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Staphylococcus Aureus RESEARCH ARTICLE For reprint orders, please contact: [email protected] Evaluation of antibacterial and antibiofilm mechanisms by usnic acid against methicillin-resistant Staphylococcus aureus Arianna Pompilio‡,1,2, Antonella Riviello‡,1,2,3, Valentina Crocetta1,2, Fabrizio Di Giuseppe1,2,3, Stefano Pomponio1,2, Marilisa Sulpizio1,2,3, Carmine Di Ilio1,2,3, Stefania Angelucci1,2,3, Luana Barone4, Andrea Di Giulio4 & Giovanni Di Bonaventura*,1,2 Aim: To evaluate the antibacterial and antibiofilm mechanisms of usnic acid (USN) against methicillin-resistant Staphylococcus aureus from cystic fibrosis patients. Materials & methods: The effects exerted by USN at subinhibitory concentrations on S. aureus Sa3 strain was evaluated by proteomic, real-time PCR and electron microscopy analyses. Results & conclusion: Proteomic analysis showed that USN caused damage in peptidoglycan synthesis, as confirmed by microscopy. Real-time PCR analysis showed that antibiofilm activity of USN is mainly due to impaired adhesion to the host matrix binding proteins, and decreasing lipase and thermonuclease expression. Our data show that USN exerts anti-staphylococcal effects through multitarget inhibitory effects, thus confirming the rationale for considering it ‘lead compound’ for the treatment of cystic fibrosis infections. First draft submitted: 9 March 2016; Accepted for publication: 7 July 2016; Published online: 16 September 2016 The most common cause of death in cystic fibrosis (CF) patients is respiratory failure secondary to KEYWORDS pulmonary infection. Pseudomonas aeruginosa and Burkholderia cepacia complex are the pathogens • biofilm most commonly associated with a shortened life span, although there has recently been an increase • Staphylococcus aureus in the prevalence of several potentially pathogenic microorganisms in CF. • usnic acid Methicillin-resistant Staphylococcus aureus (MRSA) is one such important emerging pathogen. Patients with CF are at particular risk for pulmonary colonization of MRSA because of two main factors: their difficulty in clearing mucus and their frequent hospital visits, which can increase exposure to MRSA [1–3] . S. aureus multiplies and persists in the airways of CF patients for months or even years despite appropriate anti-staphylococcal therapy [4,5]. Particularly, hospital-acquired MRSA isolates that are usually associated with SCCmec types I, II and III, tend to be resistant to all antimicrobials with the exception of glycopeptides. Despite the increasing prevalence of MRSA in CF patients, its clinical significance remains unclear. Chronic pulmonary infection with MRSA is thought to confer CF patients a worse overall clinical out- come and, in particular, result in an increased rate of lung function decline, as measured by FEV1 [3]. In contrast with this finding, another study using data from the Epidemiologic Study of Cystic Fibrosis showed that patients with MRSA had increased decline in lung function prior to MRSA 1Department of Medical, Oral & Biotechnological Sciences, ‘G d’Annunzio’ University of Chieti-Pescara, Via Vestini 31, Chieti, Italy 2Aging Research Center and Translational Medicine, ‘G d’Annunzio’ University of Chieti-Pescara, Via L Polacchi 13, Chieti, Italy 3Stem TeCh Group, Via L Polacchi 13, Chieti, Italy 4Department of Science, LIME, University Roma Tre, Viale G Marconi 446, Rome, Italy *Author for correspondence: Tel.: +39 087 1355 4812; Fax: +39 087 1355 4822; [email protected] ‡Authors contributed equally part of 10.2217/fmb-2016-0049 © 2016 Future Medicine Ltd Future Microbiol. (Epub ahead of print) ISSN 1746-0913 RESEARCH ARTICLE Pompilio, Riviello, Crocetta et al. acquisition therefore concluding that MRSA did biofilm lifestyles ofS. aureus strains isolated not influence lung function decline [6]. from CF patients [24], therefore warranting fur- In addition to methicillin resistance, other ther in vitro and in vivo studies to evaluate the adaptive strategies are adopted by S. aureus to ‘real’ potential of this lichen metabolite in the survive in CF lung, such as the formation of management of lung infections in CF patients. biofilms and the switch to small-colony variants, Although the antibiotic activity of USN is nowa- therefore making the action of antimicrobial days universally recognized, little or nothing is agents and pathogen eradication difficult [7–9]. known about its mechanism of action. The relevant morbidity and mortality associ- In the present work, for the first time, pro- ated with S. aureus infection and the increased teomic analysis was performed to investigate the antibiotic resistance demand the development of effects caused by the exposure to USN at sub- new antimicrobial strategies. inhibitory concentration on protein expression Natural products with diverse bio activities of an MRSA strain isolated from a CF patient. and structures are an important source of The morphological and ultrastructural changes novel chemicals with pharmaceutical poten- induced by USN in staphylococcal cells were tials. Lichens, symbiotic organisms between further elucidated using both transmission a fungal (mycobiont) and algal and/or ciano- and scanning electron microscopy. Finally, the bacterial (phytobiont) partner, are commonly effects of USN at subinhibitory concentrations found worldwide. This symbiotic relationship is on virulence gene expression by S. aureus were un deniably successful for lichens that can survive also investigated. a variety of harsh environmental conditions and are inherently resistant to microbial infections. Materials & methods Their intrinsic resistance is mainly due to the ●●Bacterial strain & growth conditions production of a large number of compounds that Staphylococcus aureus Sa3 strain was isolated typically arise from the secondary meta bolism from the airways of a chronically infected patient of the fungal component. Chemotaxonomic diagnosed with CF (genotype ΔF508/ΔF508) studies have shown that most lichen second- attending ‘Bambino Gesù’ Children Hospital ary metabolites belong to the chemical classes of Rome, Italy. Identification at species level of depsides, depsidones and dibenzofurans [10] . was carried out by conventional biochemical Of the hundreds of known secondary lichen tests (API® Staph System; BioMérieux, Marcy- metabolites, the benzofuran derivative usnic acid L’Etoile, France). Resistance to methicillin (USN), commonly found in the genus Usnea, is was evaluated with 30-μg cefoxitin disks and the most studied. Lichens belonging to USN pro- confirmed by a duplex PCR assay with primers ducers have been extensively used for centuries targeting nuc and mecA genes, respectively [25]. in folklorist medicine in the treatment of pul- Strain was stored at -80°C (Microbank®; Biolife monary tuberculosis, pain relief, fever control, Italiana S.r.l., Milan, Italy) until use when it was wounds, mycoses, sore throat, toothache and grown overnight at 37°C in Trypticase Soy broth several skin infections [11,12]. In fact, USN has (TSB; Oxoid S.p.A.; Garbagnate M.se, Italy), shown a variety of biological activities, includ- then plated twice on Mueller-Hinton Agar ing antimicrobial activity against a number of (MHA; Oxoid S.p.A.) to check for purity and bacterial and fungal pathogens, both tested as to restore the original phenotype. planktonic and sessile (biofilm) lifestyle [13–16] . All assays were carried out by using a stand- Toxicity in USN must be addressed due to some ardized bacterial inoculum. Briefly, some colo- adverse reports relating its use as a slimming nies grown overnight on MHA were resuspended agent and dietary supplement [17] . Hepatotoxicity in sterile NaCl to an OD550 of 1.2 (correspond- has been deeply investigated, although USN has ing to 1–3 × 108 CFU/ml), then diluted 1:1000 been reported to induce toxicity in other normal in cation-adjusted Mueller–Hinton broth and malignant cell types [18]. However, adsorb- (CAMHB; Becton, Dickinson and Company; ing USN onto different carriers (i.e., polymers, Milan, Italy; pH 7.2–7.4). magnetic nanoparticles) reduces toxicity [19,20] as well as affects biofilm development and facilitates ●●Usnic acid eradication of preformed biofilms [19,21–23]. Usnic acid powder (Sigma-Aldrich; Milan, Italy) Recently, our group found that USN shows was used to prepare a 2 mg/ml stock solution relevant activity against both planktonic and in dimethyl sulfoxide (DMSO; Sigma-Aldrich) 10.2217/fmb-2016-0049 Future Microbiol. (Epub ahead of print) future science group Antibacterial & antibiofilm mechanisms by usnic acid against methicillin-resistant S. aureus RESEARCH ARTICLE and then diluted with sterile CAMHB to obtain order to create a reference gel representative of desired concentrations. The final DMSO con- all analyzed conditions, three different gel runs centration (≤ 3%) did not affect the viability of for each group type (time zero, sedentary and the strain tested (data not shown). trained) samples were performed and then sub- jected to image analysis with ImageMaster 2D ●●Minimum inhibitory concentration Platinum 6.0 software (GE Healthcare). A ref- determination erence gel was created from a representative gel Minimum inhibitory concentration (MIC) of combining all spots common to the various ana- USN for S. aureus Sa3 strain was 64 μg/ml, as lyzed gels. The reference gel was then used to assessed in triplicate using the micro dilution determine the presence and difference in protein method, according to the Clinical and expression among gels. Background subtraction Laboratory
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