsiella pneumoniae, Escherichia coli, and Enterococcus faecalis. We confirmed a 6-fold decrease in the biofilm mass and a substantial reduction in bacterial cell density using fluorescence, atomic force, and scanning electron microscopy. Additionally, we showed that co-treatments of ciprofloxacin and Alcalase-coated Carbopol nanogels led to a 3-log reduction in viable biofilm-forming cells when compared to ciprofloxacin treatments alone. Encapsulating an equivalent concentration of ciprofloxacin into the Alcalase-coated nanogel particles boosted their antibacterial effect much further, reducing the bacterial cell viability to below detectable amounts after 6 h of treatment. The Alcalase-coated nanogel particles were noncytotoxic to human adult keratinocyte cells (HaCaT), inducing a very low apoptotic response in these cells. Overall, we demonstrated that the Alcalase-coated nanogels loaded with a cationic antibiotic elicit very strong biofilm-clearing effects against wound-associated biofilm-forming pathogenic bacteria. This nanotechnology approach has the potential to become a very powerful treatment of chronically infected wounds with biofilm-forming bacteria.

Authors+Show Affiliations

Department of Chemistry and Biochemistry , University of Hull , Hull HU6 7RX , U.K.Centre for Atherothrombosis and Metabolic Disease , Hull York Medical School , Hull HU6 7RX , U.K.Department of Chemistry and Biochemistry , University of Hull , Hull HU6 7RX , U.K.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31718141

Citation

Weldrick, Paul J., et al. "Enhanced Clearing of Wound-Related Pathogenic Bacterial Biofilms Using Protease-Functionalized Antibiotic Nanocarriers." ACS Applied Materials & Interfaces, vol. 11, no. 47, 2019, pp. 43902-43919.
Weldrick PJ, Hardman MJ, Paunov VN. Enhanced Clearing of Wound-Related Pathogenic Bacterial Biofilms Using Protease-Functionalized Antibiotic Nanocarriers. ACS Appl Mater Interfaces. 2019;11(47):43902-43919.
Weldrick, P. J., Hardman, M. J., & Paunov, V. N. (2019). Enhanced Clearing of Wound-Related Pathogenic Bacterial Biofilms Using Protease-Functionalized Antibiotic Nanocarriers. ACS Applied Materials & Interfaces, 11(47), 43902-43919. https://doi.org/10.1021/acsami.9b16119
Weldrick PJ, Hardman MJ, Paunov VN. Enhanced Clearing of Wound-Related Pathogenic Bacterial Biofilms Using Protease-Functionalized Antibiotic Nanocarriers. ACS Appl Mater Interfaces. 2019 Nov 27;11(47):43902-43919. PubMed PMID: 31718141.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced Clearing of Wound-Related Pathogenic Bacterial Biofilms Using Protease-Functionalized Antibiotic Nanocarriers. AU - Weldrick,Paul J, AU - Hardman,Matthew J, AU - Paunov,Vesselin N, Y1 - 2019/11/13/ PY - 2019/11/14/pubmed PY - 2020/4/9/medline PY - 2019/11/14/entrez KW - Alcalase 2.4 L FG KW - Klebsiella pneumoniae KW - Pseudomonas aeruginosa KW - Staphylococcus aureus KW - biofilms KW - ciprofloxacin KW - nanogels KW - protease SP - 43902 EP - 43919 JF - ACS applied materials & interfaces JO - ACS Appl Mater Interfaces VL - 11 IS - 47 N2 - Biofilms are prevalent in chronic wounds and once formed are very hard to remove, which is associated with poor outcomes and high mortality rates. Biofilms are comprised of surface-attached bacteria embedded in an extracellular polymeric substance (EPS) matrix, which confers increased antibiotic resistance and host immune evasion. Therefore, disruption of this matrix is essential to tackle the biofilm-embedded bacteria. Here, we propose a novel nanotechnology to do this, based on protease-functionalized nanogel carriers of antibiotics. Such active antibiotic nanocarriers, surface coated with the protease Alcalase 2.4 L FG, "digest" their way through the biofilm EPS matrix, reach the buried bacteria, and deliver a high dose of antibiotic directly on their cell walls, which overwhelms their defenses. We demonstrated their effectiveness against six wound biofilm-forming bacteria, Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis, Klebsiella pneumoniae, Escherichia coli, and Enterococcus faecalis. We confirmed a 6-fold decrease in the biofilm mass and a substantial reduction in bacterial cell density using fluorescence, atomic force, and scanning electron microscopy. Additionally, we showed that co-treatments of ciprofloxacin and Alcalase-coated Carbopol nanogels led to a 3-log reduction in viable biofilm-forming cells when compared to ciprofloxacin treatments alone. Encapsulating an equivalent concentration of ciprofloxacin into the Alcalase-coated nanogel particles boosted their antibacterial effect much further, reducing the bacterial cell viability to below detectable amounts after 6 h of treatment. The Alcalase-coated nanogel particles were noncytotoxic to human adult keratinocyte cells (HaCaT), inducing a very low apoptotic response in these cells. Overall, we demonstrated that the Alcalase-coated nanogels loaded with a cationic antibiotic elicit very strong biofilm-clearing effects against wound-associated biofilm-forming pathogenic bacteria. This nanotechnology approach has the potential to become a very powerful treatment of chronically infected wounds with biofilm-forming bacteria. SN - 1944-8252 UR - https://www.unboundmedicine.com/medline/citation/31718141/Enhanced_Clearing_of_Wound_Related_Pathogenic_Bacterial_Biofilms_Using_Protease_Functionalized_Antibiotic_Nanocarriers_ L2 - https://dx.doi.org/10.1021/acsami.9b16119 DB - PRIME DP - Unbound Medicine ER -