Traditional Antibiotic Therapy Research Articles

Cell membrane-coated nanoparticles for the treatment of bacterial infection.

Despite the enormous success of antibiotics in antimicrobial therapy, the rapid emergence of antibiotic resistance and the complexity of the bacterial infection microenvironment make traditional antibiotic therapy face critical challenges against resistant bacteria, antitoxin, and intracellular infections. Consequently, there is a critical need to design antimicrobial agents that target infection microenvironment and alleviate antibiotic resistance. Cell membrane-coated nanoparticles (CMCNPs) are biomimetic materials that can be obtained by wrapping the cell membrane vesicles directly onto the surface of the nanoparticles (NPs) through physical means. Incorporating the biological functions of cell membrane vesicles and the superior physicochemical properties of NPs, CMCNPs have shown great promise in recent years for targeting infections, neutralizing bacterial toxins, and designing bacterial infection vaccines. This review highlights topics where CMCNPs present great value in advancing the treatment of bacterial infections, including drug delivery, detoxification, and vaccination. Lastly, we discuss the future hurdles and prospects of translating this technique into clinical practice, providing a comprehensive review of the technological developments of CMCNPs in the treatment of bacterial infections. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Photoinactivation of Salmonella enterica exposed to 5-aminolevulinic acid: Impact of sensitization conditions and irradiation time.

The photodynamic inactivation (PDI) represents the potential alternative to traditional antibiotic therapy, and can be applied to treat various bacterial infections, including those caused by Gram-negative bacterial strains. One of the treatment modalities is based on the capacity of bacterial cells to synthesize the excess amounts of porphyrins after exposure to an externally applied 5-aminolevulinic acid (5-ALA), which makes them photosensitive and leads to reduced survival after irradiation with an appropriately selected light source. This study focuses on the sensitization and the photoinduced inactivation of Salmonella enterica cells in PBS containing 0.5mM 5-ALA, incubated at 37°C for 4h or for 20h and afterwards irradiated with violet LED light (11.1mW/cm2, a peak at 400nm). It has been found that both amounts and composition of endogenous porphyrins not only depended on the incubation duration, but also were affected by externally induced photo- and chemo-oxidation reactions. The application of different sensitization conditions has revealed that the increasing amounts of endogenously produced porphyrins do not ensure the proportional reduction of bacterial cell survival numbers. The comparative investigations also demonstrated that the presence of endogenously produced porphyrins in the medium results in secondary sensitization of bacterial cells and causes a notably stronger photoinactivation effect in comparison to their externally applied standards.

Potential risks and treatment options for colonic diverticular disease Novelties based on international guidelines

The prevalence of colonic diverticulosis is growing worldwide due to dietary and lifestyle changes. Colonic diverticulosis does not cause any complaints in a significant proportion of individuals; therefore, it is usually diagnosed by accident and does not require any treatment. Diverticular disease, which constitutes about 25% of the cases, is associated with presenting symptoms, and has various forms based on the course and severity of the disease. From the early 2000s, the better understanding of the pathophysiologic pathways which play a role in the development of the diverticular disease (genetic background, low-grade chronic inflammation and intestinal dysbiosis) promoted prevention, diagnostics and finding treatment options. The main conclusions: It is a challenge to distinguish uncomplicated but symptomatic diverticular disease from irritable bowel syndrome. The prevalence of acute diverticulitis is lower than it was previously assumed. The role of diagnostic imaging, mainly abdominal computer tomography, has become more important to aid the rapid and correct diagnosis of acute diverticulitis and to determine its severity. Although a high-fiber diet may be recommended for general health purposes, there is little evidence that it benefits recovery during acute diverticulitis episodes or prevents recurrent episodes. Traditional antibiotic therapy as the mainstay of treatment of acute uncomplicated diverticulitis such as routine hospital admission has been challenged recently. In an acute episode of diverticulitis, performing colonoscopy should be avoided as it is associated with an increased risk of colonic perforation. If there was no screening colonoscopy within 3 years, it is strongly recommended at least 6 weeks after the acute episode to exclude colorectal carcinoma. Routine colonoscopy may be omitted in certain cases. Complicated acute diverticulitis should not necessarily be treated by emergency surgery. In thecase of hemodynamically stable and immunocompetent patients, resection with primary anastomosis may be preferred over a Hartmann's procedure for the treatment of perforated diverticulitis and diffuse peritonitis. With this review, the authors intend to facilitate providing up-to-date and customized treatment of diverticular disease in the daily practice.

Polymeric Nanoplatforms for the Delivery of Antibacterial Agents

AbstractAntibiotic therapy is the first choice for the treatment of bacterial infections in the clinic. However, the continuously increasing bacterial resistance makes traditional antibiotic therapy difficult to achieve ideal therapeutic performance, necessitating the development of new antibacterial strategies. Polymeric nanoparticles have received much attention in biomedical applications. They can be used as nanocarriers to deliver a variety of antibacterial agents to the infected area. Compared to traditional drug delivery systems, polymeric nanoparticles show various advantages, including improved drug stability, long circulation time, controlled drug release, selective drug accumulation, and so on. This review summarizes the current applications of polymeric nanoparticles for the delivery of antibacterial agents. First, an extensive review of the applications of polymeric nanoplatforms in the delivery of various antibacterial drugs is conducted. The mechanisms and strategies of various stimuli‐responsive polymeric nanoplatforms are then discussed, especially focusing on how to improve the antibacterial efficacy and reduce the side effects. Finally, the challenges of future developments of polymeric nanoplatforms in the delivery of antibacterial agents are discussed.

Dual-mode antibacterial core-shell gold nanorod@mesoporous-silica/curcumin nanocomplexes for efficient photothermal and photodynamic therapy

Bacteria are becoming increasingly resistant to antibiotics because of their overuse. As a result, new therapies are urgently needed to replace traditional antibiotic therapies. Photodynamic therapy and photothermal therapy are considered to be effective sterilization methods instead of antibiotics to resist drug-resistant pathogens. In this work, silica-coated gold nanorods with photothermal conversion effects were employed as photothermal carriers, and curcumin was selected as photosensitizer, to form PTT/PDT dual-mode antibacterial nanocomposites (AuNRs@Cur). Comparing with their counterparts Cur and AuNRs, AuNRs@Cur exhibited higher singlet oxygen yield and photothermal conversion efficiency, which greatly improved the utilization rate of photosensitizer and consequently effectively enhanced the photoinactivation effect of bacteria. The inhibition rate of AuNRs@Cur on S. aureus and E. coli under 405 and 808 nm dual irradiation was higher than that of Cur or PDT alone. The changes of bacterial membrane structure were revealed by scanning electron microscopy (SEM) and confocal fluorescence imaging. The reactive oxygen species and thermal energy generated by dual-wavelength (405 + 808 nm) laser irradiation can cause the destruction of bacterial outer membrane structure, resulting in bacterial death. In addition, the cytotoxicity and hemolytic activity of AuNRs@Cur were negligible. AuNRs@Cur nanocomposites proved thatphotodynamic-photothermal synergistic treatment can greatly improve the bactericidal effect. Therefore, construction of AuNRs@Cur provides a new idea for pathogen infection caused by drug-resistant bacteria, and provides relevant nano-carrier experience for follow-up drugs.

Activation of PTH1R alleviates epididymitis and orchitis through Gq and β-arrestin-1 pathways

Inflammation in the epididymis and testis contributes significantly to male infertility. Alternative therapeutic avenues treating epididymitis and orchitis are expected since current therapies using antibiotics have limitations associated to side effects and are commonly ineffective for inflammation due to nonbacterial causes. Here, we demonstrated that type 1 parathyroid hormone receptor (PTH1R) and its endogenous agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP), were mainly expressed in the Leydig cells of testis as well as epididymal epithelial cells. Screening the secretin family G protein-coupled receptor identified that PTH1R in the epididymis and testis was down-regulated in mumps virus (MuV)- or lipopolysaccharide (LPS)-induced inflammation. Remarkably, activation of PTH1R by abaloparatide (ABL), a Food and Drug Administration-approved treatment for postmenopausal osteoporosis, alleviated MuV- or LPS-induced inflammatory responses in both testis and epididymis and significantly improved sperm functions in both mouse model and human samples. The anti-inflammatory effects of ABL were shown to be regulated mainly through the Gq and β-arrestin-1 pathway downstream of PTH1R as supported by the application of ABL in Gnaq± and Arrb1-/- mouse models. Taken together, our results identified an important immunoregulatory role for PTH1R signaling in the epididymis and testis. Targeting to PTH1R might have a therapeutic effect for the treatment of epididymitis and orchitis or other inflammatory disease in the male reproductive system.

Prospecting of potentially probiotic lactic acid bacteria from bovine mammary ecosystem: imminent partners from bacteriotherapy against bovine mastitis.

Mastitis is one of the most important causes of loss of cattle production, burdening producers due to the increased cost of milk production and decreased herd productivity. The development of alternative methods for the treatment and prevention of mastitis other than traditional chemical antibiotic therapy needs to be implemented to meet international pressures to reduce the use of these drugs and promote the elimination of multiresistant microbial strains from the environment. Treatment with probiotic bacteria or yeast strains offers a possible strategy for the control of mastitis. The objective of this work was to isolate, identify, and characterize lactic bacteria from milk and the intramammary duct of Gyr, Guzerat, Girolando 1/2, and Holstein cattle breeds from Brazil. Samples of 115 cows were taken, a total of 192 bacteria isolates belonging to 30 species were obtained, and 81 were selected to evaluate their probiotic potential in in vitro characterization tests. In general, bacteria isolated from the mammary gland have low autoaggregation, cell surface hydrophobicity, and co-aggregation with mastitis etiological bacteria Staphylococcus aureus and Escherichia coli. Also, they have biofilm assembly capacity, inability to produce exopolysaccharides, high production of H2O2, and strong antagonism against mastitis pathogens. Ten lactic bacteria isolates were used in co-culture with human MDA-MB-231 breast epithelial cells to assess their adhesion capacity and impairment of the S. aureus invasion. Our results, therefore, contribute to the future production of new prevention and treatment tools for bovine mastitis.

Маркери порушення фібрилогенезу у дітей з різними варіантами перебігу пієлонефриту

Актуальність. Останніми роками клінічний перебіг пієлонефриту у дітей характеризується збільшенням кількості латентних та «стертих» форм захворювання, підвищенням резистентності до традиційної антибактеріальної терапії, що призводить до хронізації і рецидивування патологічного процесу в нирках. При цьому в структурі нефропатій у дітей переважають захворювання вродженого та спадкового генезу, а також захворювання, пов’язані зі спадковою схильністю, що мають прихований початок та торпідний перебіг. Особливої уваги заслуговують діти з проявами дисплазії сполучної тканини. Мета дослідження: пошук можливих клініко-лабораторних маркерів, асоційованих із порушенням фібрилогенезу в дітей з різними варіантами перебігу пієлонефриту, та з’ясування ролі порушення фібрилогенезу у тяжкості перебігу пієлонефриту у дітей. Матеріали та методи. Обстежено 60 дітей з пієлонефритом від 3 до 18 років. За результатами катамнестичного спостереження вони були поділені на дві групи: І — 30 дітей з пієлонефритом, в катамнезі яких діагностувалось 3 і більше епізоди рецидиву пієлонефриту впродовж року, ІІ — 30 дітей з пієлонефритом, в яких упродовж року не відмічалось рецидивів захворювання. Контрольну групу становили 42 соматично здорові дитини того ж віку. Усім дітям проводилося рутинне комплексне клініко-лабораторне обстеження та встановлювались клініко-лабораторні маркери порушення фібрилогенезу (фенотипові ознаки недиференційованої дисплазії сполучної тканини, оксипролін в сечі). Проводилось молекулярно-генетичне тестування локусів AA та AG поліморфного локусу RS 605143 гена COL4A1. Результати. У дітей з рецидивуючим перебігом пієлонефриту вірогідно частіше відмічались фенотипові ознаки недиференційованої дисплазії сполучної тканини порівняно з даними дітей, в яких спостерігався тільки один епізод пієлонефриту протягом року, а саме: гіпермобільність суглобів (у 53 % дітей проти 6,67 % у групі порівняння, в контролі — 4,76 %), ­астенічна тілобудова (56,67 % проти 26,67 %, в контролі — 16,67 %), порушення зору (86,67 % проти 36,67 %, в контролі — 7,14 %), деформація грудної клітки (43,33 % проти 10 %, в контролі — 4,76 %), сколіотична постава (53,33 % проти 13,33 %, в контролі — 4,76 %), арахнодактилія та схильність до кровотеч відмічались лише у дітей І групи (23,33 та 6,67 % відповідно, в контролі не відмічалось). Визначення рівня оксипроліну у сечі в дітей з рецидивуючим пієлонефритом свідчить про посилення розпаду та екскреції продуктів обміну колагену в дитячому організмі у 97 % обстежених, що значно перевищує частоту виділення оксипроліну з сечею у дітей з гострим перебігом пієлонефриту (10 %), та вказує на виражене порушення катаболізму колагену в дітей, схильних до рецидивування пієлонефриту. Встановлена вірогідно вища частота «дикого» генотипу АА — rs605143 гена колагену COL4A1 у дітей із рецидивуючим перебігом пієлонефриту порівняно з даними осіб загальнопопуляційної контрольної групи (21,4 % проти 4,8 %, p < 0,05). Наявність у дитини генотипу АА поліморфного локусу rs605143 гена COL4A1 у п’ять разів збільшує ризик розвитку рецидивування хронічного пієлонефриту (відношення шансів 5,105, 95% довірчий інтервал 0,12–0,87). Висновки. З метою прогнозування у дітей генетично детермінованої схильності до рецидивування пієлонефриту рекомендується проведення молекулярно-генетичного тестування генотипів AA та AG поліморфного локусу rs605143 гена колагену COL4A1.

THEORETICAL STUDY OF THE PRINCIPLES OF MODERN BACTERIOPHAGIC THERAPY

Phagotherapy is an approach to treating bacterial infections using bacteriophages. Bacteria viruses can be used as an alternative to antibiotics in the widespread development of antibiotic resistance among microbial strains. This problem becomes more and more over time because of the misuse of antibiotic therapy. In the nature of bacteriophages have already laid specificity for certain microbes, while they do not harm the human body. Treatment using bacterium viruses provides an alternative to traditional methods in bacterial infections. It remains possible to develop bacterial resistance to bacteriophages, but such resistance is easier to overcome than antibiotic resistance. Because bacteriophages can evolve, like bacteria, causing resistance to disappear. Bacteriophages are specific and exhibit their effect on one or more species, (Maghsoodi, Chatterjee, Andricioaei, ＆ Perkins, 2019) while traditional antibiotic therapy affects both harmful bacteria and the rest of the human body microflora. It is the peculiarity of bacteriophages to exhibit their therapeutic effect on a limited range of microbes make them safe for beneficial bacteria (Choudhury, Tanmoy, Maiti, Biswajit, Venugopal, Karunasagar, ＆Indrani, 2019). Also, a significant advantage is that lytic viruses of bacteria, unlike antibiotics, do not cause bacteriostat, but have only a bactericidal effect, which prevents a possible relapse of the infectious process for a longer period. Some scientists suggest the theory that administering one dose of bacteriophages is enough to cope with the causative agent of the disease, but the main criterion is the immune clearance of phages. Also, a significant advantage in favor of using of bacteriophage drugs is those bacteriophages are distributed throughout the globe, in addition, their composition and species diversity are huge. From this point there is one minus - in our time, the mechanism of patenting phages remains incomprehensible. For pharmaceutical companies, there are many questions about the biodiversity sharing, as it is necessary to amend various protocols. However, despite this, bacteriophages bred in the laboratory attract the attention of scientists in the field of intellectual property(Saha,&Mukherjee, 2019). The article contains a classification of bacteriophages, a description of the mechanism of action on bacteria and their recognition, a comparison of bacterium viruses with antibiotics. The purpose of this study was to describe the modern classification of bacteriophages, to substantiate the use of cellular phages, and to describe the principles of bacteriophages treatment of diseases associated with the respiratory system.

Photodynamic and Photothermal Ce6-Modified Gold Nanorod as a Potent Alternative Candidate for Improved Photoinactivation of Bacteria.

The global rise of antibiotic resistance of pathogenic bacteria has become an increasing medical and public concern, which is further urging the development of antimicrobial channels for treating infectious diseases. The combination of photodynamic therapy (PDT) with photothermal therapy (PTT) has been considered as a promising alternative way for the replacement of traditional antibiotic therapy. In this research, the newly fabricated Chlorin-e6 (Ce6) conjugated mesoporous silica-coated AuNRs, designated AuNR@SiO2-NH2-Ce6, exhibited synergistic photothermal effects and single oxygen localized generation property, and showed stronger photoinactivation for bacteria compared with Ce6. AuNR@SiO2-NH2-Ce6 can anchor to the cell membrane and accumulate in the interior of cells. Furthermore, the unique porous structure of AuNR@SiO2NH2 enabled Ce6 encapsulation in the mesopores and was subsequently released and activated by photothermic effect, allowing the generated single oxygen to penetrate into the cytoplasmic membrane or directly enter the interior of bacteria cells, thus overcoming the inherent defects of single oxygen. AuNR@SiO2-NH2-Ce6 not only damaged the integrity of the cell membrane of bacteria but also facilitated the cellular permeation and accumulation of external nanoagents in the bacteria upon light irradiation. In addition, AuNR@SiO2-NH2-Ce6 exhibited negligible cytotoxicity toward mammalian cells and hemolytic activity. Therefore, AuNR@SiO2-NH2-Ce6 may be highly promising candidates as topical antibacterial agents, and this study has wide implications on the design of next-generation antimicrobial agents.

Enhanced Antibacterial Activity of CuS-BSA/Lysozyme under Near Infrared Light Irradiation.

The synthesis of multifunctional photothermal nanoagents for antibiotic loading and release remains a challenging task in nanomedicine. Herein, we investigated a simple, low-cost strategy for the preparation of CuS-BSA nanoparticles (NPs) loaded with a natural enzyme, lysozyme, as an antibacterial drug model under physiological conditions. The successful development of CuS-BSA NPs was confirmed by various characterization tools such as transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). Lysozyme loading onto CuS-BSA NPs was evaluated by UV/vis absorption spectroscopy, Fourier-transform infrared spectroscopy (FTIR), zeta potential, and dynamic light scattering measurements. The CuS-BSA/lysozyme nanocomposite was investigated as an effective means for bacterial elimination of B. subtilis (Gram-positive) and E. coli (Gram-negative), owing to the combined photothermal heating performance of CuS-BSA and lysozyme release under 980 nm (0.7 W cm−2) illumination, which enhances the antibiotic action of the enzyme. Besides the photothermal properties, CuS-BSA/lysozyme nanocomposite possesses photodynamic activity induced by NIR illumination, which further improves its bacterial killing efficiency. The biocompatibility of CuS-BSA and CuS-BSA/Lysozyme was elicited in vitro on HeLa and U-87 MG cancer cell lines, and immortalized human hepatocyte (IHH) cell line. Considering these advantages, CuS-BSA NPs can be used as a suitable drug carrier and hold promise to overcome the limitations of traditional antibiotic therapy.

Synergy between Clinical Microenvironment Targeted Nanoplatform and Near-Infrared Light Irradiation for Managing Pseudomonas aeruginosa Infections.

Chronic infections caused by Pseudomonas aeruginosa pose severe threats to human health. Traditional antibiotic therapy has lost its total supremacy in this battle. Here, nanoplatforms activated by the clinical microenvironment are developed to treat P. aeruginosa infection on the basis of dynamic borate ester bonds. In this design, the nanoplatforms expose targeted groups for bacterial capture after activation by an acidic infection microenvironment, resulting in directional transport delivery of the payload to bacteria. Subsequently, the production of hyperpyrexia and reactive oxygen species enhances antibacterial efficacy without systemic toxicity. Such a formulation with a diameter less than 200 nm can eliminate biofilm up to 75%, downregulate the level of cytokines, and finally promote lung repair. Collectively, the biomimetic design with phototherapy killing capability has the potential to be an alternative strategy against chronic infections caused by P. aeruginosa.

Fluorescent Carbon Dot-Curcumin Nanocomposites for Remarkable Antibacterial Activity with Synergistic Photodynamic and Photothermal Abilities.

Photosensitizer (PS)-mediated photodynamic therapy (PDT) has attracted more and more attention as an alternative to traditional antibiotic therapy. Nevertheless, the limitations of traditional photosensitizers seriously hinder their practical application, as a result, the methods to improve the antibacterial properties of traditional photosensitizers have become a hot topic in the field of photomedicine. Herein, a compound nano-PS system has been constructed with synergistic photodynamic and photothermal (PTT) antibacterial effects, triggered by a dual-wavelength illumination. Fluorescent carbon dots (CDs) were synthesized and employed as carriers for the delivery of curcumin (Cur) to obtain CDs/Cur. Upon combined near-infrared and 405 nm visible dual-wavelength irradiation, CDs/Cur could simultaneously generate ROS and a moderate temperature increase, triggering synergistic antibacterial effects against both Gram-positive and Gram-negative bacteria. The results of scanning electron microscopy and fluorescence confocal imaging showed that the combined effect of CDs/Cur with PDT and PTT caused more serious damage to the cell membrane. In addition, CDs/Cur exhibited low cytotoxicity and negligible hemolytic activity, showing great biocompatibility. Therefore, the construction of CDs/Cur by employing CDs as photosensitizer delivery carriers provides a strategy for the improvement of the antibacterial effect of the photosensitizer and the design of next-generation antibacterial agents in photomedicine.

Antibacterial and antibiofilm efficacy of Ag NPs, Ni NPs and Al2O3 NPs singly and in combination against multidrug-resistant Klebsiella pneumoniae isolates

BackgroundAlthough traditional antibiotic therapy provided an effective approach to combat pathogenic bacteria, the long-term and widespread use of antibiotic results in the evolution of multidrug-resistant bacteria. Recent progress in nanotechnology offers an alternative opportunity to discover and develop novel antibacterial agents. MethodsA total of 51 K. pneumoniae strains were collected from several specimens of hospitalized patients and identified by two parallel methods (biochemical tests and Vitek-2 system). The antibiotic sensitivity of isolates was evaluated by disk diffusion antibiogram and Vitek-2 system. The biofilms formation ability of antibiotic-resistant strains was examined by microtiter plate and tube methods based on crystal violet staining. The molecular technique was used to determine key genes responsible for biofilms formation of clinical isolates. The antibacterial and antibiofilm activities of Ag NPs, Ni NPs, Al2O3 NPs singly (NPs) and in combination (cNPs) were investigated against selected strains using standard methods. Moreover, the cytotoxicity of NPs was evaluated on mouse neural crest-derived (Neuro-2A) cell line. ResultsThe results of bacterial studies revealed that more than 80 % of the isolates were resistant to commonly used antibiotics and about 95 % of them were able to form biofilms. Moreover, the presence of fimA and mrkA genes were determined in all biofilm-producing strains. The results of antibacterial and antibiofilm activities of NPs and cNPs demonstrated the lower MIC and MBEC values for Al2O3 NPs singly as well as for Ag/Ni cNPs and Ag/Al2O3 cNPs in combination, respectively. Overall, the inhibitory effects of cNPs were superior to NPs against all strains. Furthermore, the results of the checkerboard assays showed that Ag NPs act synergistically with two other NPs against multidrug-resistant Klebsiella pneumoniae (MDR-K. pneumoniae) isolates. The in vitro cytotoxicity assay revealed no significant toxicity of NPs against Neuro-2A cells. ConclusionIn the present study, the combination of Ag NPs, Ni NPs, and Al2O3 NPs were used against MDR-K. pneumoniae strains and antibacterial and antibiofilm activities were observed for Ag/Ni cNPs and Ag/Al2O3 cNPs.

Stimuli-responsive nanocarriers for bacterial biofilm treatment.

Bacterial biofilm infections have been threatening the human’s life and health globally for a long time because they typically cause chronic and persistent infections. Traditional antibiotic therapies can hardly eradicate biofilms in many cases, as biofilms always form a robust fortress for pathogens inside, inhibiting the penetration of drugs. To address the issues, many novel drug carriers emerged as promising strategies for biofilm treatment. Among them, stimuli-responsive nanocarriers have attracted much attentions for their intriguing physicochemical properties, such as tunable size, shape and surface chemistry, especially smart drug release characteristic. Based on the microenvironmental difference between biofilm infection sites and normal tissue, many stimuli, such as bacterial products accumulating in biofilms (enzymes, glutathione, etc.), lower pH and higher H2O2 levels, have been employed and proved in favor of “on-demand” drug release for biofilm elimination. Additionally, external stimuli including light, heat, microwave and magnetic fields are also able to control the drug releasing behavior artificially. In this review, we summarized recent advances in stimuli-responsive nanocarriers for combating biofilm infections, and mainly, focusing on the different stimuli that trigger the drug release.摘要细菌生物膜常造成长期, 顽固的感染, 因此长久以来都严重威胁着全球人类的生命健康。 由于生物膜会为内部病原体建造其保护性屏障, 阻碍药物的渗透, 因此传统的抗生素疗法通常难以根除生物膜。 为了解决这一问题, 研究人员构建了许多新型的药物载体, 以作为颇具前景的生物膜治疗策略。 其中, 刺激响应型纳米载体具有有趣的物理-化学性质, 例如尺寸, 形状和表面化学可调节的性质, 特别是智能药物释放性质, 因此吸引了人们的广泛关注。 根据生物膜感染位置和正常组织之间的微环境差异, 人们利用多种刺激物, 比如生物膜内积累的细菌产物 (酶, 谷胱甘肽等), 低pH和高H2O2水平, 来设计药物的“按需释放”以清除生物膜。 此外, 包括光, 热, 微波和磁场在内的外源刺激, 也可以用于人工控制药物的释放行为。 本篇综述中, 我们总结了刺激响应型纳米载体在对抗细菌生物膜中的最新进展, 并着重于引发药物释放的多种刺激物。Graphic abstract

The effectiveness of extended binding affinity of prophage lysin PlyARI against Streptococcus suis infection.

Streptococcus suis is an important zoonotic pathogen. An increase in multi-drug-resistant strains has led to poor performance of traditional antibiotic therapies. Thus, alternative antibacterial agents are urgently needed. In this study, we identified a recombined and expressed lysin PlyARI derived from the novel serotype S. suis (Chz) prophage PhiARI0460-1. The recombinant PlyARI at a concentration of 10µg/mL showed high bacteriolytic activity against 30 S. suis isolates. The minimum inhibitory concentration (MIC) of PlyARI against S. suis was found to be as low as 2µg/mL, and the lytic efficiency could be maintained between the range of pH 4 and 12. Additionally, in a mouse infection model, a dose of 0.5mg of PlyARI protected 10 out of 10 mice that were challenged with highly virulent S. suis strain HA9801. Furthermore, the binding specificity of PlyARI was evaluated by constructing a green fluorescent protein (GFP-ARIb), where GFP was fused with the PlyARI-SH3b (cell wall-binding domain, CBD), revealing a high affinity to S. suis, Staphylococcus aureus, and Streptococcus equi along with exhibiting a medium affinity to Streptococcus pneumoniae as well as Streptococcus agalactiae. Overall, our findings indicated that PlyARI may be an alternative antibacterial agent that was useful in treating and possibly the prevention of Streptococcal infections.

Lactiplantibacillus plantarum strains isolated from spontaneously fermented cocoa exhibit potential probiotic properties against Gardnerella vaginalis and Neisseria gonorrhoeae

BackgroundProbiotics are important tools in therapies against vaginal infections and can assist traditional antibiotic therapies in restoring healthy microbiota. Recent research has shown that microorganisms belonging to the genus Lactobacillus have probiotic potential. Thus, this study evaluated the potential in vitro probiotic properties of three strains of Lactiplantibacillus plantarum, isolated during the fermentation of high-quality cocoa, against Gardnerella vaginalis and Neisseria gonorrhoeae. Strains were evaluated for their physiological, safety, and antimicrobial characteristics.ResultsThe hydrophobicity of L. plantarum strains varied from 26.67 to 91.67%, and their autoaggregation varied from 18.10 to 30.64%. The co-aggregation of L. plantarum strains with G. vaginalis ranged from 14.73 to 16.31%, and from 29.14 to 45.76% with N. gonorrhoeae. All L. plantarum strains could moderately or strongly produce biofilms. L. plantarum strains did not show haemolytic activity and were generally sensitive to the tested antimicrobials. All lactobacillus strains were tolerant to heat and pH resistance tests. All three strains of L. plantarum showed antimicrobial activity against the tested pathogens. The coincubation of L. plantarum strains with pathogens showed that the culture pH remained below 4.5 after 24 h. All cell-free culture supernatants (CFCS) demonstrated activity against the two pathogens tested, and all L. plantarum strains produced hydrogen peroxide. CFCS characterisation in conjunction with gas chromatography revealed that organic acids, especially lactic acid, were responsible for the antimicrobial activity against the pathogens evaluated.ConclusionThe three strains of L. plantarum presented significant probiotic characteristics against the two pathogens of clinical importance. In vitro screening identified strong probiotic candidates for in vivo studies for the treatment of vaginal infections.

Health economics matters in the nanomaterial world: Cost-effectiveness of utilizing an inhalable antibacterial nanomaterial for the treatment of multidrug-resistant pneumonia

Bacterial pathogens rapidly develop resistance to clinically approved antibiotics. Together with the subsiding economic incentives for the development of newer and more effective antibiotic therapies, this threatens to cause a bacterial disease pandemic in the next 30 years. For this reason, timely analyses of various scientific and socioeconomic aspects of alternatives to traditional antibiotic therapies are needed. Here, pharmacoeconomic cost-of-illness, cost-effectiveness and price sensitivity analyses were performed to assess the impact of multidrug resistance of Pseudomonas aeruginosa implicated in pneumonia on healthcare systems of the United States and of the developing countries. The assessment was extended to include the effects of various therapies for this condition, one group of which consisted of colistin administered intravenously or with the use of a nebulizer and another therapy coming in the form of an inhalable colloidal formulation comprising biocompatible antibacterial nanoparticles. Both colistin and nanoparticle therapies produced net gain per quality adjusted life year (QALY) saved for patients with pneumonia caused by multidrug-resistant P. aeruginosa in the United States. In the developing world, in contrast, where the pricing sensitivity is shown to be higher, there is a positive cost of $8800 and $3600 per QALY saved associated with the use of colistin at a price adjusted to the local economy and administered through a parenteral route or through a nebulizer, respectively. Simultaneously, thanks to the higher affordability compensating for the 15% lower clinical efficacy assumed in the model, there is a net gain of $10,100 per QALY saved with the use of the nanoparticle formulation, translating to $52,000 gain for each life saved by the treatment. In conclusion, inorganic nanoparticle therapies for infectious disease are not only more immune to eliciting resistance than small-molecule antibiotics, but are also more applicable in low-cost healthcare systems of the developing world. The current generation of antibiotic therapies is cost-effective in high-cost healthcare systems, such as the one of the United States, but its application in more frugal settings, where pricing is as important as efficacy, comes with tremendous costs. These results demonstrate the considerable disparity in profit margin flexibility depending on the wealth and the size of the healthcare economy, which contributes daily to the widening of the gap between the rich and the poor.

Bifunctional cupric oxide nanoparticle-catalyzed self-cascade oxidation reactions of ascorbic acid for bacterial killing and wound disinfection

The emergence of drug-resistant bacterial strains has challenged the use of traditional antibiotic therapies. Therefore, there is an urgent need to develop novel antibacterial materials or methods to effectively eradicate bacteria. Herein, we demonstrated a novel antibacterial system consisting of cupric oxide nanoparticles combined with ascorbic acid (CuO NPs/AA), which could act as a potent nanoantibiotic targeting both Escherichia coli (gram-negative) and Staphylococcus aureus (gram-positive) in vivo and in vitro, without noticeable cytotoxicity to mammalian tissue. The CuO NP/AA antibacterial system killed these microbes through a combined mechanism involving biofilm inhibition, cell membrane destruction, DNA damage, and enzyme inactivation. The antibacterial properties of CuO NPs/AA were mainly attributed to the generation of reactive oxygen species (e.g., ·OH) produced through the intrinsic ascorbate oxidase- and peroxidase-like activities of CuO NPs, highlighting their use as antibacterial nanozymes to treat bacterial infections.

Light‐Activated Conjugated Polymers for Antibacterial Photodynamic and Photothermal Therapy

With the growing crisis of the availability of effective antimicrobial treatments, the use of phototherapy has gained increasing interest as an alternative to traditional antibiotic therapy. Even though phototherapy is already used in the clinic, there is an emerging interest in new materials with enhanced antimicrobial activity triggered by light. Among the different light‐responsive materials, conjugated polymers are emerging candidates with successful application in the field of antimicrobial photodynamic and photothermal therapy. Due to their organic composition, easy processability, tailorability of physicochemical properties, and capability of reactive oxygen species (ROS) and heat generation, their use as photoresponsive agents against bacteria has greatly expanded. Conjugated polymers have been designed to interact with specific bacterial targets, and their chemical composition has been optimized to enhance ROS and/or heat generation and new cationic polymers have been developed for augmented water solubility and increased interaction with negatively charged bacteria. Herein, the use of conjugated polymers in the field of phototherapy is discussed, focusing on the different approaches that have improved their performance against bacteria and their current preclinical safety assessment.