Therapeutic Agents For Infectious Diseases Research Articles

Antibacterial Activity of River Water Bacteriophage against Multidrug-resistant Gram-negative Bacteria, An In vitro Study

Microbes show a high antimicrobial resistance due to a high rate of mutations predisposed by many factors, especially the abuse of antibiotics. Therefore, there is a great need for an alternative therapeutic agent for infectious diseases caused by microbes resistant to antibiotics. Bacteriophages are viruses parasitizing microbes, that got a big scientist’s attention due to their ability as an alternative therapy for severe bacterial infections. This study is devoted to identifying bacteriophage from river water on tested pathogenic isolates isolated from clinical cases of UTI in vitro and finding out the effect of phage on these bacterial isolates as an initial step of further in vivo phage therapeutic study on the same tested isolates. The results showed a significant bactericidal effect of the isolated bacteriophages against the pathogenic bacterial isolates.

Infection Meets Inflammation: N6-Methyladenosine, an Internal Messenger RNA Modification as a Tool for Pharmacological Regulation of Host-Pathogen Interactions.

The significance of internal mRNA modifications for the modulation of transcript stability, for regulation of nuclear export and translation efficiency, and their role in suppressing innate immunity is well documented. Over the years, the molecular complexes involved in the dynamic regulation of the most prevalent modifications have been characterized-we have a growing understanding of how each modification is set and erased, where it is placed, and in response to what cues. Remarkably, internal mRNA modifications, such as methylation, are emerging as an additional layer of regulation of immune cell homeostasis, differentiation, and function. A fascinating recent development is the investigation into the internal modifications of host/pathogen RNA, specifically N6-methyladenosine (m6A), its abundance and distribution during infection, and its role in disease pathogenesis and in shaping host immune responses. Low molecular weight compounds that target RNA-modifying enzymes have shown promising results in vitro and in animal models of different cancers and are expanding the tool-box in immuno-oncology. Excitingly, such modulators of host mRNA methyltransferase or demethylase activity hold profound implications for the development of new broad-spectrum therapeutic agents for infectious diseases as well. This review describes the newly uncovered role of internal mRNA modification in infection and in shaping the function of the immune system in response to invading pathogens. We will also discuss its potential as a therapeutic target and identify pitfalls that need to be overcome if it is to be effectively leveraged against infectious agents.

Review: Antimicrobial Activity of Coriander (Coriandrum sativum Linn.)

Bioactive chemicals are abundant in natural products; some have strong antibacterial properties. Coriander (Coriandrum sativum. Linn) is one of the spices with a long history of use in traditional medicine and foods. Apart from its use as a flavouring agent in foods, it also has a wide range of applications in man's healthcare due to its numerous phytoconstituents, with notable antibacterialactivities. This review summarizes the findings of scientific studies on the antimicrobial activity of Coriander, highlights the methods used for testing the antimicrobial activity, the part(s) of the plant used, and the compounds of Coriander with antimicrobial activity. This review concludes that Coriander is a source of therapeutic agents for infectious diseases and food-borne pathogens.&nbsp

Corporate Efforts to Research and Develop Therapeutic Agents for Infectious Diseases That Threaten Human

Overcoming serious infectious diseases such as malaria, tuberculosis, and other neglected tropical diseases (NTDs) that threaten human life around the world is an important issue in global health. Most of these diseases are concentrated in developing and low-income countries, and in order to reinforce drug discovery activities, pharmaceutical companies are actively promoting industry-academia-government partnerships and utilizing funds to stimulate global health activities. In this presentation, three examples of our drug discovery activities are introduced. The first is participation in the Booster project led by Drugs for Neglected Diseases initiative (DNDi) aimed at creating therapeutic agents for leishmaniasis and Chagas disease, an effort supported by the Global Health Innovative Technology (GHIT) Fund. As domestic and overseas pharmaceutical companies participate in the project and provide their own compounds, it is possible to obtain structure-activity relationship information in a short period of time and improve compound potency. We collaborated with DNDi to create a lead compound from one hit compound, and contributed to further enhancement of its activity. The remaining two are collaborations with academia for the creation of new therapeutic agents or vaccines: a joint research project with Hokkaido University Research Center for Zoonosis Control for emerging viral diseases, and a collaboration with Nagasaki University in malaria. In each case, our researchers were based at the university, establishing close working collaborations with the university researchers. Novel solutions for serious infectious diseases are expected by the combination of the high-level basic research capabilities of academia and the drug discovery know-how and original compound libraries possessed by pharmaceutical companies.

The Roles of c-Jun N-Terminal Kinase (JNK) in Infectious Diseases.

c-Jun N-terminal kinases (JNKs) are among the most crucial mitogen-activated protein kinases (MAPKs) and regulate various cellular processes, including cell proliferation, apoptosis, autophagy, and inflammation. Microbes heavily rely on cellular signaling pathways for their effective replication; hence, JNKs may play important roles in infectious diseases. In this review, we describe the basic signaling properties of MAPKs and JNKs in apoptosis, autophagy, and inflammasome activation. Furthermore, we discuss the roles of JNKs in various infectious diseases induced by viruses, bacteria, fungi, and parasites, as well as their potential to serve as targets for the development of therapeutic agents for infectious diseases. We expect this review to expand our understanding of the JNK signaling pathway’s role in infectious diseases and provide important clues for the prevention and treatment of infectious diseases.

In vitro Antibacterial Activity of Isopropoxy Benzene Guanidine Against Multidrug-Resistant Enterococci.

BackgroundBacterial infections cause a serious public health crisis due to the emergence of resistance towards multiple conventional antibacterial drugs. In particular, multidrug-resistant (MDR) Enterococcus faecium which belongs to “ESKAPE” organisms is causing significant problems worldwide. Hence, there is an urgent need to find alternative therapies. Recently, substituted benzene guanidine compounds have been used as lead structures to discover new promising drugs in both synthetic and medicinal chemistry.PurposeHere we investigated the antimicrobial activity of a new substituted benzene guanidine analog, isopropoxy benzene guanidine, against Enterococci.Material and methodsThe isopropoxy benzene guanidine was synthesized by Guangzhou Insighter Biotechnology Co., Ltd and tested on both reference bacterial strain and 32 clinical MDR Enterococci strains. The in vitro antibacterial activity was evaluated by microdilution method and kill kinetic assays. The potential antibacterial mechanism was measured by fluorescence spectrometry using fluorescent membrane potential probe 3, 3-diethyloxacarbocyanine iodide (DiOC2 (3)).ResultsIsopropoxy benzene guanidine exhibited potent bactericidal activity against both reference strain and MDR Enterococci isolates. The minimum inhibitory concentration (MIC) range for isopropoxy benzene guanidine was 1–4 μg/mL. Minimum bactericidal concentration (MBC) was about 2-8-fold of its MIC values. Time-kill studies showed that isopropoxy benzene guanidine provided superior bactericidal effect against reference and MDR strains within 12 hrs at 2×MIC. Furthermore, isopropoxy benzene guanidine could cause a large reduction in the magnitude of the generated membrane potential compared to that of the untreated cells.ConclusionThe present study highlights the potent bactericidal activity of isopropoxy benzene guanidine on Enterococci by disrupting the cell membrane potential. These findings demonstrate that isopropoxy benzene guanidine may be a good chemical lead for further medicinal chemistry and pharmaceutical development and could be used as a therapeutic agent for infectious diseases caused by MDR Enterococci.

Tunicamycin: chemical synthesis and biosynthesis.

Tunicamycins are nucleoside natural products and show antibacterial, antiviral and antitumor activities, which are attributed to their inhibition of enzymatic reactions between polyisoprenyl phosphate and UDP-GlcNAc or UDP-MurNAc-pentapeptide. Because of their various intriguing biological activities, tunicamycins have potential as therapeutic agents for infectious diseases or cancers. Structurally, tunicamycins have a unique structure composed of an undecodialdose skeleton, a lipid chain and a GlcNAc fragment linked by a 1,1-β,α-trehalose-type glycosidic bond. In this mini review, we summarize the total chemical syntheses and biosynthetic studies of tunicamycins.

The Utilization of Alpha-1 Anti-trypsin (A1AT) in Infectious Disease Monitoring and Treatment

Alpha one anti-trypsin (A1AT) is a major serine protease inhibitor found circulating in human blood. A1AT related studies mainly focus on A1AT potential biomarker as well as therapeutic target in non-infectious diseases. Their findings indicate A1AT beneficial features may also be applied for monitoring and treating infectious disease. However, only a few studies have reviewed A1AT’s useful properties as a biomarker and therapeutic agent for infectious diseases. This narrative review aims to summarize growing evidences that support the idea of utilizing A1AT as a tool for monitoring and therapy for infectious diseases. A1AT showed potential as a biomarker for a wide spectrum of infectious disease, from virus, bacteria, to parasite. Its level and functionality were proposed to predict risk for disease susceptibility or progression and to indicate response therapy. As promising therapeutic agent in various infectious diseases, the administration of A1AT has shown antimicrobial activity, immunomodulatory and anti-apoptotic effect, in addition to more familiar function, suppressing excessive proteolysis. The broad utilization of A1AT, both as biomarker and therapeutic agent, in studies on infectious diseases seems promising. However, there are issues need to be investigated further before establishing its feasibility as a monitoring and therapy tool against infection diseases . J Microbiol Infect Dis 2019; 9(1): 51-58.

Honey Dressing vs. Povidone Iodine Dressing.

Dear editor, we would like to discuss on the publication on “Honey Dressing vs. Povidone Iodine Dressing [1].” Gulati et al. concluded that “Honey dressing is highly effective in achieving healing in chronic wounds as compared to Povidone iodine dressing [1].” In fact, the usefulness of honey in wound care is acceptable and honey is widely used. It is approved for the antibacterial activity and proposed to be a good therapeutic agent for infectious diseases [2]. However, the important consideration is the possible contamination of honey. Honey is reported for high contamination by Clostridium pathogen that can cause botulism [3]. To use honey in surgery, good preparation and sanitation control is needed.

Comparative Study of Anti-hepatitis B Virus RNA Interference by Double-stranded Adeno-associated Virus Serotypes 7, 8, and 9

Using a hepatitis B virus (HBV) transgenic mouse model, we previously showed that a single dose of double-stranded adeno-associated virus (dsAAV) vector serotype 8 carrying a small hairpin RNA (shRNA) effectively reduces HBV replication and gene expression, but the effect gradually decreases with time. In this report, we compared the anti-HBV RNA interference (RNAi) effect of dsAAV8 with those of dsAAV7 and dsAAV9, two other hepatotropic AAV vectors, and examined whether the sequential use of these heterologous AAV vectors could prolong the anti-HBV effect. Our results showed that shRNA delivered by each of the three dsAAV vectors profoundly reduced the serum HBV titer and liver HBV mRNA and DNA levels in the transgenic mice for up to 22 weeks, with dsAAV8 having the greatest inhibitory effect, followed by dsAAV9 and dsAAV7. The potency of dsAAV8 correlated with the presence of higher levels of vector DNA and anti-HBV shRNA in the liver. An in vivo cross-administration experiment showed that preexisting anti-AAV8 antibody completely blocked the anti-HBV RNAi effect of dsAAV8, but had no effect on the potency of dsAAV7 and dsAAV9. Moreover, we demonstrated that a longer anti-HBV effect could be achieved by the sequential use of dsAAV8 and dsAAV9. These results indicate that effective and persistent HBV suppression might be achieved by a combination of the power of RNAi silencing effect and multiple treatments with different AAV serotypes.Molecular Therapy (2009) 17 2, 352-359 doi:10.1038/mt.2008.245.

Involvement of peroxynitrite in LPS-induced apoptosis of trophoblasts.

To examine whether or not peroxynitrite was involved in trophoblastic apoptosis induced by a bacterial endotoxin, lipopolysaccharide (LPS). Levels of nitrite/nitrate, stable metabolites of nitric oxide (NO), in culture medium of trophoblasts, were determined using Griess reagents. Trophoblastic apoptosis was identified morphologically and confirmed using in situ nick end labeling technique. The amount of nitrotyrosine, a footprint of peroxynitrite, was quantified by dot blotting. Statistical significance was determined by ANOVA. Treatment of trophoblasts with LPS leads to apoptosis accompanied by formation of NO and nitrotyrosine. Aminoguanidine, an inhibitor of NO synthase (NOS), reduced peroxynitrite formation and prevented apoptosis. Scavengers of peroxynitrite also prevented apoptosis in this culture model. Peroxynitrite was involved in trophoblastic apoptosis induced by LPS. Peroxynitrite scavengers or inhibitors of NOS may thus be candidate therapeutic agents for infectious diseases, which is associated with overproduction of NO and peroxynitrite.

Oligosaccharides interfere with the establishment and progression of experimental pneumococcal pneumonia.

Oligosaccharides that block the adherence of bacteria to epithelial cells in vitro--lacto-N-neotetraose (LNnT) and its alpha2-3- and alpha2-6-sialylated derivatives--were tested for their abilities to attenuate the course of pneumococcal pneumonia and to prevent colonization of the nasopharynx in animal models. Intratracheal administration of these agents concurrently with bacteria dramatically decreased pneumococcal load in the lungs of rabbits and conferred protection from bacteremia. The oligosaccharides ameliorated pneumonia and bacteremia when given therapeutically 24 h after infection was established. When administered intranasally, neoglycoconjugates of the active oligosaccharides prevented colonization of the nasopharynx of infant rats. In addition to in vitro anti-adherence properties, LNnT acted directly on cultured lung epithelial cell lines to induce changes such that pneumococcal adherence was prevented for prolonged periods. These activities encourage continued development of oligosaccharides as a class of potentially preventive and therapeutic agents for infectious diseases.

Inhibition of microbial adherence by sphinganine.

Sphingosines (precursors and degeneration products of complex sphingolipids) are mediators in membrane second-messenger cascades and in a wide variety of functions in eukaryotic cells. Sphingosines are also lethal for gram-positive microorganisms. In addition to its direct effect, sphinganine is here reported to affect the adherence of Streptococcus mitis to buccal epithelial cells and of Staphylococcus aureus to nasal mucosal cells after incubation for 90 min at 37 degrees C. When the bacteria were pretreated with 8.1, 16.2, 32.5, or (for Strep. mitis) 65 microM sphinganine for 60 min at 37 degrees C, adherence counts were reduced for Staph. aureus by 27, 37, and 60% and for Strep. mitis by 19, 44, 54, and 73%, respectively (p < 0.001). In contrast, pretreatment of buccal cells with 81.2 microM lipid increased adherence by 14% (p < 0.01), but no change occurred at either 16.2 or 325 microM lipid. These results further demonstrate the double-edged ability of sphingosines to regulate cellular activities and their potential as multifunctional therapeutic agents for infectious diseases.