Many bacterial infections in humans and animals are caused by bacteria residing in biofilms, complex communities of attached organisms embedded in an extracellular matrix. One of the key properties of microorganisms residing in a biofilm is decreased susceptibility towards antimicrobial agents. This decreased susceptibility, together with conventional mechanisms leading to antimicrobial resistance, makes biofilm-related infections increasingly difficult to treat and alternative antibiofilm strategies are urgently required. In this review, we present three such strategies to combat biofilm-related infections with the important human pathogen Staphylococcus aureus: (i) targeting the bacterial communication system with quorum sensing (QS) inhibitors, (ii) a ‘Trojan Horse’ strategy to disturb iron metabolism by using gallium-based therapeutics and (iii) the use of ‘non-antibiotics’ with antibiofilm activity identified through screening of repurposing libraries.

Introduction

The term ‘biofilms’ was first introduced by Costerton et al. [1] in 1978: although bacteria are single-celled organisms, they can organize themselves in complex sessile multicellular consortia, known as biofilms. Biofilms are formed everywhere: in industrial settings, in natural environments and in the human body. Bacterial cells residing in biofilms are attached to each other or to a surface and they are embedded in a matrix of extracellular polymeric substances [2,3]. Biofilm cells are phenotypically different from their planktonic counterparts because growth rate and gene transcription are altered [4]. Biofilm formation is a complex developmental process and adhesion, proliferation and detachment are the three major steps in biofilm formation [5]. The process is dynamic and starts with planktonic bacteria that attach reversibly to a surface. Pili, flagella, receptors or other adhesive surface appendages make contact with biotic or abiotic surfaces. Adhesion is followed by the secretion of extracellular polymeric substances resulting in an irreversible attachment. Subsequently, cells proliferate resulting in the formation of microcolonies. The biofilm grows and cells differentiate, resulting in a mature biofilm with multi-layered cell clusters. Finally, cells disperse from the biofilm and can form biofilms elsewhere [2,3,6,7]. Quorum sensing (QS), or cell-to-cell signalling, plays an important role in the development of the biofilm [8,9].

It is generally accepted that sessile microorganisms, i.e. microorganisms residing in a biofilm show decreased susceptibility towards antimicrobial agents. This is due to a decreased penetration of antibiotics, a decreased growth rate of the biofilm cells and/or a decreased metabolism of bacterial cells in biofilms. In addition, the presence of highly specialized survivor cells (so-called persister cells) and the expression of biofilm-specific resistance genes (including specific efflux pumps) contribute to this tolerance [1013]. Because of these biofilm-specific resistance and tolerance mechanisms, combined with the emergence of methicillin resistant, vancomycin intermediate resistance and vancomycin resistant Staphylococcus aureus strains (MRSA, VISA and VRSA respectively) [14,15], treatment of S. aureus infections has become increasingly difficult and alternative antibiofilm strategies are urgently required.

In the present review, we will highlight three such alternative strategies. A first alternative approach is targeting the bacterial communication system. QS is a process by which bacteria produce and detect signal molecules in a cell density dependent way, and as QS plays an important role in bacterial biofilm formation and resistance, QS inhibitors (QSIs) are promising antibiofilm agents, either alone or as potentiators of conventional antibiotics [1618]. In the second section, we will discuss the use of gallium-based therapeutics to combat S. aureus biofilm infections. The similarity between gallium and iron allows using a ‘Trojan Horse’ strategy to disturb iron metabolism, making gallium containing compounds interesting novel antimicrobial agents [19,20]. Finally, we will highlight the potential of ‘repurposing’ approaches, in which libraries of known and approved drugs are screened to identify novel compounds with antibiofilm activity and/or potentiating activity towards antibiotics [2123].

The approaches highlighted are by no means the only ones being explored to tackle the problem of microbial biofilms. Other approaches not discussed here include the use of bacteriophages, bacteriophage-derived enzymes, nanoparticles (including silver, lipid and polymer nanoparticles), surfactant-based carriers, matrix degrading enzymes like dispersin B, and the reader is referred to several recent articles on these topics for more information [2428].

The use of quorum sensing inhibitors to tackle S. aureus biofilms

As far back as 1998, Davies et al. [8] showed that QS in Pseudomonas aeruginosa is important for biofilm formation, as a QS defective mutant formed flat and undifferentiated biofilms, in contrast with the wild-type. In 2005, it was shown that if QS was blocked in P. aeruginosa (either by knocking out the relevant genes or by using QSI), biofilms formed by this organisms became more sensitive to tobramycin and H2O2 [29]. It was later shown that QSI can ‘potentiate’ the activity of antibiotics against various bacterial biofilms, in different model systems [16,30].

Hamamelitannin (HAM) is a QSI able to potentiate the activity of vancomycin against S. aureus biofilms [16]. HAM targets the S. aureus TraP QS system and its effect on biofilm susceptibility is (at least partially) due to an effect on the cell wall thickness and release of extracellular DNA (eDNA) [31]. While treatment of S. aureus biofilms with vancomycin typically results in thickening of the cell wall and release of eDNA, these defence mechanisms are down-regulated upon addition of HAM. At the molecular level, this can be explained by the differential expression of genes involved in biosynthesis of peptidoglycan and peptidoglycan precursors (including genes involved in synthesis of L-lysine and glucosamine-6-phosphate) and regulators of autolysis, like lytS [31].

Despite its activity, HAM is not an ideal drug-candidate, as it demonstrates several undesirable properties, including a high number of hydroxyl functions leading to high polarity, an aromatic hydroxyl function making the molecule oxidation- and glucuronidation-sensitive and metabolically unstable ester linkers (Figure 1) [32]. To obtain more active derivatives with more drug-like properties, an extensive structure–activity relationship study was set up and several compounds with high in vitro and in vivo activity were identified (Figure 1) [32,33]. Several of these highly active compounds showed excellent metabolic stability and lacked toxicity in MRC-5 lung fibroblast cells, making them prime candidates for testing in more advanced models [32].

Chemical structure of HAM (top) and two more active derivatives

Figure 1
Chemical structure of HAM (top) and two more active derivatives

Table shows some key properties of HAM. The EC50 values shown are the concentrations needed to double the effect of vancomycin in vitro.

Figure 1
Chemical structure of HAM (top) and two more active derivatives

Table shows some key properties of HAM. The EC50 values shown are the concentrations needed to double the effect of vancomycin in vitro.

Combatting S. aureus biofilm infections with gallium-based therapeutics

The underlying rationale of gallium-based therapeutics lies in disrupting bacterial iron metabolism. Iron plays a crucial role in cellular processes, including DNA synthesis, respiration, energy production, for the protection against reactive oxygen species (ROS) and for biofilm formation [20,34], which depends on iron levels higher than needed for vegetative growth [35]. The most abundant iron source in the human body is haem (iron protoporphyrin IX) as part of haemoglobin inside erythrocytes (Figure 2) [3638] and this is the preferred iron source for S. aureus that is equipped with various systems, such as the iron-regulated surface determinant system, to sequester iron/haem from the host [38,39]. Once inside bacteria, iron is liberated from haem to be utilized for cellular processes or stored to foster bacterial survival and virulence, while excess iron/haem and their toxic metabolites are removed via efflux pumps [20,39].

Structural similarities between haem and gallium–protoporphyrin that is able to mimic haem as iron source

Figure 2
Structural similarities between haem and gallium–protoporphyrin that is able to mimic haem as iron source
Figure 2
Structural similarities between haem and gallium–protoporphyrin that is able to mimic haem as iron source

Bacterial iron metabolism as therapeutic target

As virtually all pathogens rely on iron for growth and virulence, bacterial iron metabolism represents a target for medical intervention strategies. Gallium and iron are two very similar elements and gallium can be utilized as iron analogue [40]. By following a ‘Trojan Horse’ strategy, gallium containing compounds exploit bacterial iron acquisition systems for internal uptake or penetrate through the bacterial cell wall [19,20]. On a cellular level, gallium competes with iron and interferes with its absorption, metabolism and activity, thereby disrupting vital iron-dependent processes [19]. Most importantly gallium is unable to transfer electrons and cannot induce redox reactions, thereby impeding respiration, DNA synthesis and bacterial proliferation and generating ROS [41,42]. Development of resistance against gallium is unlikely because if bacteria down-regulate receptors to reduce the binding and uptake of gallium, the uptake of iron would also be reduced [43,44].

Gallium therapeutics

Gallium can be delivered as simple salt or complex/conjugate with other molecules. Substantial antimicrobial effects were shown against various pathogens in vitro and in vivo, however, the antibiofilm activity appears to be species and strain dependent [4550].

Gallium nitrate [Ga(NO3)3] is a salt whose pharmacokinetic profile and low-to-moderate toxicity are already known in humans [51]. Ga(NO3)3 is mainly excreted by the kidneys and can potentially cause nephrotoxicity; however, in a clinical phase I trial this was dependent on the dose, treatment duration and the way Ga(NO3)3 was delivered [51]. It was shown that renal toxicity can be reduced by a low drug dosage and longer infusion times. Apart from that, Ga(NO3)3 was shown to exhibit antibiofilm activity against S. aureus [52]. It was reported that it is antibacterial even against stationary phase bacteria, which are usually found in the centre of biofilms and which frequently show reduced susceptibility to antibiotics [45]. Another salt, gallium maltolate was reported to exhibit antimicrobial activity in a mouse model for burn wound infections, showing higher efficacy than Ga(NO3)3 and preventing the systemic spreading of P. aeruginosa. In the same model, a substantially reduced wound colonization of S. aureus was also demonstrated [53]. While the in vitro and in vivo antimicrobial activity of gallium salts are interesting to note, their administration is challenging. After oral intake, gallium forms poorly soluble precipitates in the gastrointestinal tract limiting the bioavailability and antimicrobial activity in humans [40]. Complexes like gallium citrate offer improved stability [54]. Several in vitro studies showed broad antibacterial and antibiofilm activity of gallium citrate against Gram-positive and Gram-negative bacteria, as well as low drug resistance [19,48], and it was shown to impair biofilm formation on wound dressings and soft tissue in vivo, thereby improving wound healing [49]. Siderophore–gallium complexes are another strategy to introduce gallium to bacteria. Siderophores are small molecules released by bacteria under iron limitation to sequester iron outside bacteria for internal uptake. Staphyloferrin A, a siderophore produced by S. aureus, was synthesized and loaded with gallium. This complex, however, failed to exhibit antimicrobial effects against MRSA [19].

Other gallium complexes with antimicrobial properties include synthetic haem analogues [5557]. Being most similar to haem, gallium–protoporphyrin IX (GaPP, Figure 2) demonstrated strong activity against MRSA [5860]. S. aureus is known to favour haem as preferred nutrient source [38] and is equipped with more active haem uptake systems than siderophore-based systems, facilitating the use of haem analogues like GaPP [61]. However, GaPP’s low water solubility and modest dose-depending toxicity pose challenges for its applicability as therapeutic drug [59,62]. Cytotoxicity studies in human bronchial epithelial cells and murine fibroblasts showed no toxicity of GaPP at concentrations of up to 500 and 1000 μg/ml respectively [63], and GaPP used in a mouse model also showed no toxicity [59]. There is potential for the development of synthetic gallium complexes with improved aqueous solubility and potency, and for incorporation of gallium into smart drug-delivery systems that overcome solubility and toxicity concerns.

Combination therapies with gallium

A multi-pronged approach using compounds with different modes of action offers the potential of additive or synergistic antimicrobial effects, while possibly reducing the risk for emerging resistance compared with monotherapy. As an example, by first starving bacteria with the iron chelator deferiprone (Def) and simultaneously introducing the haem-analogue GaPP as iron mimic, a significant antibiofilm activity was shown against S. aureus and MRSA [63]. In addition, certain gallium compounds have the ability to potentiate antibiotics and combining antimicrobial compounds with gallium may lead to promising antibiofilm strategies [64].

Repurposing as a novel approach to find compounds active against S. aureus biofilms

What is drug repurposing?

The use of drugs (either drug candidates, abandoned drugs, approved drugs or withdrawn drugs) to treat a disease for which they were initially not developed for is called drug repurposing or repositioning [2123]. The main advantages of drug repurposing over de novo drug development are reduced time and costs in the R&D process, as knowledge concerning safety and pharmacology are available for the repurposing candidates [65]. For lack of a better name, drugs in use for non-bacteriological indications but with antibacterial activity are in literature often called ‘non-antibiotic drugs’ or ‘non-antibiotics’ [66]. These compounds might possess a direct antibacterial activity and/or enhance the activity of existing antibiotics by increasing the susceptibility of the bacteria towards the antibiotics, e.g. by controlling efflux pumps. In addition, they might also affect the pathogenicity of bacteria (virulence inhibitors) [67] or interfere with the host resulting in an improved pathogen clearance [68,69]. Several drug classes (e.g. antihistamines, local anesthetics, anti-hypertensive drugs, tranquilizers, statins and anti-inflammatory drugs) are known to possess antibacterial activity, although they were not developed to treat bacterial infections [67,7072]. In the next paragraphs, we will discuss the activity of some of these non-antibiotics against S. aureus biofilms.

Terfenadine

Jacobs et al. [73] screened the Prestwick Chemical Library for antimicrobial agents active against planktonic S. aureus; to this end they developed an adenylate kinase assay that identifies compounds that disrupt cellular integrity. Following their initial screen, they evaluated the activity of one hit compound, i.e. the antihistamine terfenadine, for activity against biofilms formed by S. aureus UAMS1 (an osteomyelitis clinical isolate). Treatment with terfenadine at 10× MIC resulted in a 2.7-fold increase in adenylate kinase release, corresponding to a 1.1-log reduction in biofilm cell viability. However, treating S. aureus infected Galleria mellonella larvae with terfenadine did not increase the latter’s survival [73]. More recently, 84 terfenadine-based analogues were synthesized and evaluated for activity towards S. aureus planktonic cells. Two compounds had lower MIC in comparison with terfenadine, also against other Gram-positive pathogens but their antibiofilm activity has not yet been evaluated [74].

Antibacterial and antibiofilm activity of niclosamide and analogues

In another comprehensive screening using the same Prestwick Chemical Library, activity was evaluated by measuring inhibition of growth of planktonic S. aureus TCH1516; the screen resulted in the identification of 104 hits, most of them belonging to the group of antimicrobials and antiseptics. However, 18 non-antibiotic drugs were also identified and 9 of these hit compounds were evaluated for activity against S. aureus biofilms [75]. Three of these showed modest activity, including the anthelmintic niclosamide that caused a reduction in the number of culturable S. aureus cells of 1–2 log [75]. Rajamuthiah et al. [76] investigated the activity of niclosamide and another salicylanilide anthelmintic drug, oxyclozanide against planktonic grown ESKAPE pathogens (Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa and Enterobacter species) [76]. MICs against multiple S. aureus isolates ranged between 0.0625 and 0.5 μg/ml for niclosamide and between 0.5 and 2 μg/ml for oxyclozanide. These two compounds were also found to prolong survival of C. elegans infected with S. aureus MW2, with a similar effect as treatment with vancomycin. A third salicylanilide anthelmintic drug closantel was identified as a hit compound in a screen of the Biomol 4 compound library (containing 640 FDA-approved drugs) using a C. elegansS. aureus infection assay [77]. In this assay, C. elegans was infected with S. aureus MW2 BAA-1707 and treated with the library compounds in 384-well MTPs for 5 days. Next, Sytox Orange, a dye that stains death larvae, was added to the wells and an automated microscope was used the next day to generate both transmitted light and fluorescent images enabling the calculation of the number of surviving C. elegans. Using this approach, almost all antibiotics present in the library were identified as hits, as well as ten anticancer drugs, an antiviral drug, an antifungal, an antiarthritic drug, a non-steroidal estrogen and closantel. Although closantel turned out to have low MICs against several antibiotic-resistant S. aureus strains, the number of S. aureus cells in the infection assay using C. elegans was not reduced upon closantel exposure. It is thus possible that closantel targets bacterial virulence rather than survival, and/or has a direct effect on C. elegans [77].

Antibacterial and antibiofilm activity of 5-fluorouracil and analogues

5-fluorouracil is an antimetabolite widely used in treatment of cancers [78]. Activity against biofilms was reported in 1992, as sub-MIC levels of 5-fluorouracil diminished biofilm formation of S. epidermidis [78,79]. Later, carmofur (1-hexylcarbamoyl-5-fluorouracil) was identified as a hit in the primary screen against planktonic cells of S. aureus and showed antibiofilm activity in a secondary screen [75]. Recently, 5-fluorouracil and 5-fluoro-2'-deoxyfluridine, another fluoropyrimidine, were identified in a screen against planktonic S. aureus USA300 and activity of 5-fluoro-2'-deoxyfluridine was confirmed in a septicemic MRSA mice infection model with concentrations much lower than the concentrations therapeutically used for cancer treatment, and thus with reduced toxicity [80]. The usefulness of 5-fluorouracil has been demonstrated in human clinical trials in which central venous catheters externally coated with 5-fluorouracil scored better in preventing catheter colonization than the control catheters coated with silver sulfadiazine or chlorhexidine [78].

Statins

Statins have been described for antibacterial effects by several research groups [72]. Simvastatin at 1/16× MIC up to 4× MIC (62.5 μg/ml) significantly inhibited biofilm formation and at 4× MIC it significantly reduced the number of CFU/ml in mature biofilms of S. aureus ATCC 29213 [81,82]. Simvastatin was found to be able to disrupt S. aureus and S. epidermidis biofilms and its potency was higher than that of linezolid or vancomycin: at 2× and 4× MIC of simvastatin, the biofilm mass (as measured by Crystal Violet staining) was reduced by 40%, while 64 and 128× MIC of linezolid or vancomycin reduced biofilm mass by only 10% [83].

Repurposing candidates with potentiator activity

The combination of antibiotics with non-antibiotic drugs as potentiators could be a valuable approach to overcome antibacterial drug resistance [8486]. Combination therapy might result in a broader spectrum of drug activity, synergy, a more rapid effect and the use of reduced drug concentrations [87]. In a screening with 1059 previously approved drugs against planktonic P. aeruginosa PAO1, E. coli BW25113 and S. aureus ATCC 29213 in the presence of minocycline, 6, 41 and 35 hits respectively, were identified. These hits were non-antibiotic drugs that synergized with minocycline but had never been used clinically to treat bacterial infections [88]. Disulfiram was one of the hits against S. aureus: alone, disulfiram has only weak antibacterial activity but it improved the activity of minocycline in a synergistic way against several MRSA strains, including MRSA USA300.

Ooi et al. [89] evaluated the antibiofilm activity of 15 redox-active compounds that have been safely used in humans for several applications (healthcare, cosmetics and consumption) and of which antibacterial activity had been described previously, but not against S. aureus planktonic cells and biofilms. All compounds tested were active against planktonic cells (MICs between 0.25 and 128 mg/l) and seven compounds (i.e. AO 2246, bakuchiol, benzoyl peroxide, carnosic acid, celastrol, nordihydroguaiaretic acid and totarol) were able to eradicate established biofilms of S. aureus SH1000 at concentrations ≤256 mg/l [89]. Moreover, celastrol and nordihydroguaiaretic acid synergized the activity of gentamicin against S. aureus SH1000 biofilms [89]. As both compounds did not cause irritation in a human living skin equivalent model, they might be valuable potentiators to treat superficial skin infections caused by S. aureus biofilms [89].

We recently screened the NIH Clinical Collection 1&2 against S. aureus Mu50 biofilms, formed in 96-well MTP [90]. The screening was performed in the presence of vancomycin and resulted in the identification of 25 hit compounds that potentiated the activity of the antibiotic. Among these hits, we identified the disinfectants triclosan and hexachlorophene, the antiviral drug efavirenz and the antifungal imidazole drugs miconazole, econazole and oxiconazole. Antifungal imidazoles are known for activity against planktonic S. aureus for decades and perform activity by membrane damage and binding to flavohaemoglobins [91,92]. In addition, two anthracyclines, three selective estrogen receptor modulators, flutamide, oxymetholone, amiodarone, carvedilol, honokiol, loxoprofen, MK 886, 5-nonyloxytryptamide and ethacrynic acid were identified as well in our screen. Antibacterial activity of some of these hits had been reported before, e.g. for honokiol [93,94], MK-886 and 5-nonyloxytryptamine [80], but for most of the hits there were no previous indications for potential use as an anti-infective. Also four antipsychotic phenothiazine drugs (fluphenazine, perphenazine, thioridazine and trifluoperazine) and the antidepressant sertraline were hits. Anti-staphylococcal activity had been reported before for these compounds, both in vitro [95] and in vivo [96,97], but activity against biofilm was not investigated before. We showed that thioridazine enhances the activity of tobramycin, flucloxacillin and linezolid against in vitro grown S. aureus Mu50 biofilms (>1 log additional reduction in CFU/biofilm). Unfortunately, we were unable to confirm this activity in a biofilm model for chronic wounds.

Concluding remarks

The growing awareness about the problems associated with antimicrobial resistance and the role biofilms play in infectious diseases has increased the interest in the development of novel approaches to treat infections. In the present review, we highlighted three such alternative approaches for treating biofilm-related S. aureus infections, i.e. QS inhibition, gallium-based therapeutics and use of repurposed drugs.

While these approaches often appear very promising in early studies, there is a long road ahead of us before these compounds will make it to the market. For example, although gallium compounds show antimicrobial and antibiofilm activity against various bacteria, they have not found their way into clinical practice. There are two FDA approved gallium formulations on the market that are used as diagnostic agents in cancer therapy. The formulation Ganite (a gallium nitrate-citrate injection for cancer-related hypercalcaemia, FDA approved from 2003 to 2014) showed antimicrobial activity in vitro, however, this effect appeared species and strain dependent. Concentrations higher than the recommended dose would be required for a broad antibiofilm effect, raising toxicity concerns [62]. In addition, it is worth stressing that promising results in in vitro tests are no guarantee for success in more advanced biofilm models and/or in vivo studies as the work with repurposing libraries has shown [86,98].

Despite these pitfalls, at least some of the approaches outlined above have considerable potential for the treatment of various biofilm-related infections. For example, HAM and a more potent derivative showed high potentiating activity in a mouse model for S. aureus mastitis [31,32]. By using an in vitro wound biofilm model, we could demonstrate that it is feasible to load wound care dressings with cyclodextrin–HAM complexes to increase the effect of antibiotics [99], opening the road towards further pharmaceutical developments. Finally, an exciting option is combining several of the novel approaches outlined above. For example, we have recently observed that the combination of Def, GaPP and HAM exceeded the antibiofilm activity of the individual compounds and the antibiotic control against S. aureus (Richter and Coenye, unpublished data), indicating that such combinations may lead to increased antibiofilm activity.

Summary

  • Biofilm formation contributes to the growing problem of reduced susceptibility to antimicrobial agents; this reduced susceptibility is multifactorial and is partially mediated by quorum sensing (QS).

  • There is an urgent need for alternative approaches to treat biofilm-related infections. Examples of such alternative approaches that have been explored to combat S. aureus biofilm infections are QS inhibition, gallium-based therapeutics and identification of potentiators from repurposing libraries.

  • Hamamelitannin and analogs inhibit QS in S. aureus and by doing so increase the susceptibility of S. aureus biofilms to antibiotics.

  • Gallium compounds exhibit antibiofilm activity by exploiting bacterial iron acquisition systems and disrupting cellular processes vital for bacterial growth, survival and pathogenesis.

  • Repurposing libraries contain a fair number of ‘non-antibiotics’ with antimicrobial activity against S. aureus biofilms (including statins and 5-fluorouracil) as well as potentiators (including phenothiazines and imidazoles).

  • Despite difficulties of translating results from in vitro to in vivo, some of the approaches outlined (or combinations thereof) seem to hold promise for future treatment of S. aureus biofilm-related infections.

Competing interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • CFU

    colony forming unit

  •  
  • Def

    deferiprone

  •  
  • eDNA

    extracellular DNA

  •  
  • GaPP

    gallium–protoporphyrin IX

  •  
  • HAM

    hamamelitannin

  •  
  • MIC

    minimum inhibitory concentration

  •  
  • MRSA

    methicillin resistant Staphylococcus aureus

  •  
  • MTP

    microtiterplate

  •  
  • QS

    quorum sensing

  •  
  • QSI

    QS inhibitor

  •  
  • ROS

    reactive oxygen species

  •  
  • VISA

    vancomycin intermediate Staphylococcus aureus

  •  
  • VRSA

    vancomycin resistant Staphylococcus aureus

References

References
1
Costerton
J.W.
,
Geesey
G.G.
and
Cheng
K. J.
(
1978
)
How bacteria stick
.
Sci. Am.
238
,
86
95
2
Costerton
J.W.
,
Stewart
P.S.
and
Greenberg
E.P.
(
1999
)
Bacterial biofilms: a common cause of persistent infections
.
Science (N.Y.)
284
,
1318
1322
3
Hall-Stoodley
L.
,
Costerton
J.W.
and
Stoodley
P.
(
2004
)
Bacterial biofilms: from the natural environment to infectious diseases
.
Nat. Rev. Microbiol.
2
,
95
108
4
Coenye
T.
(
2010
)
Response of sessile cells to stress: from changes in gene expression to phenotypic adaptation
.
FEMS Immunol. Med. Microbiol.
59
,
239
252
5
Periasamy
S.
,
Joo
H.S.
,
Duong
A.C.
,
Bach
T.H.
,
Tan
V.Y.
,
Chatterjee
S.S.
et al
(
2012
)
How Staphylococcus aureus biofilms develop their characteristic structure
.
Proc. Natl. Acad. Sci. U.S.A.
109
,
1281
1286
6
Hall-Stoodley
L.
and
Stoodley
P.
(
2005
)
Biofilm formation and dispersal and the transmission of human pathogens
.
Trends Microbiol.
13
,
7
10
7
Flemming
H.C.
and
Wingender
J.
(
2010
)
The biofilm matrix
.
Nat. Rev. Microbiol.
8
,
623
633
8
Davies
D.G.
,
Parsek
M.R.
,
Pearson
J.P.
,
Iglewski
B.H.
,
Costerton
J.W.
and
Greenberg
E.P.
(
1998
)
The involvement of cell-to-cell signals in the development of a bacterial biofilm
.
Science (N.Y.)
280
,
295
298
9
Parsek
M.R.
and
Greenberg
E.P.
(
2005
)
Sociomicrobiology: the connections between quorum sensing and biofilms
.
Trends Microbiol.
13
,
27
33
10
Fux
C.A.
,
Costerton
J.W.
,
Stewart
P.S.
and
Stoodley
P.
(
2005
)
Survival strategies of infectious biofilms
.
Trends Microbiol.
13
,
34
40
11
Soto
S. M.
(
2013
)
Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm
.
Virulence
4
,
223
229
12
Van Acker
H.
,
Van Dijck
P.
and
Coenye
T.
(
2014
)
Molecular mechanisms of antimicrobial tolerance and resistance in bacterial and fungal biofilms
.
Trends Microbiol.
22
,
326
333
13
Van Acker
H.
and
Coenye
T.
(
2016
)
The role of efflux and physiological adaptation in biofilm tolerance and resistance
.
J. Biol. Chem.
291
,
12565
12572
14
Gould
I.M.
(
2013
)
Treatment of bacteraemia: meticillin-resistant Staphylococcus aureus (MRSA) to vancomycin-resistant S. aureus (VRSA)
.
Int. J. Antimicrob. Agents
42
,
S17
S21
15
Gardete
S.
and
Tomasz
A.
(
2014
)
Mechanisms of vancomycin resistance in Staphylococcus aureus
.
J. Clin. Invest.
124
,
2836
2840
16
Brackman
G.
,
Cos
P.
,
Maes
L.
,
Nelis
H.J.
and
Coenye
T.
(
2011
)
Quorum sensing inhibitors increase the susceptibility of bacterial biofilms to antibiotics in vitro and in vivo
.
Antimicrob. Agents Chemother.
55
,
2655
2661
17
Brackman
G.
and
Coenye
T.
(
2015
)
Quorum sensing inhibitors as anti-biofilm agents
.
Curr. Pharm. Des.
21
,
5
11
18
Brackman
G.
and
Coenye
T.
(
2015
)
Inhibition of quorum sensing in Staphylococcus spp
.
Curr. Pharm. Des.
21
,
2101
2108
19
Kelson
A.B.
,
Carnevali
M.
and
Truong-Le
V.
(
2013
)
Gallium-based anti-infectives targeting microbial iron-uptake mechanisms
.
Curr. Opin. Pharmacol.
13
,
707
716
20
Cassat
J.E.
and
Skaar
E.P.
(
2013
)
Iron in infection and immunity
.
Cell Host Microbe
13
,
509
519
21
Langedijk
J.
,
Mantel-Teeuwisse
A.K.
,
Slijkerman
D.S.
and
Schutjens
M.H.
(
2015
)
Drug repositioning and repurposing: terminology and definitions in literature
.
Drug Discov. Today
20
,
1027
1034
22
Matthews
H.
,
Usman-Idris
M.
,
Khan
F.
,
Read
M.
and
Nirmalan
N.
(
2013
)
Drug repositioning as a route to anti-malarial drug discovery: preliminary investigation of the in vitro anti-malarial efficacy of emetine dihydrochloride hydrate
.
Malar. J.
12
,
359
23
Ashburn
T.T.
and
Thor
K.B.
(
2004
)
Drug repositioning: identifying and developing new uses for existing drugs
.
Nat. Rev. Drug Discov.
3
,
673
683
24
Chung
P.Y.
and
Toh
Y.S.
(
2014
)
Anti-biofilm agents: recent breakthrough against multi-drug resistant Staphylococcus aureus
.
Pathog. Dis.
70
,
231
239
25
Forier
K.
,
Raemdonck
K.
,
De Smedt
S.C.
,
Demeester
J.
,
Coenye
T.
and
Braeckmans
K.
(
2014
)
Lipid and polymer nanoparticles for drug delivery to bacterial biofilms
.
J. Control. Release
190
,
607
623
26
Thomas
N.
,
Dong
D.
,
Richter
K.
,
Ramezanpour
M.
,
Vreugde
S.
,
Thierry
B.
et al
(
2015
)
Quatsomes for the treatment of Staphylococcus aureus biofilm
.
J. Mater. Chem. B
3
,
2770
2777
27
Kaplan
J.B.
(
2009
)
Therapeutic potential of biofilm-dispersing enzymes
.
Int. J. Artif. Organs
32
,
545
554
28
Chan
B.K.
and
Abedon
S.T.
(
2015
)
Bacteriophages and their enzymes in biofilm control
.
Curr. Pharm. Des.
21
,
85
99
29
Bjarnsholt
T.
,
Jensen
P.
,
Burmølle
M.
,
Hentzer
M.
,
Haagensen
J.A.J.
,
Hougen
H.
et al
(
2005
)
Pseudomonas aeruginosa tolerance to tobramycin, hydrogen peroxide and polymorphonuclear leukocytes is quorum-sensing dependent
.
Microbiology
151
,
373
383
30
Christensen
L.D.
,
van Gennip
M.
,
Jakobsen
T.H.
,
Alhede
M.
,
Hougen
H.P.
,
Høiby
N.
et al
(
2012
)
Synergistic antibacterial efficacy of early combination treatment with tobramycin and quorum-sensing inhibitors against Pseudomonas aeruginosa in an intraperitoneal foreign-body infection mouse model
.
J. Antimicrob. Chemother.
67
,
1198
1206
31
Brackman
G.
,
Breyne
K.
,
De Rycke
R.
,
Vermote
A.
,
Van Nieuwerburgh
F.
,
Meyer
E.
et al
(
2016
)
The quorum sensing inhibitor hamamelitannin increases antibiotic susceptibility of Staphylococcus aureus biofilms by affecting peptidoglycan biosynthesis and eDNA release
.
Sci. Rep.
6
,
20321
32
Vermote
A.
,
Brackman
G.
,
Risseeuw
M.D.
,
Vanhoutte
B.
,
Cos
P.
,
Van Hecke
K.
et al
(
2016
)
Hamamelitannin analogues that modulate quorum sensing as potentiators of antibiotics against Staphylococcus aureus
.
Angew. Chem. Int. Ed.
55
,
6551
6555
33
Vermote
A.
,
Brackman
G.
,
Risseeuw
M.D.
,
Coenye
T.
and
Van Calenbergh
S.
(
2016
)
Design, synthesis and biological evaluation of novel hamamelitannin analogues as potentiators for vancomycin in the treatment of biofilm related Staphylococcus aureus infections
.
Bioorg. Med. Chem.
24
,
4563
4575
34
Banin
E.
,
Vasil
M.L.
and
Greenberg
E.P.
(
2005
)
Iron and Pseudomonas aeruginosa biofilm formation
.
Proc. Natl. Acad. Sci. U.S.A.
102
,
11076
11081
35
Weinberg
E.D.
(
2009
)
Iron availability and infection
.
BBA Gen. Sub.
1790
,
600
605
36
Crichton
R.
and
Boelaert
J.R.
(
2001
)
Inorganic Biochemistry of Iron Metabolism: From Molecular Mechanisms to Clinical Consequences
.
John Wiley & Sons
,
Chichester, UK
37
Reniere
M.L.
,
Torres
V.J.
and
Skaar
E.P.
(
2007
)
Intracellular metalloporphyrin metabolism in Staphylococcus aureus
.
Biometals
20
,
333
345
38
Skaar
E.P.
,
Humayun
M.
,
Bae
T.
,
DeBord
K.L.
and
Schneewind
O.
(
2004
)
Iron-source preference of Staphylococcus aureus infections
.
Science
305
,
1626
1628
39
Mazmanian
S.K.
,
Skaar
E.P.
,
Gaspar
A.H.
,
Humayun
M.
,
Gornicki
P.
,
Jelenska
A.
et al
(
2003
)
Passage of heme-iron across the envelope of Staphylococcus aureus
.
Science
299
,
906
909
40
Bernstein
L.R.
(
1998
)
Mechanisms of therapeutic activity for gallium
.
Pharmacol. Rev.
50
,
665
682
41
Olakanmi
O.
,
Britigan
B.E.
and
Schlesinger
L.S.
(
2000
)
Gallium disrupts iron metabolism of mycobacteria residing within human macrophages
.
Infect. Immun.
68
,
5619
5627
42
Gielen
M.
and
Tiekink
E.R.
(
2005
)
Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine
.
John Wiley & Sons
,
Chichester, UK
43
Alvarez-Ortega
C.
,
Wiegand
I.
,
Olivares
J.
,
Hancock
R.E.
and
Martínez
J. L.
(
2011
)
The intrinsic resistome of Pseudomonas aeruginosa to β-lactams
.
Virulence
2
,
144
146
44
Costa
S.S.
,
Viveiros
M.
,
Amaral
L.
and
Couto
I.
(
2013
)
Multidrug efflux pumps in Staphylococcus aureus: an update
.
Open Microbiol. J.
7
,
59
71
45
Kaneko
Y.
,
Thoendel
M.
,
Olakanmi
O.
,
Britigan
B.E.
and
Singh
P.K.
(
2007
)
The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity
.
J. Clin. Invest.
117
,
877
888
46
Peeters
E.
,
Nelis
H.J.
and
Coenye
T.
(
2008
)
Resistance of planktonic and biofilm-grown Burkholderia cepacia complex isolates to the transition metal gallium
.
J. Antimicrob. Chemother.
61
,
1062
1065
47
Banin
E.
,
Lozinski
A.
,
Brady
K.M.
,
Berenshtein
E.
,
Butterfield
P.W.
,
Moshe
M.
et al
(
2008
)
The potential of desferrioxamine-gallium as an anti-Pseudomonas therapeutic agent
.
Proc. Natl. Acad. Sci. U.S.A.
105
,
16761
16766
48
Rzhepishevska
O.
,
Ekstrand-Hammarstörm
B.
,
Popp
M.
,
Björn
E.
,
Bucht
A.
,
Sjöstedt
A.
et al
(
2011
)
The antibacterial activity of Ga3+ is influenced by ligand complexation as well as the bacterial carbon source
.
Antimicrob. Agents Chemother.
55
,
5568
5580
49
Thompson
M.G.
,
Truong-Le
V.
,
Alamneh
Y.A.
,
Black
C.C.
,
Anderl
J.
,
Honnold
C.L.
et al
(
2015
)
Evaluation of gallium citrate formulations against a multidrug-resistant strain of Klebsiella pneumoniae in a murine wound model of infection
.
Antimicrob. Agents Chemother.
59
,
6484
6493
50
de Léséleuc
L.
,
Harris
G.
,
KuoLee
R.
,
Xu
H.H.
and
Chen
W.
(
2014
)
Serum resistance, gallium nitrate tolerance and extrapulmonary dissemination are linked to heme consumption in a bacteremic strain of Acinetobacter baumannii
.
Int. J. Med. Microbiol.
304
,
360
369
51
Kelsen
D.P.
,
Alcock
N.
,
Yeh
S.
,
Brown
J.
and
Young
C.
(
1980
)
Pharmacokinetics of gallium nitrate in man
.
Cancer
46
,
2009
2013
52
Garcia
R.A.
,
Tennent
D.J.
,
Chang
D.
,
Wenke
J.C.
and
Sanchez
C.J.
(
2016
)
An in vitro comparison of PMMA and calcium sulfate as carriers for the local delivery of gallium (III) nitrate to Staphylococcal infected surgical sites
.
BioMed Res. Int.
2016
,
2016:7078989
,
53
DeLeon
K.
,
Balldin
F.
,
Watters
C.
,
Hamood
A.
,
Giswold
J.
,
Sreedharan
S.
et al
(
2009
)
Gallium maltolate treatment eradicates Pseudomonas aeruginosa infection in thermally injured mice
.
Antimicrob. Agents Chemother.
3
,
1331
1337
54
Krieg
S.
,
Huché
F.
,
Diederichs
K.
,
Izadi-Pruneyre
N.
,
Lecroisey
A.
,
Wandersman
C.
et al
(
2009
)
Heme uptake across the outer membrane as revealed by crystal structures of the receptor–hemophore complex
.
Proc. Natl. Acad. Sci. U.S.A.
106
,
1045
1050
55
Olczak
T.
,
Maszczak-Seneczko
D.
,
Smalley
J.W.
and
Olczak
M.
(
2012
)
Gallium(III), cobalt(III) and copper(II) protoporphyrin IX exhibit antimicrobial activity against Porphyromonas gingivalis by reducing planktonic and biofilm growth and invasion of host epithelial cells
.
Arch. Microbiol.
194
,
719
724
56
Stojiljkovic
I.
,
Evavold
B.D.
and
Kumar
V.
(
2001
)
Antimicrobial properties of porphyrins
.
Expert Opin. Investig. Drugs
10
,
309
320
57
Moriwaki
Y.
,
Caaveiro
J.M.
,
Tanaka
Y.
,
Tsutsumi
H.
,
Hamachi
I.
and
Tsumoto
K.
(
2011
)
Molecular basis of recognition of antibacterial porphyrins by heme-transporter IsdH-NEAT3 of Staphylococcus aureus
.
Biochemistry
50
,
7311
7320
58
Abdalla
M.Y.
,
Switzer
B.L.
,
Goss
C.H.
,
Aitken
M.L.
,
Singh
P.K.
and
Britigan
B.E.
(
2015
)
Gallium compounds exhibit potential as new therapeutic agents against Mycobacterium abscessus
.
Antimicrob. Agents Chemother.
59
,
4826
4834
59
Stojiljkovic
I.
,
Kumar
V.
and
Srinivasan
N.
(
1999
)
Non-iron metalloporphyrins: potent antibacterial compounds that exploit haem/Hb uptake systems of pathogenic bacteria
.
Mol. Microbiol.
31
,
429
442
60
Begum
K.
,
Kim
H.-S.
,
Kumar
V.
,
Stojiljkovic
I.
and
Wataya
Y.
(
2003
)
In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum
.
Parasitol. Res.
90
,
221
224
61
Hammer
N.D.
and
Skaar
E.P.
(
2011
)
Molecular mechanisms of Staphylococcus aureus iron acquisition
.
Annu. Rev. Microbiol.
65
,
129
147
62
Chang
D.
,
Garcia
R.A.
,
Akers
K.S.
,
Mende
K.
,
Murray
C.K.
,
Wenke
J.C.
et al
(
2016
)
Activity of gallium meso-and protoporphyrin IX against biofilms of multidrug-resistant Acinetobacter baumannii isolates
.
Pharmaceuticals
9
,
9:E16
,
63
Richter
K.
,
Ramezanpour
M.
,
Thomas
N.
,
Prestidge
C.A.
,
Wormald
P.J.
and
Vreugde
S.
(
2016
)
Mind “De GaPP”: in vitro efficacy of deferiprone and gallium-protoporphyrin against Staphylococcus aureus biofilms
.
Int. Forum Allergy Rhinol.
6
,
737
743
64
Halwani
M.
,
Yebio
B.
,
Suntres
Z.E.
,
Alipour
M.
,
Azghani
A.O.
and
Omri
A.
(
2008
)
Co-encapsulation of gallium with gentamicin in liposomes enhances antimicrobial activity of gentamicin against Pseudomonas aeruginosa
.
J. Antimicrob. Chemother.
62
,
1291
1297
65
Imperi
F.
,
Massai
F.
,
Pillai
C.R.
,
Longo
F.
,
Zennaro
E.
,
Rampioni
G.
et al
(
2013
)
New life for an old drug: the anthelmintic drug niclosamide inhibits Pseudomonas aeruginosa quorum sensing
.
Antimicrob. Agents Chemother.
57
,
996
1005
66
Martins
M.
,
Dastidar
S.G.
,
Fanning
S.
,
Kristiansen
J.E.
,
Molnar
J.
,
Pagès
J.M.
et al
(
2008
)
Potential role of non-antibiotics (helper compounds) in the treatment of multidrug-resistant Gram-negative infections: mechanisms for their direct and indirect activities
.
Int. J. Antimicrob. Agents
31
,
198
208
67
Munoz-Bellido
J.L.
,
Munoz-Criado
S.
and
Garcia-Rodriguez
J.A.
(
2000
)
Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors
.
Int. J. Antimicrob. Agents
14
,
177
180
68
Andersson
J.A.
,
Fitts
E.C.
,
Kirtley
M.L.
,
Ponnusamy
D.
,
Peniche
A.G.
,
Dann
S.M.
et al
(
2016
)
New role for FDA-approved drugs in combating antibiotic-resistant bacteria
.
Antimicrob. Agents Chemother.
60
,
3717
3729
69
Mazumdar
K.
,
Asok Kumar
K.
and
Dutta
N. K.
(
2010
)
Potential role of the cardiovascular non-antibiotic (helper compound) amlodipine in the treatment of microbial infections: scope and hope for the future
.
Int. J. Antimicrob. Agents
36
,
295
302
70
Worthington
R.J.
and
Melander
C.
(
2013
)
Combination approaches to combat multidrug-resistant bacteria
.
Trends Biotechnol.
31
,
177
184
71
Johnson
S.M.
,
Saint John
B.E.
and
Dine
A.P.
(
2008
)
Local anesthetics as antimicrobial agents: a review
.
Surg. Infect. (Larchmt)
9
,
205
213
72
Hennessy
E.
,
Adams
C.
,
Reen
F.J.
and
O’Gara
F.
(
2016
)
Is there potential for repurposing statins as novel antimicrobials?
Antimicrob. Agents Chemother.
60
,
5111
5121
73
Jacobs
A.C.
,
DiDone
L.
,
Jobson
J.
,
Sofia
M.K.
,
Krysan
D.
and
Dunman
P.M.
(
2013
)
Adenylate kinase release as a high-throughput-screening-compatible reporter of bacterial lysis for identification of antibacterial agents
.
Antimicrob. Agents Chemother.
57
,
26
36
74
Perlmutter
J.I.
,
Forbes
L.T.
,
Krysan
D.J.
,
Ebswoth-Mojica
K.
,
Colquhoun
J.M.
,
Wang
J.L.
et al
(
2014
)
Repurposing the antihistamine terfenadine for antimicrobial activity against Staphylococcus aureus
.
J. Med. Chem.
57
,
8540
8562
75
Torres
N.S.
,
Abercrombie
J.J.
,
Srinivasan
A.
,
Lopez-Ribot
J.L.
,
Ramasubramanian
A.K.
and
Leung
K.P.
(
2016
)
Screening a commercial library of pharmacologically active small molecules against Staphylococcus aureus biofilms
.
Antimicrob. Agents Chemother.
,
60
,
5663
5672
76
Rajamuthiah
R.
,
Fuchs
B.B.
,
Conery
A.L.
,
Kim
W.
,
Jayamani
E.
,
Kwon
B.
et al
(
2015
)
Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus
.
PLoS ONE
10
,
e0124595
77
Rajamuthiah
R.
,
Fuchs
B.B.
,
Jayamani
E.
,
Kim
Y.
,
Larkins-Ford
J.
,
Conery
A.
et al
(
2014
)
Whole animal automated platform for drug discovery against multi-drug resistant Staphylococcus aureus
.
PLoS ONE
9
,
e89189
78
Rangel-Vega
A.
,
Bernstein
L.R.
,
Mandujano-Tinoco
E.A.
,
Garcia-Contreras
S.J.
and
Garcia-Contreras
R.
(
2015
)
Drug repurposing as an alternative for the treatment of recalcitrant bacterial infections
.
Front. Microbiol.
6
,
282
79
Hussain
M.
,
Collins
C.
,
Hastings
J.G.
and
White
P.J.
(
1992
)
Radiochemical assay to measure the biofilm produced by coagulase-negative staphylococci on solid surfaces and its use to quantitate the effects of various antibacterial compounds on the formation of the biofilm
.
J. Med. Microbiol.
37
,
62
69
80
Younis
W.
,
Thangamani
S.
and
Seleem
M.N.
(
2015
)
Repurposing non-antimicrobial drugs and clinical molecules to treat bacterial infections
.
Curr. Pharm. Des.
21
,
4106
4111
81
Graziano
T.S.
,
Cuzzullin
M.C.
,
Franco
G.C.
,
Schwartz-Filho
H.O.
,
Dias de Andrade
E.
,
Groppo
F.C.
et al
(
2015
)
Statins and antimicrobial effects: simvastatin as a potential drug against Staphylococcus aureus Biofilm
.
PLoS ONE
10
,
e0128098
82
Wang
C.C.
,
Yang
P.W.
,
Yang
S.F.
,
Hsieh
S.P.
,
Tseng
S.P.
and
Lin
Y.C.
(
2015
)
Topical simvastatin promotes healing of Staphylococcus aureus-contaminated cutaneous wounds
.
Int. Wound J.
13
,
1150
1157
83
Thangamani
S.
,
Mohammad
H.
,
Abushahba
M.F.N.
,
Hamed
M.I.
,
Sobreira
T.J.P.
,
Hedrick
V.E.
et al
(
2015
)
Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent
.
Sci. Rep.
5
,
16407
84
Kristiansen
J.E.
,
Hendricks
O.
,
Delvin
T.
,
Butterworth
T.S.
,
Aagaard
L.
,
Christensen
J. B.
et al
(
2007
)
Reversal of resistance in microorganisms by help of non-antibiotics
.
J. Antimicrob. Chemother.
59
,
1271
1279
85
Bohnert
J.A.
,
Szymaniak-Vits
M.
,
Schuster
S.
and
Kern
W.V.
(
2011
)
Efflux inhibition by selective serotonin reuptake inhibitors in Escherichia coli
.
J. Antimicrob. Chemother.
66
,
2057
2060
86
El-Nakeeb
M.A.
,
Abou-Shleib
H.M.
,
Khalil
A.M.
,
Omar
H.G.
and
El-Halfawy
O.M.
(
2012
)
Reversal of antibiotic resistance in Gram-positive bacteria by the antihistaminic azelastine
.
APMIS
120
,
215
220
87
De Cremer
K.
,
Lanckacker
E.
,
Cools
T.L.
,
Bax
M.
,
De Brucker
K.
,
Cos
P.
et al
(
2015
)
Artemisinins, new miconazole potentiators resulting in increased activity against Candida albicans biofilms
.
Antimicrob. Agents Chemother.
59
,
421
426
88
Ejim
L.
,
Farha
M.A.
,
Falconer
S.B.
,
Wildenhain
J.
,
Coombes
B.K.
,
Tyers
M.
et al
(
2011
)
Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy
.
Nat. Chem. Biol.
7
,
348
350
89
Ooi
N.
,
Eady
E.A.
,
Cove
J.H.
and
O’Neill
A.J.
(
2015
)
Redox-active compounds with a history of human use: antistaphylococcal action and potential for repurposing as topical antibiofilm agents
.
J. Antimicrob. Chemother.
70
,
479
488
90
Van den Driessche
F.
,
Rigole
P.
,
Brackman
G.
and
Coenye
T.
(
2016
)
Screening a repurposing library for potentiators of antibiotics against Staphylococcus aureus biofilms
.
PLoS ONE.
in press
91
Sud
I.J.
and
Feingold
D.S.
(
1982
)
Action of antifungal imidazoles on Staphylococcus aureus
.
Antimicrob. Agents Chemother.
22
,
470
474
92
Nobre
L.S.
,
Todorovic
S.
,
Tavares
A.F.N.
,
Oldfield
E.
,
Hildebrandt
P.
,
Teixeira
M.
et al
(
2010
)
Binding of azole antibiotics to Staphylococcus aureus flavohemoglobin increases intracellular oxidative stress
.
J. Bacteriol.
192
,
1527
1533
93
Kim
S.Y.
,
Kim
J.
,
Jeong
S.I.
,
Jahng
K.Y.
and
Yu
K.Y.
(
2015
)
Antimicrobial effects and resistant regulation of magnolol and honokiol on methicillin-resistant Staphylococcus aureus
.
Biomed Res. Int.
2015
,
283630
94
Liu
T.
,
Pan
Y.
and
Lai
R.
(
2014
)
New mechanism of magnolol and honokiol from Magnolia officinalis against Staphylococcus aureus
.
Nat. Prod. Commun.
9
,
1307
1309
95
Amaral
L.
,
Viveiros
M.
and
Molnar
J.
(
2004
)
Antimicrobial activity of phenothiazines
.
In Vivo
18
,
725
731
96
Stenger
M.
,
Hendel
K.
,
Bollen
P.
,
Licht
P.B.
,
Kolmos
H.J.
and
Stenger
J.K.
(
2015
)
Assessments of thioridazine as a helper compound to dicloxacillin against methicillin-resistant Staphylococcus aureus: in Vivo trials in a mouse peritonitis model
.
PLoS ONE
10
,
e0135571
97
Poulsen
M.O.
,
Schøler
L.
,
Nielsen
M.N.
,
Skov
M.N.
,
Kolmos
H.J.
,
Kallipolitis
B.H.
et al
(
2014
)
Combination therapy with thioridazine and dicloxacillin combats meticillin-resistant Staphylococcus aureus infection in Caenorhabditis elegans
.
J. Med. Microbiol.
63
,
1174
1180
98
Coenye
T.
and
Nelis
H.J.
(
2010
)
In vitro and in vivo model systems to study microbial biofilm formation
.
J. Microbiol. Methods
83
,
89
105
99
Brackman
G.
,
Garcia-Fernandez
M.J.
,
Lenoir
J.
,
De Meyer
L.
,
Remon
J.P.
,
De Beer
T.
et al
(
2016
)
Dressings loaded with cyclodextrin-hamamelitannin complexes increase Staphylococcus aureus susceptibility toward antibiotics both in single as well as in mixed biofilm communities
.
Macromol. Biosci.
16
,
859
869