Water dispersible magnetite nanoparticles influence the efficacy of antibiotics against planktonic...

RESEARCH PAPER

In vitro activity of the new water-dispersible Fe3O4@usnicacid nanostructure against planktonic and sessile bacterialcells

Alexandru Mihai Grumezescu • Ani Ioana Cotar • Ecaterina Andronescu •

Anton Ficai • Cristina Daniela Ghitulica • Valentina Grumezescu •

Bogdan Stefan Vasile • Mariana Carmen Chifiriuc

Received: 21 January 2013 / Accepted: 30 May 2013

� Springer Science+Business Media Dordrecht 2013

Abstract A new water-dispersible nanostructure

based on magnetite (Fe3O4) and usnic acid (UA) was

prepared in a well-shaped spherical form by a precip-

itation method. Nanoparticles were well individualized

and homogeneous in size. The presence of Fe3O4@UA

was confirmed by transmission electron microscopy,

Fourier transform-infrared spectroscopy, and X-ray

diffraction. The UA was entrapped in the magnetic

nanoparticles during preparation and the amount of

entrapped UA was estimated by thermogravimetric

analysis. Fabricated nanostructures were tested on

planktonic cells growth (minimal inhibitory concentra-

tion assay) and biofilm development on Gram-positive

Staphylococcus aureus (S. aureus), Enterococcus

faecalis (E. faecalis) and Gram-negative Escherichia

coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa)

reference strains. Concerning the influence of

Fe3O4@UA on the planktonic bacterial cells, the

functionalized magnetic nanoparticles exhibited a sig-

nificantly improved antimicrobial activity against E.

faecalis and E. coli, as compared with the Fe3O4 control.

The UA incorporated into the magnetic nanoparticles

exhibited a very significant inhibitory effect on the

biofilm formed by the S. aureus and E. faecalis, on a

wide range of concentrations, while in case of the Gram-

negative microbial strains, the UA-loaded nanoparticles

inhibited the E. coli biofilm development, only at high

concentrations, while for P. aeruginosa biofilms, no

inhibitory effect was observed. The obtained results

demonstrate that the new water-dispersible Fe3O4@UA

nanosystem, combining the advantages of the intrinsic

antimicrobial features of the UA with the higher surface

to volume ratio provided by the magnetic nanocarrier

dispersible in water, exhibits efficient antimicrobial

activity against planktonic and adherent cells, especially

on Gram-positive strains.

Keywords Usnic acid � Anti-biofilm activity �Water-dispersible nanostructure � Magnetite

Introduction

Nowadays, the concept of antibiotic resistance was

extended from the situation in which bacteria exhibit

A. M. Grumezescu (&) � E. Andronescu �A. Ficai � C. D. Ghitulica � V. Grumezescu � B. S. Vasile

Department of Science and Engineering of Oxidic

Materials and Nanomaterials, Faculty of Applied

Chemistry and Materials Science, University Politehnica

of Bucharest, Polizu Street no. 1-7, 011061 Bucharest,

Romania

e-mail: [email protected]

A. I. Cotar � M. C. Chifiriuc

Department of Microbiology Immunology, Faculty

of Biology, University of Bucharest, Aleea Portocalelor

no. 1-3, 060101 Bucharest, Romania

V. Grumezescu

Laser-Surface-Plasma Interactions Laboratory, Lasers

Department, National Institute for Lasers, Plasma and

Radiation Physics, Institute of Atomic Physics, Magurele,

77125 Bucharest, Romania

123

J Nanopart Res (2013) 15:1766

DOI 10.1007/s11051-013-1766-3

significantly reduced susceptibility to antimicrobials

in laboratory tests by mechanisms such as altered drug

uptake, altered drug target, and drug inactivation, to

the phenotypic resistance of bacteria growing as

adherent biofilms, formed on medical devices or

human tissues (Szomolay et al. 2005). A series of

therapeutic approaches targeting the biofilm develop-

ment have been proposed (Martinez and Casadevall

2005). One of them include the improved delivery of

antibiotics or quorum sensing inhibitory agents into

the biofilm by using nanostructured carriers (Sousa

et al. 2011).

The (?)-UA, a secondary lichen metabolite, pos-

sesses antimicrobial activity against a number of

planktonic bacteria, and, similar with other secondary

lichen metabolites, offers protection to lichen com-

munities against the adherent microorganisms (Smith

2005). Presently, there are a lot of studies suggesting

that UA exhibits antimicrobial activity against a

number of planktonic Gram-positive bacteria, includ-

ing S. aureus, E. faecalis, and E. faecium (Francolini

et al. 2004). The mechanism of action expressed by

(?)-UA is still unknown, although very recent studies

are stating that the natural L-(-)-UA exerts its

antibacterial activity against methicillin-resistant S.

aureus strains by disruption of the cell membrane

(Gupta et al. 2012). Further, the natural L-(-)-UA was

found to be safe up to 100 mg/kg body weight,

thereby, making it a potential candidate for treating S.

aureus infections (Gupta et al. 2012). Our previous

results have shown that UA renders the exposed

bacterial cells sensitive to the usual doses of antimi-

crobials, probably acting as a quorum sensing inhib-

itor, which interferes with the coordinate expression of

the virulence factors, including the synthesis of

adhesins and biofilm development (Chifiriuc et al.

2009).

The development of magnetite materials has dra-

matically increased in the past decade for its wide

range of applications in the biomedical field (Guan

et al. 2009). Many of the potential biotechnological

applications of magnetite nanostructures require the

presence of reactive functional groups to act as

coupling sites allowing them to be tailor-made to

react in a specific way to their environment (Chen et al.

2007; Frimpong and Hilt 2008; Sun et al. 2012).

Biocompatible magnetic nanoparticles coated with

organic molecular shell is able to ensure active

pharmaceutical agents (Masoudi et al. 2012a;

Grumezescu et al. 2012a; Park et al. 2012; Jansch

et al. 2012, Gustafsson et al. 2010; Kipp 2004).

Functionalized magnetite nanostructures have been

subjects of great interest due to their versatile appli-

cations such as inhibition of microbial growth and

biofilm development (Anghel et al. 2012a), stabiliza-

tion of essential oils (Anghel et al. 2012b; Grumezescu

et al. 2012b), drug delivery (Perez-Artacho et al. 2012;

Grumezescu et al. 2012a, b, c, d, e, f, g; Grumezescu

et al. 2012c, d, e; Andhariya et al. 2013), magnetic

resonance imaging (Masoudi et al. 2012b), hyperther-

mia (Alphandery et al. 2012; Lahonian et al. Lahonian

and Golneshan 2011), or tumor treatment (Grumeze-

scu et al. 2012d; Barreto et al. 2011; Santos et al.

2011).

In our previous studies, we have obtained a Fe3O4/

oleic acid nanofluid, which proved to potentiate the

microbicidal and anti-biofilm activity of UA on S.

aureus strains (Grumezescu et al. 2011b). However,

there are some limitations of the obtained nanocom-

posite, due to the apolar nature of the used organic

shell, represented by the oleic acid, which is making

them insoluble in water and promotes the nanoparti-

cles aggregation in aqueous solution. Moreover, the

obtained nanosystem was tested exclusively on the

Gram-positive S. aureus bacterial strain.

In this study, we aimed to improve and extend the

microbiological applications of a UA magnetic nano-

carrier, by the successful fabrication of a new water-

dispersible nanostructure based on magnetite and

usnic acid (Fe3O4@UA) and to evaluate their biolog-

ical activity against a wide spectrum of bacterial

strains, both Gram-positive and Gram-negative.

Materials and methods

Materials

All chemicals were used as received. FeCl3, FeS-

O4�7H2O, NH4OH (25 %), usnic acid, and CH3OH

were purchased from Sigma-Aldrich ChemieGmbh

(Munich, Germany).

Fabrication of nanostructure

Magnetic iron oxide nanoparticles are usually pre-

pared by wet chemical precipitation from aqueous iron

of 10 J Nanopart Res (2013) 15:1766

123

salt solutions by means of alkaline media, like HO-

and NH3 (Grumezescu et al. 2012e, f, g). Briefly,

500 mg of UA and 8 mL of NH4OH (25 %) were

added in 200 mL deionized water under vigorous

stirring. Then, 1 g of FeCl3 and 1.6 g of FeSO4�7H2O

were dissolved in 200 mL of deionized water and

Fe?3/Fe2? solution was dropped into the basic solu-

tion of UA. After precipitation, magnetite–usnic acid

crystals (Fe3O4@UA) were repeatedly washed with

methanol, separated with a strong NdFeB permanent

magnet. Subsequently, the Fe3O4@UA was added into

the 100 mL solution of acetic acid 0.1 N and stirred

for 10 min. After this, the Fe3O4@UA was separated

with a strong NdFeB permanent magnet, repeatedly

washed with deionized water, and finally solubilized

in ultrapure water (Millipore Water Purification

Systems).

Characterization of nanostructure

XRD

X-ray diffraction analysis was performed on a Shima-

dzu XRD 6000 diffractometer at room temperature. In

all the cases, Cu Ka radiation from a Cu X-ray tube

(run at 15 mA and 30 kV) was used. The samples were

scanned in the Bragg angle 2h range of 10–80�.

FT-IR

A Nicolet 6700 FT-IR spectrometer (Thermo Nicolet,

Madison, WI) connected to the software of the

OMNIC operating system (Version 8.2 Thermo

Nicolet) was used to obtain FT-IR spectra of the

Fe3O4@AU and AU. The samples were placed in

contact with attenuated total reflectance (ATR) on a

multibounce plate of ZnSe crystal at controlled

ambient temperature (25 �C). FT-IR spectra were

collected in the frequency range of 4.000–650 cm-1

by co-adding 32 scans and at a resolution of 4 cm-1

with strong apodization. All spectra were ratioed

against a background of an air spectrum.

TGA

The thermogravimetric (TG) analysis of the biocom-

posite was assessed with a Shimadzu DTG-TA-50H

instrument. Samples were screened to 200 mesh prior

to analysis, were placed in alumina crucible, and

heated with 10 K�min-1 from room temperature to

800 �C, under the flow of 20 mL�min-1 dried syn-

thetic air (80 % N2 and 20 % O2).

TEM

The transmission electron microscopy (TEM) images

were obtained on finely powdered samples using a

TecnaiTM G2 F30 S-TWIN high-resolution transmis-

sion electron microscope from FEI Company (OR,

USA) equipped with EDS and SAED. The microscope

was operated in transmission mode at 300 kV with

TEM point resolution of 2 A and line resolution of

1 A. The fine MNP powder was dispersed into pure

ethanol and ultrasonicated for 15 min. After that,

diluted sample was put onto a holey carbon-coated

copper grid and left to dry before TEM analysis.

Influence of Fe3O4@AU on planktonic cells

growth and microbial biofilm development

In this purpose, 2-fold microdilutions of nanoparti-

cules stock solutions prepared in sterile saline were

performed in liquid culture medium (nutrient broth)

distributed in 96 multi-well plates, starting from 1,000

to 0.48 lg/mL). Each well was inoculated with 5 lL

of microbial suspensions of 0.5 Mc Farland turbidity

prepared from 24-h fresh cultures of Gram-positive (S.

aureus American type culture collection (ATCC)

29213, E. faecalis ATCC 29212) and Gram-negative

(P. aeruginosa ATCC 27853, E. coli ATCC 25922)

bacterial reference strains (Biomerieux). Sterility

control wells (glucose broth) and microbial growth

controls (inoculated glucose broth) were used. The

plates were incubated for 24 h at 30 �C, and the

influence of nanoparticles on the planktonic cells

growth in liquid medium was appreciated by measur-

ing the A 600 nm of the obtained cultures. The MIC

was considered as the last dilution of the tested

compound which inhibited the microbial growth.

Thereafter, the 96-well plates were emptied, washed

3 times with phosphate-buffered saline, fixed with

cold methanol, and stained with violet crystal solution

1 % for 30 min. The biofilm formed onto the plastic

wells was resuspended in 30 % acetic acid and the

intensity of the colored suspension was assayed by

measuring the absorbance at 490 nm.

J Nanopart Res (2013) 15:1766 of 10

123

Results and discussion

Many of the potential biomedical applications of

different nanostructures require the presence of func-

tional groups acting as coupling sites (Guan et al.

2009; Grumezescu et al. 2012a, c; Mihaiescu et al.

2012) resulting in versatile, multi-responsive func-

tionalized nanomaterials (Saviuc et al. 2011a; Saviuc

et al. 2011b; Dhanasingh et al. 2011; Karmali et al.

2011; Saviuc et al. 2011c; Grumezescu et al. 2011a, b;

Mihaiescu et al. 2011; Andronescu et al. 2012; Baier

et al. 2012).

In the present study we report the successful

fabrication of new water-dispersible nanostructures

based on magnetite and usnic acid (Fe3O4@UA) and

the assessment of their biological activity against a

wide spectrum of bacterial strains.

The purity and crystalline properties of the

Fe3O4@UA were investigated by powder X-ray dif-

fraction (XRD). The XRD pattern is shown in Fig. 1.

In this case, all lines can be indexed using the JCPDS

file no. 19-0629 corresponding to magnetite. The

pattern has characteristic peaks at 30.5o(220),

35.9o(311), 37o(222), 43.5o(400), 57.3o(511), and

63.1o(440), which match the standard pattern of

Fe3O4 well (Jean et al. 2012; Grumezescu et al. 2012a).

The UA and Fe3O4@UA samples were analyzed by

FT-IR method. The spectrum of the Fe3O4@UA

(Fig. 2) exhibits a characteristic peak of Fe3O4 at

about 569 cm-1 (Fe–O stretching) (Cornell and

Schwertmann 2003; Anghel et al. 2012a; Fang et al.

2009). Also in this spectrum the UA on the surface of

the magnetite nanoparticles can be identified (Fig. 2).

The peaks recorded at about 2,974 and 2,923 cm-1

were assigned to stretching vibration of C–H. In

addition, there are many well-defined peaks in the

fingerprint region between 1,700 and 800 cm-1. The

fingerprint region of the UA and Fe3O4@UA regions

shows no major differences after precipitation of

magnetite. Conjugation, electron-donating ring sub-

stituents, and possible intra-molecular hydrogen bond-

ing, all contribute to the lower wavenumber position

of the aromatic methyl ketone at 1,629 cm-1. It is also

possible to assign the antisymmetric and symmetric

(COC) aryl alkyl ether to the band at approximately

1,067 cm-1 (Edwards et al. 2003).

TGA analysis is plotted in Fig. 3. UA content was

estimated as the difference between weight loss for the

region at approximately 800 �C for Fe3O4@UA and

Fe3O4, and it is approximately 6.4 %. Figure 4

displays the physical appearance of Fe3O4@UA

nanoparticles as observed in TEM. These nanoparti-

cles exhibit a rather spherical shape and are relatively

monodispersed, with a mean diameter of 10 nm. The

selected area electron diffraction (SAED) pattern

proves the presence of magnetite as the single

crystalline phase, the most intense planes being:

(440), (333), (422), (400), (222), (220). These results

are in agreement with the literature (Santra et al. 2001;

Kamruzzaman Selim et al. 2007) and with the

obtained EDS data.

The EDS spectrum proves the presence of Fe and O

as main elements of the sample (the other peaks–Cu,

C, and Au being characteristic of the carbon-coated

grid). Small amount of chloride can be visualized (less

than 1 %).

Fig. 1 XRD pattern of

Fe3O4@UA nanostructure


123

Concerning the influence of Fe3O4@UA against the

planktonic bacterial cells, it could be observed that the

functionalized magnetic nanoparticles exhibited a

significantly improved antimicrobial activity against

both Gram-positive E. faecalis and the Gram-negative

E.coli, strains as compared to the Fe3O4 control

(Fig. 5). These results are proving that the magnetic

nanoparticles could efficiently deliver the UA to the

bacterial target suspended in the liquid culture

medium, probably due to the solubility of the obtained

nanostructures in water, preventing their aggregation

and assuring their homogenous interaction with the

bacterial target, at a higher volume to surface ratio.

The UA incorporated into the magnetic nanoparti-

cles exhibited a very significant inhibitory effect on

the biofilm formed by the Gram-positive bacterial

strains (Figs. 6, 7), on a wide range of concentrations,

while in case of the Gram-negative microbial strains

(Figs. 8, 9), the UA-loaded nanoparticles inhibited the

E. coli biofilm development, only at the two highest

tested concentration, i.e., 1,000 and 500 lg/mL. In our

previous studies, we have demonstrated that UA

selectively inhibited biofilm development by Gram-

positive bacteria and expression of hemolytic proper-

ties of the strains isolated from dental plaque, dem-

onstrating its interference with the intra- and inter-

species signaling mechanisms based on quorum

sensing and response especially in Gram-positive

microorganisms. The growth rate of the isolated

strains was changed after contact with UA, by

extension of the lag phase to 6–10 h (this time interval

being considered as the persistence time of

Fig. 2 FT-IR spectra of UA and Fe3O4@UA


123

antimicrobial activity) and by a significant decrease of

the viable cell number and prolongation of the

generation time. At the same time, it was observed

that UA could induce the change of the Gram-staining

properties of the isolated strains, probably by affecting

the cell wall structure (Sousa et al. 2011).

Fig. 3 TGA of Fe3O4 and Fe3O4@UA

Fig. 4 TEM images (a,b), SAED (c) pattern, and EDS (d) spectrum of fabricated water-dispersible Fe3O4@UA


123

In case of E. faecalis, as well as S. aureus strains,

the Fe3O4@UA nanoparticles exhibited an inhibitory

effect on biofilm development from 1,000 to 7.8125,

and to 15.6 lg/mL, respectively, demonstrating that

the loading of UA into magnetic nanoparticles assures

an improved delivery of the active compound to the

bacterial target, even when it grows in biofilm; the

efficiency of the UA being similar against planktonic

and adherent Gram-positive bacterial strains (Figs. 6,

7). This aspect could be very important, having in view

that generally, the biofilm is leading to a protected

environment against adverse conditions and the host’s

defenses, the sessile bacterial cells becoming more

resistant to traditional antibiotic doses effective on

Fig. 5 The graphic representation of the MIC of Fe3O4@UA versus Fe3O4 against different bacterial strains

Fig. 6 The graphic representation of E. faecalis biofilm development in the presence of different concentrations of Fe3O4@UA

Fig. 7 The graphic representation of S. aureus biofilm development in the presence of different concentrations of Fe3O4@UA


123

planktonic cells, the MIC and minimal bactericidal

concentration (MBC) of antibiotics to biofilm-grow-

ing bacteria being up to 100–1,000-fold higher than for

planktonic bacteria, and possibly 150–3,000 times

more resistant to disinfectants (Mah and O’Toole

2001; Patel 2005; Paraje 2011). There are few studies

reporting the efficiency of UA against Gram-negative

bacterial strains, such as Y. enterocolitica (Ghione

et al. 1988). However, the majority of other similar

studies are stating that (?)UA is not active against E.

coli and P. aeruginosa strains (Lauterwein et al. 1995;

Tay et al. 2004). The lack of any inhibitory effect on P.

aeruginosa biofilms (Fig. 8) observed in our work

comes into agreement with other studies, demonstrat-

ing that P. aeruginosa biofilm did form on UA-coated

polymer, although its morphology differed from the

biofilm formed on untreated polymer, leading the

authors to suggest that signaling pathways within the

biofilm may have been also perturbed in Gram-

negative bacterial strains (Martinez and Casadevall

2005). Furthermore, more research is needed to

investigate the in vitro antibacterial activity and the

mechanism of action of usnic acid, in order to allow

the design of appropriate nanocarriers for the improve-

ment of its activity against the planktonic and sessile

Gram-negative strains.

Conclusions

New water-dispersible Fe3O4@UA nanostructures with

uniform size and morphology were fabricated and

characterized by TEM, XRD, TGA, and FT-IR. The

obtained results demonstrate that the new water-

dispersible Fe3O4@UA nanosystem exhibits efficient

antimicrobial activity against planktonic and adherent

cells, especially on Gram-positive strains. The obtained

nanosystem is successfully combining the advantages of

Fig. 8 The graphic representation of P. aeruginosa biofilm development in the presence of different concentrations of Fe3O4@UA

Fig. 9 The graphic representation of E. coli biofilm development in the presence of different concentrations of Fe3O4@UA


123

the intrinsic antimicrobial features of the usnic acid with

the higher surface to volume ratio provided by the

magnetic nanocarrier dispersible in water, and thus

homogenously distributed into solution, facilitating the

interaction between the functionalized nanoparticles

and the bacterial cell surface, and thus the improved

release of the active natural compound.

Acknowledgments This paper is supported by the Sectoral

Operational Programme Human Resources Development,

financed from the European Social Fund, and by the Romanian

Government under the contract number POSDRU/86/1.2/S/

58146 (MASTERMAT).

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