Targeting the hard to reach: challenges and novel strategies in the treatment of intracellular bacterial infections: Targeting intracellular bacteria

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Abstract

<div class="section"> <a class="named-anchor" id="bph13664-sec-2002">  </a> <p class="first" id="d9263590e210">Infectious diseases continue to threaten human and animal health and welfare globally, impacting millions of lives and causing substantial economic loss. The use of antibacterials has been only partially successful in reducing disease impact. Bacterial cells are inherently resilient, and the therapy challenge is increased by the development of antibacterial resistance, the formation of biofilms and the ability of certain clinically important pathogens to invade and localize within host cells. Invasion into host cells provides protection from both antibacterials and the host immune system. Poor delivery of antibacterials into host cells causes inadequate bacterial clearance, resulting in chronic and unresolved infections. In this review, we discuss the challenges associated with existing antibacterial therapies with a focus on intracellular pathogens. We consider the requirements for successful treatment of intracellular infections and novel platforms currently under development. Finally, we discuss novel strategies to improve drug penetration into host cells. As an example, we discuss our recent demonstration that the cell penetrating cationic polymer polyhexamethylene biguanide has antibacterial activity against intracellular <i>Staphylococcus aureus.</i> </p> </div><div class="section"> <a class="named-anchor" id="bph13664-sec-1100">  </a> <h5 class="section-title" id="d9263590e216">Linked Articles</h5> <p id="d9263590e218">This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro‐organisms. To view the other articles in this section visit <a data-untrusted="" href="http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc" id="d9263590e220" target="xrefwindow">http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc</a> </p> </div>

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Strain specificity in antimicrobial activity of silver and copper nanoparticles.

Jayesh P Ruparelia, Arup Chatterjee, Siddhartha P Duttagupta … (2008)

The antimicrobial properties of silver and copper nanoparticles were investigated using Escherichia coli (four strains), Bacillus subtilis and Staphylococcus aureus (three strains). The average sizes of the silver and copper nanoparticles were 3 nm and 9 nm, respectively, as determined through transmission electron microscopy. Energy-dispersive X-ray spectra of silver and copper nanoparticles revealed that while silver was in its pure form, an oxide layer existed on the copper nanoparticles. The bactericidal effect of silver and copper nanoparticles were compared based on diameter of inhibition zone in disk diffusion tests and minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of nanoparticles dispersed in batch cultures. Bacterial sensitivity to nanoparticles was found to vary depending on the microbial species. Disk diffusion studies with E. coli and S. aureus revealed greater effectiveness of the silver nanoparticles compared to the copper nanoparticles. B. subtilis depicted the highest sensitivity to nanoparticles compared to the other strains and was more adversely affected by the copper nanoparticles. Good correlation was observed between MIC and MBC (r2=0.98) measured in liquid cultures. For copper nanoparticles a good negative correlation was observed between the inhibition zone observed in disk diffusion test and MIC/MBC determined based on liquid cultures with the various strains (r2=-0.75). Although strain-specific variation in MIC/MBC was negligible for S. aureus, some strain-specific variation was observed for E. coli.

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Endosomal escape pathways for delivery of biologicals.

Amir K Varkouhi, Marije Scholte, Gert Storm … (2011)

Despite continuous improvements in delivery systems, the development of methods for efficient and specific delivery of targeted therapeutic agents still remains an issue in biological treatments such as protein and gene therapy. The endocytic pathway is the major uptake mechanism of cells and any biological agents, such as DNA, siRNA and proteins. These agents become entrapped in endosomes and are degraded by specific enzymes in the lysosome. Thus, a limiting step in achieving an effective biological based therapy is to facilitate the endosomal escape and ensure cytosolic delivery of the therapeutics. Bacteria and viruses are pathogens which use different mechanisms to penetrate the membranes of their target cells and escape the endosomal pathway. Different mechanisms such as pore formation in the endosomal membrane, pH-buffering effect of protonable groups and fusion into the lipid bilayer of endosomes have been proposed to facilitate the endosomal escape. Several viral and bacterial proteins have been identified that are involved in this process. In addition, chemical agents and photochemical methods to rupture the endosomal membrane have been described. New synthetic biomimetic peptides and polymers with high efficacy in facilitating the endosomal escape, low pathogenicity and toxicity have been developed. Each strategy has different characteristics and challenges for designing the best agents and techniques to facilitate the endosomal escape are ongoing. In this review, several mechanisms and agents which are involved in endosomal escape are introduced. Copyright © 2010 Elsevier B.V. All rights reserved.

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Antimicrobial activity of metal oxide nanoparticles against Gram-positive and Gram-negative bacteria: a comparative study

Ameer Azam, Arham Ahmed, Mohammad Oves … (2012)

Background Nanomaterials have unique properties compared to their bulk counterparts. For this reason, nanotechnology has attracted a great deal of attention from the scientific community. Metal oxide nanomaterials like ZnO and CuO have been used industrially for several purposes, including cosmetics, paints, plastics, and textiles. A common feature that these nanoparticles exhibit is their antimicrobial behavior against pathogenic bacteria. In this report, we demonstrate the antimicrobial activity of ZnO, CuO, and Fe2O3 nanoparticles against Gram-positive and Gram-negative bacteria. Methods and results Nanosized particles of three metal oxides (ZnO, CuO, and Fe2O3) were synthesized by a sol–gel combustion route and characterized by X-ray diffraction, Fourier-transform infrared spectroscopy, and transmission electron microscopy techniques. X-ray diffraction results confirmed the single-phase formation of all three nanomaterials. The particle sizes were observed to be 18, 22, and 28 nm for ZnO, CuO, and Fe2O3, respectively. We used these nanomaterials to evaluate their antibacterial activity against both Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus and Bacillus subtilis) bacteria. Conclusion Among the three metal oxide nanomaterials, ZnO showed greatest antimicrobial activity against both Gram-positive and Gram-negative bacteria used in this study. It was observed that ZnO nanoparticles have excellent bactericidal potential, while Fe2O3 nanoparticles exhibited the least bactericidal activity. The order of antibacterial activity was demonstrated to be the following: ZnO > CuO > Fe2O3.