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  • Shaqour, Bahaa; Reigada, Ines; Gorecka, Zaneta; Choinska, Emilia; Verleije, Bart; Beyers, Koen; Swieszkowski, Wojciech; Fallarero, Adyary; Cos, Paul (2020)
    Additive manufacturing technologies have been widely used in the medical field. More specifically, fused filament fabrication (FFF) 3D-printing technology has been thoroughly investigated to produce drug delivery systems. Recently, few researchers have explored the possibility of directly 3D printing such systems without the need for producing a filament which is usually the feedstock material for the printer. This was possible via direct feeding of a mixture consisting of the carrier polymer and the required drug. However, as this direct feeding approach shows limited homogenizing abilities, it is vital to investigate the effect of the pre-mixing step on the quality of the 3D printed products. Our study investigates the two commonly used mixing approaches-solvent casting and powder mixing. For this purpose, polycaprolactone (PCL) was used as the main polymer under investigation and gentamicin sulfate (GS) was selected as a reference. The produced systems' efficacy was investigated for bacterial and biofilm prevention. Our data show that the solvent casting approach offers improved drug distribution within the polymeric matrix, as was observed from micro-computed topography and scanning electron microscopy visualization. Moreover, this approach shows a higher drug release rate and thus improved antibacterial efficacy. However, there were no differences among the tested approaches in terms of thermal and mechanical properties.
  • Vahermo, Mikko; Krogerus, Sara; Nasereddin, Abdelmajeed; Kaiser, Marcel; Brun, Reto; Jaffe, Charles L.; Yli-Kauhaluoma, Jari; Moreira, Vânia M. (2016)
    Derivatives of dehydroabietic acid bearing different amino acids scaffolds have potent antiprotozoal activity against Leishmania donovani and Trypanosoma cruzi, with good to high selectivity, and can therefore be regarded as good models for further development into new drugs to fight leishmaniasis and Chagas disease. Several of the tested compounds were able to kill parasites residing inside cells, with IC50 values ranging from 2.3 to 9 mu M (L. donovani) and 1.4 to 5.8 mu M (T. cruzi), reflecting their ability to fight these infections at the relevant stage responsible for disease. One of the compounds, bearing a 3-pyridyl-Dalanine side chain, was 1.5-fold more potent against T. cruzi amastigotes residing in L6 cells than the reference compound benznidazole.
  • Vanic, Zeljka; Rukavina, Zora; Manner, Suvi; Fallarero, Adyary; Uzelac, Lidija; Kralj, Marijeta; Klaric, Daniela Amidzic; Bogdanov, Anita; Raffai, Timea; Virok, Dezso Peter; Filipovic-Grcic, Jelena; Skalko-Basnet, Natasa (2019)
    Background: Efficient localized cervicovaginal antibacterial therapy, enabling the delivery of antibiotic to the site of action at lower doses while escaping systemic drug effects and reducing the risk of developing microbial resistance, is attracting considerable attention. Liposomes have been shown to allow sustained drug release into vaginal mucosa and improve delivery of antibiotics to bacterial cells and biofilms Azithromycin (AZI), a potent broad-spectrum macrolide antibiotic, has not yet been investigated for localized therapy of cervicovaginal infections, although it is administered orally for the treatment of sexually transmitted diseases. Encapsulation of AZI in liposomes could improve its solubility, antibacterial activity, and allow the prolonged drug release in the cervicovaginal tissue, while avoiding systemic side effects. Purpose: The objective of this study was to develop AZI-liposomes and explore their potentials for treating cervicovaginal infections. Methods: AZI-liposomes that differed in bilayer elasticity/rigidity and surface charge were prepared and evaluated under simulated cervicovaginal conditions to yield optimized liposomes, which were assessed for antibacterial activity against several planktonic and biofilm-forming Escherichia coli strains and intracellular Chlamydia trachomatis, ex vivo AZI vaginal deposition/penetration, and in vitro cytotoxicity toward cervical cells. Results: Negatively charged liposomes with rigid bilayers (CL-3), propylene glycol liposomes (PGL-2) and deformable propylene glycol liposomes (DPGL-2) were efficient against planktonic E. coli ATCC 700928 and K-12. CL-3 was superior for preventing the formation of E. coli ATCC 700928 and K-12 biofilms, with IC50 values (concentrations that inhibit biofilm viability by 50%) up to 8-fold lower than those of the control (free AZI). DPGL-2 was the most promising for eradication of already formed E. coli biofilms and for treating C. trachomatis infections. All AZI-liposomes were biocompatible with cervical cells and improved localization of the drug inside vaginal tissue compared with the control. Conclusion: The performed studies confirm the potentials of AZI-liposomes for localized cervicovaginal therapy.
  • Bakour, Meryem; Laaroussi, Hassan; Ousaaid, Driss; El Ghouizi, Asmae; Es-Safi, Imane; Mechchate, Hamza; Lyoussi, Badiaa (2022)
    Bee bread is a natural product obtained from the fermentation of bee pollen mixed with bee saliva and flower nectar inside the honeycomb cells of a hive. Bee bread is considered a functional product, having several nutritional virtues and various bioactive molecules with curative or preventive effects. This paper aims to review current knowledge regarding the chemical composition and medicinal properties of bee bread, evaluated in vitro and in vivo, and to highlight the benefits of the diet supplementation of bee bread for human health. Bee bread extracts (distilled water, ethanol, methanol, diethyl ether, and ethyl acetate) have been proven to have antioxidant, antifungal, antibacterial, and antitumoral activities, and they can also inhibit alpha-amylase and angiotensin I-converting enzyme in vitro. More than 300 compounds have been identified in bee bread from different countries around the world, such as free amino acids, sugars, fatty acids, minerals, organic acids, polyphenols, and vitamins. In vivo studies have revealed the efficiency of bee bread in relieving several pathological cases, such as hyperglycemia, hyperlipidemia, inflammation, and oxidative stress.
  • Poojari, Chetan; Wilkosz, Natalia; Lira, Rafael B.; Dimova, Rumiana; Jurkiewicz, Piotr; Petka, Rafal; Kepczynski, Mariusz; Rog, Tomasz (2019)
    1,6-Diphenyl-1,3,5-hexatriene (DPH) is one of the most commonly used fluorescent probes to study dynamical and structural properties of lipid bilayers and cellular membranes via measuring steady-state or time-resolved fluorescence anisotropy. In this study, we present a limitation in the use of DPH to predict the order of lipid acyl chains when the lipid bilayer is doped with itraconazole (ITZ), an antifungal drug. Our steady-state fluorescence anisotropy measurements showed a significant decrease in fluorescence anisotropy of DPH embedded in the ITZ-containing membrane, suggesting a substantial increase in membrane fluidity, which indirectly indicates a decrease in the order of the hydrocarbon chains. This result or its interpretation is in disagreement with the fluorescence recovery after photobleaching measurements and molecular dynamics (MD) simulation data. The results of these experiments and calculations indicate an increase in the hydrocarbon chain order. The MD simulations of the bilayer containing both ITZ and DPH provide explanations for these observations. Apparently, in the presence of the drug, the DPH molecules are pushed deeper into the hydrophobic membrane core below the lipid double bonds, and the probe predominately adopts the orientation of the ITZ molecules that is parallel to the membrane surface, instead of orienting parallel to the lipid acyl chains. For this reason, DPH anisotropy provides information related to the less ordered central region of the membrane rather than reporting the properties of the upper segments of the lipid acyl chains.
  • Han, Huijie; Bartolo, Raquel; Li, Jiachen; Shahbazi, Mohammad-Ali; Santos, Helder A. (2022)
    The development of cell membrane-modified biomimetic nanoparticles has extensively increased during the past years due to their exceptional biocompatibility, evasion from the immune system, and targeting ability. Known as a cutting-edge area of research in nanomedicine, such novel nanoplatforms can mimic different functions of the primary cells, while successfully delivering their cargos to the defect site with the aim of enhancing the therapeutic responses and reducing the side effects. Platelet is a key factor for haemostasis and a major player in wound healing, inflammation, and many other biological functions and pathological conditions. As a highly responsive cell, platelets can adapt to environment modifications and release several soluble biomolecules, such as growth factors, coagulant factors, and extracellular vesicles. Additionally, platelets are capable of immune system evasion, sub-endothelial adhesion, and pathogen interaction. These characteristics have inspired the design of several platelet membrane-coated nanoparticles as drug delivery systems. This review describes the current developments in platelet membrane-coated nanoparticles for targeted therapy, specifically, their advantages compared to other biomimetic cell-derived nanoparticles and their applicability in the medical field are elucidated. Finally, the challenges and future perspectives associated with this nanoplatform are summarised.
  • Zhang, Ji; Ketola, Tarmo; Örmälä, Anni-Maria; Mappes, Johanna; Laakso, Jouni (2014)
  • Douillard, Francois P.; Kant, Ravi; Ritari, Jarmo; Paulin, Lars; Palva, Airi; de Vos, Willem M. (2013)
  • Andreevskaya, Margarita; Hultman, Jenni; Johansson, Per; Laine, Pia; Paulin, Lars; Auvinen, Petri; Björkroth, Johanna (2016)
    Leuconostoc gelidum subsp. gasicomitatum is a predominant lactic acid bacterium (LAB) in spoilage microbial communities of different kinds of modified-atmosphere packaged (MAP) food products. So far, only one genome sequence of a poultry-originating type strain of this bacterium (LMG 18811T) has been available. In the current study, we present the completely sequenced and functionally annotated genome of strain KG16-1 isolated from a vegetable-based product. In addition, six other vegetable-associated strains were sequenced to study possible “niche” specificity suggested by recent multilocus sequence typing. The genome of strain KG16-1 consisted of one circular chromosome and three plasmids, which together contained 2,035 CDSs. The chromosome carried at least three prophage regions and one of the plasmids encoded a galactan degradation cluster, which might provide a survival advantage in plant-related environments. The genome comparison with LMG 18811T and six other vegetable strains suggests no major differences between the meat- and vegetable-associated strains that would explain their “niche” specificity. Finally, the comparison with the genomes of other leuconostocs highlights the distribution of functionally interesting genes across the L. gelidum strains and the genus Leuconostoc.
  • Abdelrehiem, Dina Ahmed Mosselhy; Assad, Mhd Adel; Sironen, Tarja; Elbahri, Mady (2021)
    The COVID-19 pandemic is expanding worldwide. This pandemic associated with COVID-19 placed the spotlight on how bacterial (e.g., methicillin-resistant Staphylococcus aureus) co-infections may impact responses to coronavirus. In this review the ways in which nanoparticles can contain and rapidly diagnose COVID-19 under the umbrella of nanotheranostics (i.e., smart, single agents combining nanodiagnostics and nanotherapeutics) are elaborated. The present work provides new insights into the promising incorporation of antiviral nanotheranostics into nanostructured materials, including electrospun fibers with tailored pore sizes and hydrophobicity, namely "superhydrophobic self-disinfecting electrospun facemasks/fabrics (SSEF)." SSEFs are proposed as smart alternatives to address the drawbacks of N95 respirators. The challenges of coronavirus containment are underscored, literature is reviewed, and "top-five suggestions" for containing COVID-19 are offered, including: i) preventive appraisals-avoiding needless hospital admission and practicing frequent hand washing (from 20 to 60 s). ii) Diagnostics-highly recommending nanodiagnostics, detecting COVID-19 within 10 min. iii) Therapeutics-expanding nanotherapeutics to treat COVID-19 and bacterial co-infections after safety assessments and clinical trials. iv) Multipronged and multinational, including China, collaborative appraisals. v) Humanitarian compassion to traverse this pandemic in a united way.
  • Tomašič, Tihomir; Mirt, Matic; Barančoková, Michaela; Ilaš, Janez; Zidar, Nace; Tammela, Päivi Sirpa Marjaana; Kikelj, Danijel (2017)
    Development of novel DNA gyrase B inhibitors is an important field of antibacterial drug discovery whose aim is to introduce a more effective representative of this mechanistic class into the clinic. In the present study, two new series of Escherichia coli DNA gyrase inhibitors bearing the 4,5-dibromopyrrolamide moiety have been designed and synthesized. 4,5,6,7-Tetrahydrobenzo[1,2-d] thiazole-2,6-diamine derivatives inhibited E. coli DNA gyrase in the submicromolar to low micromolar range (IC50 values between 0.891 and 10.4 mu M). Their "ring-opened" analogues, based on the 2-(2-aminothiazol-4-yl) acetic acid scaffold, displayed weaker DNA gyrase inhibition with IC50 values between 15.9 and 169 mu M. Molecular docking experiments were conducted to study the binding modes of inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.
  • Abbeloos, Elke; Pyörälä, Satu; Rajala-Schultz, Päivi; Myllys, Vesa (2018)
    The aim of this study was to determine the intramammary dose of benzylpenicillin required to maintain a concentration in the milk above the MIC for the Gram-positive bacteria that cause mastitis. The product used in this study was a commercially available procaine benzylpenicillin in an oily suspension with micronized particles. Three dose levels were used: 200,000, 300,000, and 600,000IU. Concentrations of benzylpenicillin in cow milk and plasma were determined after a single intramammary dose was administered into one quarter of each of the five cows in each treatment group. Samples were analyzed using an HPLC-MS/MS method, which was validated during the study. Concentrations in the milk were well above the MIC for the target pathogens for all doses tested. There was a linear dose-dependent increase in the mean AUCs of benzylpenicillin concentrations in plasma and milk. At the first milking, 12hr after dosing, there was a significant difference between the mean milk benzylpenicillin concentrations in cows treated with a dose of 600,000IU, and those treated with 200,000 or 300,000IU. Although this study shows a linear relationship between the dose of procaine benzylpenicillin administered and the concentration in the milk in the healthy udder, it would be useful to conduct studies on cows with mastitis to define the optimum dose and duration of intramammary treatment with benzylpenicillin.
  • Jakopin, Ziga; Ilas, Janez; Barancokova, Michaela; Brvar, Matjaz; Tammela, Paivi; Dolenc, Marija Sollner; Tomasic, Tihomir; Kikelj, Danijel (2017)
    DNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50 of 1.2 mu M for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Grampositive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90 of 75 mu M. Our study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IV. (C) 2017 Elsevier Masson SAS. All rights reserved.
  • Lebreton, Francois; van Schaik, Willem; McGuire, Abigail Manson; Godfrey, Paul; Griggs, Allison; Mazumdar, Varun; Corander, Jukka; Cheng, Lu; Saif, Sakina; Young, Sarah; Zeng, Qiandong; Wortman, Jennifer; Birren, Bruce; Willems, Rob J. L.; Earl, Ashlee M.; Gilmore, Michael S. (2013)
  • He, Wei; Zhang, Zhaoyu; Chen, Jing; Zheng, Yudong; Xie, Yajie; Liu, Wenbo; Wu, Jian; Mosselhy, Dina A. (2021)
    Chronic wounds are a serious worldwide problem, which are often accompanied by wound infections. In this study, bacterial cellulose (BC)-based composites introduced with tannic acid (TA) and magnesium chloride (BC-TA-Mg) were fabricated for anti-biofilm activities. The prepared composites' surface properties, mechanical capacity, thermal stability, water absorption and retention property, releasing behavior, anti-biofilm activities and potential cytotoxicity were tested. Results showed that TA and MgCl2 particles closely adhered to the nanofibers of BC membranes, thus increasing surface roughness and hydrophobicity of the membranes. While the introduction of TA and MgCl2 did not influence the transparency of the membranes, making it beneficial for wound inspection. BC-TA and BC-TA-Mg composites displayed increased tensile strength and elongation at break compared to pure BC. Moreover, BC-TA-Mg exhibited higher water absorption and retention capacity than BC and BC-TA, suitable for the absorption of wound exudates. BC-TA-Mg demonstrated controlled release of TA and good inhibitory effect on both singly cultured Staphylococcus aureus and Pseudomonas aeruginosa biofilm and co-cultured biofilm of S. aureus and P. aeruginosa. Furthermore, the cytotoxicity grade of BC-TA-6Mg membrane was eligible based on standard toxicity classifications. These indicated that BC-TA-Mg is potential to be used as wound dressings combating biofilms in chronic wounds.
  • Stefani, Caroline; Gonzalez-Rodriguez, David; Senju, Yosuke; Doye, Anne; Efimova, Nadia; Janel, Sebastien; Lipuma, Justine; Tsai, Meng Chen; Hamaoui, Daniel; Maddugoda, Madhavi P.; Cochet-Escartin, Olivier; Prevost, Coline; Lafont, Frank; Svitkina, Tatyana; Lappalainen, Pekka; Bassereau, Patricia; Lemichez, Emmanuel (2017)
    Transendothelial cell macroaperture (TEM) tunnels control endothelium barrier function and are triggered by several toxins from pathogenic bacteria that provoke vascular leakage. Cellular dewetting theory predicted that a line tension of uncharacterized origin works at TEM boundaries to limit their widening. Here, by conducting high-resolution microscopy approaches we unveil the presence of an actomyosin cable encircling TEMs. We develop a theoretical cellular dewetting framework to interpret TEM physical parameters that are quantitatively determined by laser ablation experiments. This establishes the critical role of ezrin and non-muscle myosin II (NMII) in the progressive implementation of line tension. Mechanistically, fluorescence-recovery-after-photobleaching experiments point for the upstream role of ezrin in stabilizing actin filaments at the edges of TEMs, thereby favouring their crosslinking by NMIIa. Collectively, our findings ascribe to ezrin and NMIIa a critical function of enhancing line tension at the cell boundary surrounding the TEMs by promoting the formation of an actomyosin ring.
  • van Belkum, Alex; Almeida, Carina; Bardiaux, Benjamin; Barrass, Sarah V.; Butcher, Sarah J.; Çaykara, Tuğçe; Chowdhury, Sounak; Datar, Rucha; Eastwood, Ian; Goldman, Adrian; Goyal, Manisha; Izadi-Pruneyre, Nadia; Jacobsen, Theis; Johnson, Pirjo H.; Kempf, Volkhard A.J.; Kiessling, Andreas; Bueno, Juan Leva; Malik, Anchal; Malmström, Johan; Meuskens, Ina; Milner, Paul A.; Nilges, Michael; Pamme, Nicole; Peyman, Sally A.; Rodrigues, Ligia R.; Rodriguez-Mateos, Pablo; Sande, Maria G.; Silva, Carla Joana; Stehle, Thilo; Thibau, Arno; Vaca, Diana J.; Linke, Dirk (2021)
    Infectious diseases are an existential health threat, potentiated by emerging and re-emerging viruses and increasing bacterial antibiotic resistance. Targeted treatment of infectious diseases requires precision diagnostics, especially in cases where broad-range therapeutics such as antibiotics fail. There is thus an increasing need for new approaches to develop sensitive and specific in vitro diagnostic (IVD) tests. Basic science and translational research are needed to identify key microbial molecules as diagnostic targets, to identify relevant host counterparts, and to use this knowledge in developing or improving IVD. In this regard, an overlooked feature is the capacity of pathogens to adhere specifically to host cells and tissues. The molecular entities relevant for pathogen-surface interaction are the so-called adhesins. Adhesins vary from protein compounds to (poly-)saccharides or lipid structures that interact with eukaryotic host cell matrix molecules and receptors. Such interactions co-define the specificity and sensitivity of a diagnostic test. Currently, adhesin-receptor binding is typically used in the pre-analytical phase of IVD tests, focusing on pathogen enrichment. Further exploration of adhesin-ligand interaction, supported by present high-throughput "omics" technologies, might stimulate a new generation of broadly applicable pathogen detection and characterization tools. This review describes recent results of novel structure-defining technologies allowing for detailed molecular analysis of adhesins, their receptors and complexes. Since the host ligands evolve slowly, the corresponding adhesin interaction is under selective pressure to maintain a constant receptor binding domain. IVD should exploit such conserved binding sites and, in particular, use the human ligand to enrich the pathogen. We provide an inventory of methods based on adhesion factors and pathogen attachment mechanisms, which can also be of relevance to currently emerging pathogens, including SARS-CoV-2, the causative agent of COVID-19.
  • Paino, Annamari; Ahlstrand, Tuuli; Nuutila, Jari; Navickaite, Indre; Lahti, Maria; Tuominen, Heidi; Välimaa, Hannamari; Lamminmaki, Urpo; Pollanen, Marja T.; Ihalin, Riikka (2013)
  • Kajova, Mikael; Khawaja, Tamim; Kangas, Jonas; Mäkinen, Hilda; Kantele, Anu (2021)
    Background: While 20–80% of regular visitors to (sub)tropical regions become colonised by extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE), those hospitalised abroad often also carry other multidrug-resistant (MDR) bacteria on return; the rates are presumed to be highest for interhospital transfers. Aim: This observational study assessed MDR bacterial colonisation among patients transferred directly from hospitals abroad to Helsinki University Hospital. We investigated predisposing factors, clinical infections and associated fatalities. Methods: Data were derived from screening and from diagnostic samples collected between 2010 and 2019. Risk factors of colonisation were identified by multivariable analysis. Microbiologically verified symptomatic infections and infection-related mortality were recorded during post-transfer hospitalisation. Results: Colonisation rates proved highest for transfers from Asia (69/96; 71.9%) and lowest for those within Europe (99/524; 18.9%). Of all 698 patients, 208 (29.8%) were colonised; among those, 163 (78.4%) carried ESBL-PE, 28 (13.5%) MDR Acinetobacter species, 25 (12.0%) meticillin-resistant Staphylococcus aureus, 25 (12.0%) vancomycin-resistant Enterococcus, 14 (6.7%) carbapenemase-producing Enterobacteriaceae, and 12 (5.8%) MDR Pseudomonas aeruginosa; 46 strains tested carbapenemase gene-positive. In multivariable analysis, geographical region, intensive care unit (ICU) treatment and antibiotic use abroad proved to be risk factors for colonisation. Clinical MDR infections, two of them fatal (1.0%), were recorded for 22 of 208 (10.6%) MDR carriers. Conclusions: Colonisation by MDR bacteria was common among patients transferred from foreign hospitals. Region of hospitalisation, ICU treatment and antibiotic use were identified as predisposing factors. Within 30 days after transfer, MDR colonisation manifested as clinical infection in more than 10% of the carriers.
  • Ahlstrand, Tuuli; Torittu, Annamari; Elovaara, Heli; Välimaa, Hannamari; Pöllänen, Marja T.; Kasvandik, Sergo; Högbom, Martin; Ihalin, Riikka (2018)
    Naturally competent bacteria acquire DNA from their surroundings to survive in nutrient-poor environments and incorporate DNA into their genomes as new genes for improved survival. The secretin HofQ from the oral pathogen Aggregatibacter actinomycetemcomitans has been associated with DNA uptake. Cytokine sequestering is a potential virulence mechanism in various bacteria and may modulate both host defense and bacterial physiology. The objective of this study was to elucidate a possible connection between natural competence and cytokine uptake in A. actinomycetemcomitans. The extramembranous domain of HofQ (emHofQ) was shown to interact with various cytokines, of which IL-8 exhibited the strongest interaction. The dissociation constant between emHofQ and IL-8 was 43nM in static settings and 2.4M in dynamic settings. The moderate binding affinity is consistent with the hypothesis that emHofQ recognizes cytokines before transporting them into the cells. The interaction site was identified via crosslinking and mutational analysis. By structural comparison, relateda type I KH domain with a similar interaction site was detected in the Neisseria meningitidis secretin PilQ, which has been shown to participate in IL-8 uptake. Deletion of hofQ from the A. actinomycetemcomitans genome decreased the overall biofilm formation of this organism, abolished the response to cytokines, i.e., decreased eDNA levels in the presence of cytokines, and increased the susceptibility of the biofilm to tested -lactams. Moreover, we showed that recombinant IL-8 interacted with DNA. These results can be used in further studies on the specific role of cytokine uptake in bacterial virulence without interfering with natural-competence-related DNA uptake.