Biofilm Dispersal Research Articles

Review of New Approaches for Fouling Mitigation in Membrane Separation Processes in Water Treatment Applications

This review investigates antifouling agents used in the process of membrane separation (MS), in reverse osmosis (RO), ultrafiltration (UF), nanofiltration (NF), microfiltration (MF), membrane distillation (MD), and membrane bioreactors (MBR), and clarifies the fouling mechanism. Membrane fouling is an incomplete substance formed on the membrane surface, which will quickly reduce the permeation flux and damage the membrane. Foulant is colloidal matter: organic matter (humic acid, protein, carbohydrate, nano/microplastics), inorganic matter (clay such as potassium montmorillonite, silica salt, metal oxide, etc.), and biological matter (viruses, bacteria and microorganisms adhering to the surface of the membrane in the case of nutrients) The stability and performance of the tested nanometric membranes, as well as the mitigation of pollution assisted by electricity and the cleaning and repair of membranes, are reported. Physical, chemical, physico-chemical, and biological methods for cleaning membranes. Biologically induced biofilm dispersion effectively controls fouling. Dynamic changes in membrane foulants during long-term operation are critical to the development and implementation of fouling control methods. Membrane fouling control strategies show that improving membrane performance is not only the end goal, but new ideas and new technologies for membrane cleaning and repair need to be explored and developed in order to develop future applications.

Reactor scale modeling of quorum sensing induced biofilm dispersal

We present a simple reactor-scale mathematical model of active biofilm dispersal that is controlled by a quorum sensing system. The model is cast as a system of three ordinary differential equations for the dependent variables biofilm thickness, quorum sensing signal concentration in the reactor, and concentration of the growth limiting substrate in the reactor. The model is investigated with analytical and numerical techniques. We find that a single QS dispersal mechanism, depending on parameters, can lead to (i) continuous cell loss at a signal level at which the biofilm is entirely up-regulated, (ii) periodically repeating almost instantaneous cell loss with the biofilm switching between down- and up-regulated states, (iii) continuous cell loss at a signal level at which the biofilm is entirely down-regulated, or (iv) complete washout. We contrast this with a simple model of starvation induced dispersal, which is cast in the same modeling framework, but shows entirely different dynamic behavior, in that it only permits washout or asymptotic convergence to a steady state at break-even concentration, depending on parameters.

Sequence diversity of the Pseudomonas aeruginosa population in loci that undergo microevolution in cystic fibrosis airways.

Five hundred and thirty-four unrelated Pseudomonas aeruginosa isolates from inanimate habitats, patients with cystic fibrosis (CF) and other human infections were sequenced in 19 genes that had been identified previously as the hot spots of genomic within-host evolution in serial isolates from 12 CF lungs. Amplicon sequencing confirmed a significantly higher sequence diversity of the 19 loci in P. aeruginosa isolates from CF patients compared to those from other habitats, but this overrepresentation was mainly due to the larger share of synonymous substitutions. Correspondingly, non-synonymous substitutions were either rare (gltT, lepA, ptsP) or benign (nuoL, fleR, pelF) in some loci. Other loci, however, showed an accumulation of non-neutral coding variants. Strains from the CF habitat were often mutated at evolutionarily conserved positions in the elements of stringent response (RelA, SpoT), LPS (PagL), polyamine transport (SpuE, SpuF) and alginate biosynthesis (AlgG, AlgU). The strongest skew towards the CF lung habitat was seen for amino acid sequence variants in AlgG that clustered in the carbohydrate-binding/sugar hydrolysis domain. The master regulators of quorum sensing lasR and rhlR were frequent targets for coding variants in isolates from chronic and acute human infections. Unique variants in lasR showed strong evidence of positive selection indicated by d N/d S values of ~4. The pelA gene that encodes a multidomain enzyme involved in both the formation and dispersion of Pel biofilms carried the highest number of single-nucleotide variants among the 19 genes and was the only gene with a higher frequency of missense mutations in P. aeruginosa strains from non-CF habitats than in isolates from CF airways. PelA protein variants are widely distributed in the P. aeruginosa population. In conclusion, coding variants in a subset of the examined loci are indeed characteristic for the adaptation of P. aeruginosa to the CF airways, but for other loci the elevated mutation rate is more indicative of infections in human habitats (lasR, rhlR) or global diversifying selection (pelA).

Pillar[5]arene-Based Acid-Triggered Supramolecular Porphyrin Photosensitizer for Combating Bacterial Infections and Biofilm Dispersion.

The treatment of pathogenic bacterial infection has long been the most serious threat to human life and attracted widespread attention. Herein, a supramolecular photosensitizer platform based on carboxylatopillar[5]arene (CP5) and tetrafluorophenyl porphyrin functionalized with a quaternary ammonium group (TFPP-QA) for combating bacteria and dispersing biofilm via photodynamic treatment is constructed. By introducing the host macrocycle CP5 and host-guest interaction, the supramolecular photosensitizer has great biocompatibility and acid responsiveness. On the one hand, the acid-triggered dissociation of TFPP-QA/CP5 could induce the porphyrin photosensitizer to target bacterial cells and disrupt the charge balance of bacterial membranes, enhance the permeability of the bacterial membrane. On the other hand, the TFPP-QA/CP5 antibacterial platform possesses superb reactive oxygen species (ROS) generation capability under light irradiation, leading to enhanced photodynamic antibacterial efficacy. The in vitro and in vivo studies show that the supramolecular photosensitizers exhibit high antibacterial efficiency and biofilm dissipation effect under 660nm light irradiation. Therefore, it is anticipated that the rational design and integration of photosensitizers and quaternary ammonium compounds through the supramolecular strategy would provide a promising prospect for clinical photodynamic antimicrobial therapy.

Combating Biofilm by Targeting Its Formation and Dispersal Using Gallic Acid against Single and Multispecies Bacteria Causing Dental Plaque.

Exploring biological agents to control biofilm is a vital alternative in combating pathogenic bacteria that cause dental plaque. This study was focused on antimicrobial, biofilm formation and biofilm dispersal efficacy of Gallic acid (GA) against bacteria, including Proteus spp., Escherichia coli, Pseudomonas spp., Salmonella spp., Streptococcus mutans, and Staphylococcus aureus and multispecies bacteria. Biofilm was qualitatively and quantitatively assessed by crystal violet assay, florescence microscopy (bacterial biomass (µm2), surface coverage (%)) and extracellular polymeric substances (EPS). It was exhibited that GA (1–200 mg/L) can reduce bacterial growth. However, higher concentrations (100–200 mg/L) markedly reduced (86%) bacterial growth and biofilm formation (85.5%), while GA did not exhibit any substantial dispersal effects on pre-formed biofilm. Further, GA (20–200 mg/L) exhibited 93.43% biomass reduction and 88.6% (p < 0.05) EPS (polysaccharide) reduction. Microscopic images were processed with BioImageL software. It was revealed that biomass surface coverage was reduced to 2% at 200 mg/L of GA and that 13,612 (µm2) biomass was present for control, while it was reduced to 894 (µm2) at 200 mg/L of GA. Thus, this data suggest that GA have antimicrobial and biofilm control potential against single and multispecies bacteria causing dental plaque.

Efficacy and safety of biofilm dispersal by glycoside hydrolases in wounds

Novel anti-biofilm and dispersal agents are currently being investigated in an attempt to combat biofilm-associated wound infections. Glycoside hydrolases (GHs) are enzymes that hydrolyze the glycosidic bonds between sugars, such as those found within the exopolysaccharides of the biofilm matrix. Previous studies have shown that GHs can weaken the matrix, inducing bacterial dispersal, and improving antibiotic clearance. Yet, the number of GH enzymes that have been examined for potential therapeutic effects is limited. In this study, we screened sixteen GHs for their ability to disperse mono-microbial and polymicrobial biofilms grown in different environments. Six GHs, α-amylase (source: A. oryzae), alginate lyase (source: various algae), pectinase (source: Rhizopus sp.), amyloglucosidase (source: A. niger), inulinase (source: A. niger), and xylanase (source: A. oryzae), exhibited the highest dispersal efficacy in vitro. Two GHs, α-amylase (source: Bacillus sp.) and cellulase (source: A. niger), used in conjunction with meropenem demonstrated infection clearing ability in a mouse wound model. GHs were also effective in improving antibiotic clearance in diabetic mice. To examine their safety, we screened the GHs for toxicity in cell culture. Overall, there was an inverse relationship between enzyme exposure time and cellular toxicity, with twelve out of sixteen GHs demonstrating some level of toxicity in cell culture. However, only one GH exhibited harmful effects in mice. These results further support the ability of GHs to improve antibiotic clearance of biofilm-associated infections and help lay a foundation for establishing GHs as therapeutic agents for chronic wound infections.

NIR-activated nanosystems with self-modulated bacteria targeting for enhanced biofilm eradication and caries prevention

The efficacious delivery of antimicrobial drugs to intractable oral biofilms remains a challenge due to inadequate biofilm penetration and lack of pathogen targeting. Herein, we have developed a microenvironment-activated poly(ethylene glycol) (PEG)-sheddable nanoplatform to mediate targeted delivery of drugs into oral biofilms for the efficient prevention of dental caries. The PEGylated nanoplatform with enhanced biofilm penetration is capable of deshielding the PEG layer under slightly acidic conditions in a PEG chain length-dependent manner to re-expose the bacteria-targeting ligands, thereby facilitating targeted codelivery of ciprofloxacin (CIP) and IR780 to the bacteria after accumulation within biofilms. The nanoplatform tends to induce bacterial agglomeration and suffers from degradation in the acidic oral biofilm microenvironment, triggering rapid drug release on demand around bacterial cells. The self-modulating nanoplatform under near-infrared (NIR) irradiation accordingly displays greatly augmented potency in oral biofilm penetration and disruption compared with drugs alone. Topical oral treatment with nanoplatforms involving synergetic pharmacological and photothermal/photodynamic trinary therapy results in robust biofilm dispersion and efficacious suppression of severe tooth decay in rats. This versatile nanoplatform can promote local accumulation and specific drug transport into biofilms and represents a new paradigm for targeted drug delivery for the management of oral biofilm-associated infections.

Bacterial cellulose synthesis gene regulates cellular c-di-GMP that control Biofilm formation and mussel larval settlement

Bacterial cellulose is a widely dispersed biofilm matrix component, yet the role of cellulose synthesis-encoding gene on the settlement of macrofouling organisms remains elusive. Here, the functional role of the cellulose synthesis gene bcsQ of the bacterium Pseudoalteromonas marina on settlement of Mytilus coruscus larvae was investigated. It was found that the deficiency of the gene bcsQ was associated with biofilm-settlement inducing activity, the secretion of bacterial α- and β-polysaccharides, and cytosolic c-di-GMP content change. The deletion of the gene bcsQ downregulated c-di-GMP level accompanied by reduced production of polysaccharides including cellulose and colanic acid. Bacterial characteristics in the deficient knockout of bcsQ also changed showing a slow cell growth, reducing biofilm forming capacity and increasing biofilm dispersion. The larval settlement rate of M. coruscus onto the ΔbcsQ biofilm was about 46% lower than that of the wild-type strain in comparison. Therefore, the gene bcsQ manipulates cytosolic c-di-GMP that controls secretion of exopolysaccharides and biofilm formation, and indirectly regulates mussel settlement. The present findings shed new light on interactions among function of bacterial cellulose biosynthesis gene, biofilm formation and the settlement of typical fouling organisms.

Characterizations of the viability and gene expression of dispersal cells from Pseudomonas aeruginosa biofilms released by alginate lyase and tobramycin.

Biofilm infections are hard to manage using conventional antibiotic treatment regimens because biofilm structures discourage antibiotics from reaching the entire bacterial community and allow pathogen cells to persistently colonize and develop a plethora of tolerance mechanisms towards antibiotics. Moreover, the dispersed cells from biofilms can cause further complications by colonizing different sites and establishing new cycles of biofilms. Previously, we showed that alginate lyase enzyme (AlyP1400), purified from a marine Pseudoalteromonas bacterium, reduced Pseudomonas aeruginosa biofilm biomass and boosted bactericidal activity of tobramycin by degrading alginate within the biofilm extracellular polymeric substances matrix. In this work, we used a flow cytometry-based assay to analyze collected dispersal cells and demonstrated the synergy between tobramycin with AlyP1400 in enhancing the release of both live and dead biofilm cells from a mucoid P. aeruginosa strain CF27, which is a clinical isolate from cystic fibrosis (CF) patients. Interestingly, this enhanced dispersal was only observed when AlyP1400 was combined with tobramycin and administered simultaneously but not when AlyP1400 was added in advance of tobramycin in a sequential manner. Moreover, neither the combined nor sequential treatment altered the dispersal of the biofilms from a non-mucoid P. aeruginosa laboratory strain PAK. We then carried out the gene expression and tobramycin survival analyses to further characterize the impacts of the combined treatment on the CF27 dispersal cells. Gene expression analysis indicated that CF27 dispersal cells had increased expression in virulence- and antibiotic resistance-related genes, including algR, bdlA, lasB, mexF, mexY, and ndvB. In the CF27 dispersal cell population, the combinational treatment of AlyP1400 with tobramycin further induced bdlA, mexF, mexY, and ndvB genes more than non-treated and tobramycin-treated dispersal cells, suggesting an exacerbated bacterial stress response to the combinational treatment. Simultaneous to the gene expression analysis, the survival ability of the same batch of biofilm dispersal cells to a subsequent tobramycin challenge displayed a significantly higher tobramycin tolerant fraction of cells (~60%) upon the combinational treatment of AlyP1400 and tobramycin than non-treated and tobramycin-treated dispersal cells, as well as the planktonic cells (all below 10%). These results generate new knowledge about the gene expression and antibiotic resistance profiles of dispersed cells from biofilm. This information can guide the design of safer and more efficient therapeutic strategies for the combinational use of alginate lyase and tobramycin to treat P. aeruginosa biofilm-related infections in CF lungs.

Aqueous extracts of spices inhibit biofilm in Listeria monocytogenes by downregulating release of eDNA

Listeria monocytogenes is a Gram-positive mesophilic foodborne pathogen whose pathogenicity is regulated by various environmental stress factors. The ability to form robust biofilm makes it difficult to eradicate this bacteria from food processing environments. Also, there is an increase in the antibiotic resistant food isolates of L. monocytogenes. Therefore, there is a constant need for the development of novel food preservation techniques and therapeutics. In this study, we sought to determine the effectiveness of clove and cinnamon water extracts on the listerial biofilm initiation, dispersion, and expression of the virulence genes. It was observed that the spice water extracts not only inhibited the biofilm formation of L. monocytogenes but also accelerated the dispersion. The spice extracts at higher concentrations were found to be bactericidal to L. monocytogenes. The extracts downregulated the expression of virulence genes and the release of extracellular DNA (eDNA) in the biofilm. The decreased ability to form biofilm could be attributed to the inhibition of eDNA secretion. Thus the water extracts of cinnamon and clove can be used as food preservatives against the biofilm formation of L. monocytogenes.

Antibiofilm activity of Cutibacterium acnes cell-free conditioned media against Staphylococcus spp.

Staphylococcus spp. and Cutibacterium acnes are members of the skin microbiome but can also act as pathogens. Particularly, Staphylococcus species are known to cause medical devices-associated infections, and biofilm production is one of their main virulence factors. Biofilms allow bacteria to adhere and persist on surfaces, protecting them from antimicrobials and host defenses. Since both bacteria are found in the human skin, potentially competing for niches, we aimed to investigate if C. acnes produces molecules that affect Staphylococcus spp. biofilm formation and dispersal. Thus, we evaluated the impact of C. acnes cell-free conditioned media (CFCM) on S. aureus, S. epidermidis, S. hominis, and S. lugdunensis biofilm formation. S. lugdunensis and S. hominis biofilm formation was significantly reduced with C. acnes CFCM without impact on their planktonic growth. C. acnes CFCM also significantly disrupted S. hominis established biofilms. The active molecules against S. lugdunensis and S. hominis biofilms appeared to be distinct since initial characterization points to different sizes and sensitivity to sodium metaperiodate, although the activity is highly resistant to heat in both cases. Mass spectrometry analysis of the fractions active against S. hominis revealed several potential candidates. Investigating how species present in the same environment interact, affecting the dynamics of biofilm formation, may reveal clinically useful compounds as well as molecular aspects of interspecies interactions.

Anti-Biofilm Activity of Cannabigerol against Streptococcus mutans.

Streptococcus mutans is a common cariogenic bacterium in the oral cavity involved in plaque formation. Previous studies showed that Cannabigerol (CBG) has bacteriostatic and bacteriocidic activity against S. mutans. The aim of the present study was to study its effect on S. mutans biofilm formation and dispersion. S. mutans was cultivated in the presence of CBG, and the resulting biofilms were examined by CV staining, MTT assay, qPCR, biofilm tracer, optical profilometry, and SEM. Gene expression was determined by real-time qPCR, extracellular polysaccharide (EPS) production was determined by Congo Red, and reactive oxygen species (ROS) were determined using DCFH-DA. CBG prevented the biofilm formation of S. mutans shown by reduced biofilm biomass, decreased biofilm thickness, less EPS production, reduced DNA content, diminished metabolic activity, and increased ROS levels. CBG altered the biofilm roughness profile, resulting in a smoother biofilm surface. When treating preformed biofilms, CBG reduced the metabolic activity of S. mutans with a transient effect on the biomass. CBG reduced the expression of various genes involved in essential metabolic pathways related to the cariogenic properties of S. mutans biofilms. Our data show that CBG has anti-biofilm activities against S. mutans and might be a potential drug for preventive treatment of dental caries.

Biofilm dispersal induced by mechanical cutting leads to heightened foodborne pathogen dissemination

The biofilm life cycle where bacteria alternate between biofilm and planktonic lifestyles poses major implications in food spoilage and gastrointestinal infections. Recent studies had shown that freshly biofilm-dispersed cells have a unique physiology from planktonic cells, raising the fundamental question if biofilm-dispersed cells and planktonic cells disseminate differently across food surfaces. Mechanical dislodging via cutting can cause biofilm dispersal and eventual food cross-contamination. Here, we showed that biofilm-dispersed bacteria from various foodborne pathogens were transferred from freshly cut surface at a higher rate to the cutting material than that of planktonic bacteria. When the cutting tool was used to cut a fresh surface, more biofilm-dispersed bacteria were disseminated from the cutting tool to the newly cut surface than planktonic bacteria. Our observations were applicable to cutting tools of various materials and cut surfaces, where polystyrene and surfaces with high water content were most susceptible to biofilm transfer, respectively. Simple washing with detergent and mechanical wiping could aid bacterial removal from cutting tools. Our work revealed that biofilm-dispersed cells were transferred at a higher rate than planktonic cells and cutting tool was an important medium for pathogen cross-contamination, thus providing insights in maintaining their cleanliness in food processing industries.

Carbon starvation of Pseudomonas aeruginosa biofilms selects for dispersal insensitive mutants

BackgroundBiofilms disperse in response to specific environmental cues, such as reduced oxygen concentration, changes in nutrient concentration and exposure to nitric oxide. Interestingly, biofilms do not completely disperse under these conditions, which is generally attributed to physiological heterogeneity of the biofilm. However, our results suggest that genetic heterogeneity also plays an important role in the non-dispersing population of P. aeruginosa in biofilms after nutrient starvation.ResultsIn this study, 12.2% of the biofilm failed to disperse after 4 d of continuous starvation-induced dispersal. Cells were recovered from the dispersal phase as well as the remaining biofilm. For 96 h starved biofilms, rugose small colony variants (RSCV) were found to be present in the biofilm, but were not observed in the dispersal effluent. In contrast, wild type and small colony variants (SCV) were found in high numbers in the dispersal phase. Genome sequencing of these variants showed that most had single nucleotide mutations in genes associated with biofilm formation, e.g. in wspF, pilT, fha1 and aguR. Complementation of those mutations restored starvation-induced dispersal from the biofilms. Because c-di-GMP is linked to biofilm formation and dispersal, we introduced a c-di-GMP reporter into the wild-type P. aeruginosa and monitored green fluorescent protein (GFP) expression before and after starvation-induced dispersal. Post dispersal, the microcolonies were smaller and significantly brighter in GFP intensity, suggesting the relative concentration of c-di-GMP per cell within the microcolonies was also increased. Furthermore, only the RSCV showed increased c-di-GMP, while wild type and SCV were no different from the parental strain.ConclusionsThis suggests that while starvation can induce dispersal from the biofilm, it also results in strong selection for mutants that overproduce c-di-GMP and that fail to disperse in response to the dispersal cue, starvation.

Антибиопленочная активность антиматриксных молекул

Внеклеточный матрикс биопленок обеспечивает фиксацию биопленки на биологической поверхности и защиту ее бактерий от внешних неблагоприятных факторов. Основным структурным компонентом био­пленок является внеклеточное полисахаридное вещество. Ключевыми молекулярными структурами, поддерживающими трехмерную структуру биопленки, считают экзополисахариды и амилоидоподобные волокна. До недавнего времени предполагалось, что большинство механизмов диспергирования биопленок ассоциировано с функционированием матриксных деградирующих ферментов, таких как гликозидгидролазы, полисахаридные лиазы и протеазы. Однако продемонстрировано, что в процессе разрушения матриксных экзополисахаридов и амилоидоподобных волокон играют самостоятельную роль малые молекулы. Среди соединений, нарушающих матрикс биопленки, различают антиматриксные молекулы, соединения, взаимодействующие с микродоменами бактериальной мембраны, и бактериальные поверхностно-активные вещества (биосурфагенты). Продемонстрировано, что соединения данных групп могут ингибировать образование биопленок и способствовать их диспергированию. Из группы антиматриксных молекул полиаминное соединение норспермидин взаимодействует с экзополисахаридами, а производные бензохинона AA-861 и сесквитерпеновый лактон партенолид — с TasA-амилоидоподобными волокнами. Норспермидин предотвращает образование и диспергирует биопленки различных бактерий, включая Acinetobacter baumannii, Bacillus subtili, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis. Соединение AA-861 проявляет активность против биопленок, которые образованы бактериями Streptococcus mutans, Bacillus cereus, Escherichia coli, а партенолид диспергирует биопленки, сформированные Escherichia coli и Bacillus cereus. Сарагосовые кислоты, взаимодействуя с микродоменами бактериальной мембраны, нарушают функционирование рафт-ассоциированных протеинов бактерий. Малые антиматриксные молекулы и нацеленные на микродомены мембраны бактерий, инициирующие диспергирование биопленки, безусловно, станут основанием для разработки эффективных антибиопленочных терапевтических лекарственных средств.

Медикаментозное влияние на диспергирование биопленки. Аминокислоты и их дериваты

В научном обзоре представлено значение некоторых аминокислот в процессе диспергирования бактериальных биопленок. Для написания статьи осуществлялся поиск информации с использованием баз данных Scopus, Web of Science, MedLine, PubMed, Google Scholar, EMBASE, Global Health, The Cochrane Library, CyberLeninka. Отражено влияние аминокислот как нутриентов на поздние стадии жизни биопленки, представлено влияние D-энантиомеров аминокислот, триптофана и его дериватов на диспергирование биопленки. Подчеркнуто, что D-аминокислоты, а именно D-тирозин, D-метионин, D-лейцин, D-триптофан, препятствуют адгезии амилоидных волокон, которые удерживают в агрегации бактерии биопленок. D-аминокислоты ингибируют экспрессию генов, участвующих в продукции компонентов матрикса биопленки, и таким образом реализуют свое антибиопленочное действие. Раскрыта способность триптофана предупреждать развитие и вызывать диспергирование биопленок, в частности, ассоциированных с бактериями Pseudomonas aeruginosa. Указано, что роль антранилатов заключается в нарушении структуры биопленки и стимулировании отрыва участков от биопленок, сформированных бактериями Pseudomonas aeruginosa. Антранилаты могут способствовать прерыванию хронизации инфекционного процесса. Предположено, что использование аминокислот и их дериватов, создание новых химических соединений, которые имитируют структуры молекул аминокислот или изменяют активность синтеза и деградации определенных аминокислот, позволит целенаправленно управлять циклом жизни биопленок некоторых видов патогенных бактерий, что будет способствовать излечению инфекционных рецидивирующих и хронических заболеваний. Представлена перспектива разработки новых препаратов на основе антраниловой кислоты и галогенерированных индолов, способствующих бактериальной эрадикации при инфекциях респираторного тракта, ассоциированных с развитием биопленок бактерий антибиотикорезистентных бактериальных агентов.

Медикаментозное влияние на диспергирование биопленки. Доноры оксида азота

В научном обзоре отражены современные представления о значении низких концентраций оксида азота в процессе диспергирования и эрадикации бактериальной биопленки. Для написания статьи осуществлялся поиск информации с использованием баз данных Scopus, Web of Science, MedLine, PubMed, Google Scholar, EMBASE, Global Health, The Cochrane Library, CyberLeninka. Охарактеризовано значение оксида азота в развитии рецидивов инфекционно-воспалительных заболеваний респираторного тракта. Подчеркнута способность оксида азота при высоких (микромолярных) концентрациях быть высокотоксичным соединением для бактерий и важнейшим компонентом неспецифической защиты макроорганизма от патогенных микроорганизмов, а при низких (наномолярных) концентрациях выполнять роль сигнальной молекулы. Отражена способность монооксида азота диспергировать биопленку бактерий через усиление экспрессии или активности протеинов, связанных с подвижностью бактерий: пили, рамнолипидов. Представлена характеристика основных доноров оксида азота и молекулярных платформ, которые могут быть использованы для их доставки в макроорганизм. Описаны основные группы доноров оксида азота, такие как органические нитраты, соединения нитрозилированных металлов, диолаты диазения (N-diazeniumdiolate — NONOate) и S-нитрозотиолы (S-nitrosothiol — RSNO). Указано, что доноры оксида азота усиливают диспергирование биопленки и способствуют повышению антибактериальной активности антибиотиков. Охарактеризованы молекулярные платформы доставки и оптимизации режима высвобождения оксида азота: неорганические и полимерные наночастицы, металлорганические координационные полимеры, дендримеры, липосомы, мицеллы. Подчеркнута возможность использования данных соединений для разработки новых препаратов, которые будут эффективны при лечении заболеваний, ассоциированных с формированием биопленок патогенными бактериями.

Диспергирование бактериальной биопленки и хронизация инфекционного процесса респираторного тракта

Научный обзор посвящен современным представлениям о процессе диспергирования биопленки патогенных бактерий. Для написания статьи осуществлялся поиск информации с использованием баз данных Scopus, Web of Science, MedLine, PubMed, Google Scholar, EMBASE, Global Health, The Cochrane Library, CyberLeninka. Диспергирование биопленки представляет собой скоординированное высвобождение из матрикса дифференцированных подвижных хемотаксических бактерий и их распространение на новые локусы колонизации. Продемонстрирована зависимость диспергирования биопленки от влияния плотности в ней бактерий, сигналов кворум-сенсинга и обеспечения питательными веществами. Дана характеристика механизмам, фазам и типам диспергирования биопленки. Выделены три фазы диспергирования бактериальной биопленки: 1) отделение клеток от бактериальной колонии биопленок; 2) транслокация бактерий на новое место локализации; 3) адгезия бактерий к субстрату нового региона. Описаны активный и пассивный механизмы диспергирования биопленки. Охарактеризованы три типа диспергирования: эрозия, шелушение и отсев. Рассмотрена последовательность событий, ведущих к деструкции биопленки. Описаны триггеры диспергирования бактериальной биопленки, которыми являются различные экзо- и эндогенные факторы. Акцентировано внимание на лизисе бактерий, который способствует образованию полостей в матриксе биопленки, как важнейшем компоненте ее диспергирования. Охарактеризована роль диспергирования биопленки в развитии рецидивирующих и хронических инфекционно-воспалительных заболеваний респираторного тракта. Акцентировано внимание на особенности популяции диспергированных патогенов, состоящей как из отдельных бактерий, так и из бактериальных агрегатов, что позволяет бактериям лучше адаптироваться к изменениям окружающей среды.

Антибиопленочные эффекты муколитических лекарственных средств

Муколитические лекарственные средства обладают способностью нарушать структуру матрикса и разрушать сформированные бактериальные биопленки. Наиболее изученным является N-ацетилцистеин. Впервые антибиопленочная активность N-ацетилцистеина была продемонстрирована Ciro Pérez-Giraldo и соавт. в 1997 году. Они показали, что вещество оказывает ингибирующее действие на рост бактерий и способствует диспергированию биопленок, образованных бактериями Staphylococcus epidermidis. В настоящее время установлено, что N-ацетилцистеин обладает выраженной активностью, направленной против биопленок, сформированных различными грамположительными и грамотрицательными бактериями, в том числе и антибиотикорезистентными бактериальными штаммами метициллинрезистентного золотистого стафилококка и хинолонрезистентных синегнойных палочек. N-ацетилцистеин способствует проникновению пенициллинов, полимиксинов, фторхинолонов в самые глубокие слои биопленки, преодолевая антибио­тикорезистентность причинно-значимых бактериальных агентов. N-ацетилцистеин может применяться как антибиопленочное лекарственное средство при хронических бактериально-ассоциированных заболеваниях, в частности при эпизодах респираторных инфекций у больных муковисцидозом, хроническом бронхите, хронической обструктивной болезни легких. Полагают, что N-ацетилцистеин обладает превосходным профилем безопасности и эффективности при лечении заболеваний, которые сопровождаются образованием бактериальных биопленок. N-ацетилцистеин и нанотехнологические лекарственные средства, в которых его молекулы скомбинированы с частицами галлия или серебра, могут стать средствами выбора, диспергирующими биопленки и усиливающими эффективность антибактериальной терапии, особенно при заболеваниях, вызванных антибиотикорезистентными штаммами микроорганизмов.

Медикаментозное управление диспергированием биопленки за счет регуляции активности бактериального циклического дигуанозинмонофосфата (часть 2)

Инфекционный процесс, вызванный патогенными бактериями, может сопровождаться формированием биопленки, что предопределяет сохранность бактерий и снижение эффективности действия антибактериальных средств. Разработка препаратов, которые способствуют диспергированию бактериальной биопленки, является одним из важнейших терапевтических направлений, способствующих решению проблемы лечения бактериальных инфекций, вызванных микроорганизмами, резистентными к действию антибактериальных средств. Одной из целевых, участвующих в формировании биопленок бактериальных молекул, которые могут быть подвергнуты медикаментозной регуляции, является вторичная мессенджерная нуклеозидная молекула — циклический дигуанозинмонофосфат (ц-ди-ГМФ). Медикаментозное подавление внутрибактериальной концентрации мессенджерной молекулы ц-ди-ГМФ или блокирование ее активности позволяет предотвратить формирование и вызвать разрушение бактериальной биопленки, что сопровождается повышением эффективности лечения бактериальных инфекций. Снижение уровня внутрибактериальной концентрации ц-ди-ГМФ может быть достигнуто ингибированием процессов синтеза за счет 1) подавления активности DGC; 2) ограничения доступности субстратов, необходимых для синтеза ц-ди-ГМФ; 3) усиления деградации молекулы ц-ди-ГМФ за счет усиления активности PDE. Терапия инфекционных заболеваний, которые сопровождаются формированием биопленок, требует медикаментозной индукции диспергирования бактерий из биопленок и применения целенаправленных антибиотических лекарственных средств, вызывающих гибель высвобожденных из биопленок бактерий. Использование аналогов ц-ди-ГМФ, нарушающих функционирование нативного ц-ди-ГМФ, и блокирование таргетных рецепторов и других молекулярных структур также может приводить к диспергированию бактериальной биопленки. Лекарственные средства, модулирующие активность ц-ди-ГМФ, позволят повысить эффективность лечения бактериальных инфекций, которые сопровождаются формированием биопленок.