Abstract
Nanoconjugated antibiotics can be regarded as next-generation drugs as they possess remarkable potential to overcome multidrug resistance in pathogenic bacteria. Iron oxide nanoparticles (IONPs) have been extensively used in the biomedical field because of their biocompatibility and magnetic properties. More recently, IONPs have been investigated as potential nanocarriers for antibiotics to be magnetically directed to/recovered from infection sites. Here, we conjugated the “last-resort” glycopeptide antibiotic teicoplanin to IONPs after surface functionalization with (3-aminopropyl) triethoxysilane (APTES). Classical microbiological methods and fluorescence and electron microscopy analysis were used to compare antimicrobial activity and surface interactions of naked IONPs, amino-functionalized NPs (NP-APTES), and nanoconjugated teicoplanin (NP-TEICO) with non-conjugated teicoplanin. As bacterial models, differently resistant strains of three Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis, and Bacillus subtilis) and a Gram-negative representative (Escherichia coli) were used. The results indicated that teicoplanin conjugation conferred a valuable and prolonged antimicrobial activity to IONPs toward Gram-positive bacteria. No antimicrobial activity was detected using NP-TEICO toward the Gram-negative E. coli. Although IONPs and NP-APTES showed only insignificant antimicrobial activity in comparison to NP-TEICO, our data indicate that they might establish diverse interaction patterns at bacterial surfaces. Sensitivity of bacteria to NPs varied according to the surface provided by the bacteria and it was species specific. In addition, conjugation of teicoplanin improved the cytocompatibility of IONPs toward two human cell lines. Finally, NP-TEICO inhibited the formation of S. aureus biofilm, conserving the activity of non-conjugated teicoplanin versus planktonic cells and improving it toward adherent cells.
Highlights
According to a recent survey of the World Health Organization (WHO, 2017), antibiotic resistance represents one of the greatest threats to global health today and contributes significantly to longer hospital permanence, higher medical costs, and increased mortality
Experiments were conducted in 50-mL tubes containing a final volume of 10 mL of LB or MHB2 added after 1 h of growth from inocula with equivalent volumes of Iron oxide nanoparticles (IONPs), NP-APTES, and NP-TEICO preparations (4 mg/mL) previously resuspended in 30 mM MES buffer, pH 6.0, or with the teicoplanin control solution (500 μg/mL)
IONPs and NP-APTES did not show any inhibition halos toward either the Gram-positive or the Gram-negative bacteria. These data indicate that the antimicrobial activity measured by the agar diffusion assay was conferred to NP-TEICO by the conjugation of the antibiotic and that it was not an intrinsic feature of IONPs
Summary
According to a recent survey of the World Health Organization (WHO, 2017), antibiotic resistance represents one of the greatest threats to global health today and contributes significantly to longer hospital permanence, higher medical costs, and increased mortality. The advantages of using NPs in this way depend on the nature of both the NPs and the drugs under consideration, as recently reviewed (Natan and Banin, 2017) These advantages might include (i) protecting the nanoconjugated drug from degradation and oxidation; (ii) increasing drug solubility, antimicrobial activity, and biodistribution; (iii) delivering the antibiotic to the site of the infection; and (iv) enhancing drug penetration into biofilms, facilitating the killing of encased bacteria. Teicoplanin is a complex molecule with a peptide core of seven aromatic amino acids tailored with sugar residues, chlorine atoms, methyl groups, and a lipid chain It forms five specific hydrogen bonds with the D-alanyl-D-alanine terminus of the peptidoglycan precursors of the bacterial cell wall, blocking its synthesis and causing cell lysis (Binda et al, 2014). To the best of our knowledge, this is the first study exploring the feasibility of conjugating teicoplanin to IONPs and testing the potential of nanoconjugated teicoplanin as a promising tool for treating bacterial infections caused by resistant bacteria
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