Anti-Infective Agents - Volume 15, Issue 1, 2017

Introduction: With the development of the direct acting antivirals aganist hepatitis C virus (HCV), the treatment of HCV has showed significiant progress. However, hepatitis B virus (HBV) therapy is still a topic of discussion. Objectives: Because of that approved agents for HBV have some disadvantages including indefinite therapy, drug resistance, adverse effects and persistence of covalently closed circular deoxyribonucleic acid (cccDNA), there is a need for new treatment targets and approaches for HBV. And, there are several trials about this subject. New treatment targets for HBV consist revers transcription, immunoregulation, cccDNA formation and regulation, maturation and secretion of infectious virions and subviral particules, viral receptor, entry and cytosolic transport, nucleocapsid assembly. Therapeutic vaccination and traditional Chinese medicine are the other options for novel agents for HBV treatment. We summarised new treatment targets and approaches for HBV. Conclusion: It is a certain fact that large-scale studies about all these molecules and approaches are required, in order to highlight the efficiency, drug interaction, safety and appropriate dose.

The report is an overview of the scientific presentations at the 36th International Symposium on Intensive Care and Emergency Medicine (ISICEM) which were related to fungal infections with a specific focus on Candidiasis. Key topics covered include Candida infections associated with the increase in incidence of sepsis in intensive care units, emerging strategies for early identification of appropriate patients for empiric antifungal therapy, the new IDSA guidelines, dosing considerations for echinocandins in critically ill patients with and without hepatic impairment, and the latest evidence to guide treatment de-escalation decisions.

Background: Severe acute liver failure by Epstein-Barr virus is a rare event. A specific antiviral treatment is not available and steroid use is controversial. Objective: We report the beneficial effect of steroid therapy in this clinical condition. Case Report: We observed the case of a 19-year male patient admitted to our Gastroenterology Unit for an acute Epstein-Barr virus-related hepatitis (significant transaminase flare: aspartate transaminase x 91 and alanine transaminase x 56 the upper limit of normal, Model for End-stage Liver Disease: MELD score 14). A severe liver injury occurred about 20 days after onset (MELD score 29). A prompt dramatic improvement of liver damage markers was achieved after eight-day methylprednisolone intravenous administration (MELD score 9) despite viral disappearance (i.e. absence of EBV-DNA in blood and nasopharyngeal swab) occurred after 6 months. Anti-EBV IgM positivity was observed at the 14th month despite presence of specific IgG (“past infection, IgM persisting”). Conclusion: Therapeutic response suggests that the short-term use of steroids, even if not recommended for routine treatment of infectious mononucleosis, may be effective to treat the immunemediated symptoms. Possible steroid interactions with the host immune-response to the virus have not been demonstrated in short-term administration. Our case suggests focusing on this last topic.

The European Society for Blood and Marrow Transplantation (EBMT), established in 1974, is the leading scientific society for professionals involved in haematopoietic stem-cell transplantation (HSCT). The 2016 EBMT Annual Meeting, held in Valencia, Spain, brought together over 4,500 scientists, physicians, nurses, biologists, pharmacists, technicians and patients to discuss scientific data across a wide range of topics. New for this year was the 1st EBMT Pharmacists' Day, viewing therapies from the pharmacist’s perspective, with the objective of achieving maximum clinical benefit. Here, and across the entire meeting, a major focus was invasive fungal infections (IFI). Despite the availability of three classes of antifungals (AFs) to treat IFI (including polyenes, azoles and echinocandins), mortality in haemato-oncology patients remains unacceptably high. Across the EBMT 2016 sessions, key opinion leaders highlighted the urgent need to improve management of IFI, and the bioavailability (BA) of azoles. Current strategies include the new tablet formulation of posaconazole, administered once a day (o.d.) without food; the extended half-life of the new prodrug isavuconazole; use of combination therapy; and personalized therapy such as dosing voriconazole according to CYP2C19 genotype. Looking to the future experimental strategies, including developing agents that destroy the biofilm which prevents AFs from reaching intracellular targets and loading neutrophils with azoles, were presented.

Background: A series of new symmetric disulfonamide and dicarbamate derivatives of 4,4#136;-oxydianiline were designed and synthesized in a simple method. These compounds were characterized by IR, 1H, 13C-NMR, mass spectral data and elemental analysis. Method: The compounds were screened for their in vitro antibacterial and antifungal activities against various pathogenic organisms. Among the title compounds 10f, 10a and 10h showed promising antibacterial activity and 10g, 10d and 10a showed good antifungal activity. Conclusion: The results also emphasized that the disulfonamide derivatives were better antibacterial agents than the corresponding dicarbamate derivatives.

Introduction: Aegle marmelos (L.) Correa, a member of the Rutaceae family, is a very common fruit and medicinal plant in Bangladesh. The seeds of Aegle marmelos has showed important therapeutic applications like Antiulcer, Phytoremediation , Antimicrobial , Antidiabeic and Neuroprotective role. Materials and Method: In the present investigation, methanol, ethyl acetate and chloroform extracts of A. marmelos seeds were assessed for their antifungal activity using well diffusion methods against two fungal strains Fusarium oxysporum and Colletotrichum melongenae and antibacterial activity against five bacterial strains namely; Bacillus subtilis IFO3026, Sarcina lutea IFO3232, Xanthomonas campestris IAM1671, Escherichia coli IFO3007 and Pseudomonas sp. ATCC13867 using disk diffusion methods. Discussion: Among the three extracts methanol, ethyl acetate extracts revealed an antifungal activity against F. oxysporum and C. melongenae. But chloroform extract showed no activity against both the tested fungi. The seed extracts (512μg/disc) displayed a great potential of antibacterial activity against two Gram-positive bacteria: B. subtilis, S. lutea and two Gram-negative bacteria: E.coli, Pseudomonas sp. The zones of inhibition of different concentration of extracts against the tested bacteria were found in the range of 13mm -19 mm and the minimum inhibitory concentrations (MIC) were recorded 256 μg/ml against S. lutea by methanol extract. Results: The results obtained in the present study suggested that seed extracts of A. marmelos revealed a significant scope to develop a novel broad spectrum of antimicrobial herbal formulation.

Background: The emergence of multi-drug resistant and extensively drug-resistant cases of tuberculosis has lead to the search for new structural classes of anti-tuberculosis drugs. There are many reports on antimycobacterial screening of compounds containing the 4-thiazolidinone moiety. The 5- arylidene moiety in the 2-heteroarylimino-5-benzylidene-4-thiazolidinone scaffold plays an important role in antimicrobial activity against Gram-positive and Gram-negative bacteria, yeasts and moulds. Objective: To synthesize 2-thiazolylimino-5-arylidene-4-thiazolidinone derivatives, with different substituents on the aryl ring, and evaluate their in vitro antimycobacterial activity against M. tb H37Rv. Methods: The derivatives were synthesized by previously reported methods, and structures confirmed by spectral data. Qikprop, the ADME prediction program was used in predicting pharmacokinetic properties of the derivatives, which helped in designing and synthesis of novel and more potent analogs. In vitro antimycobacterial activity against drug-sensitive M. tb H37Rv was performed in BACTEC-460 TB radiometric system. Results: The synthesis and antimycobacterial activities of 2-thiazolylimino-5-arylidene-4-thiazolidinone derivatives have been reported. The chemical modifications not only altered the physicochemical properties but also pharmacological activities. The compounds exhibited moderate to excellent in vitro activity (88-99.7% inhibition) against M. tb H37Rv, and few demonstrated >99% inhibition at 6.25 μg/mL. The activity was considerably affected by various substituents and compounds with di- and trisubstitutions on the aromatic ring of the 4-thiazolidinone were more active. Conclusion: These preliminary but encouraging results indicate that 2-thiazolylimino-5-arylidene-4-thiazolidinones are promising scaffolds for design and development of new molecules for antimycobacterial activity. Several compounds were identified as novel and potential lead for design and synthesis of new antimycobacterial agents.

Background: The pyrazole moiety hold a unique position in heterocyclic chemistry. Novel pyrazole scaffolds with more potency can be very effective against resistant strains of various microorganisms. Objective: To carry out the synthesis, characterization and antimicrobial screening of novel 3, 5 dimethyl pyrazole analogs. Method: A series of novel pyrazole scaffolds were synthesized by treating 3, 5 dimethyl pyrazole with various propionamide under nitrogen atmosphere. Compounds were evaluated for their in vitro antibacterial activity in comparison to ciprofloxacin and norfloxacin, against both Gram-positive (S.aureus, B.subtilis) and Gram-negative (E.coli, P.aeruginosa, S.typhi, K.pneumonia) bacteria. They were also screened for their antifungal activity against C.albicans and A.niger using fluconazole as a standard drug. Results: The structures of synthesized pyrazole analogs were successfully elucidated using their 1H NMR, Mass, IR, elemental analysis data. Compounds 28 and 29 showed a relatively good inhibitory profile against both Gram-positive and Gram-negative bacteria. Compound 21, 28 and 29 were found to be more active against both Gram-positive bacteria and compound 26, 28, 29, and 38 exhibited good inhibitory activity against all Gram-negative bacteria. Antifungal screening results showed that compounds 20, 22, 25, 26, 27, 30, 31, 32, 33, 36 and 37 were equally potent when compared to fluconazole. Thus, from the results of anti-microbial screening data, it was evident that the presence of a halogen group at different positions of the aromatic ring was responsible for their potency. Conclusion: These newly synthesized pyrazole analogs are better scaffolds to be developed as broad spectrum chemotherapeutic agents.

In HCV genome, the NS5B RNA-dependent RNA polymerase (RdRp) plays central role in the replication. It is the most preferred target for design and screening of small molecule HCV inhibitors. From in house compound library screening using NS5B polymerase enzymatic assay, we identified some benzimidazole derivatives. The activities were predicted using the QSAR generated models. Along with QSAR predictions, molecular docking studies help to study binding of these series of compounds at allosteric pocket (AP-1).

Introduction: Leishmaniasis is an endemic disease caused by the protozoan parasite Leishmania. Current treatments for the parasite are limited by cost, availability and drug resistance as the occurrence of leishmaniasis continues to be more prevalent. Sulfonamides are a class of compounds with medicinal properties which have been used to treat bacterial and parasitic disease via various pathways especially as antimetabolites for folic acid. Methods: New derivatives of sulfonamide compounds were assessed for their impact on Leishmania cell viability and potential pathways for inhibition were evaluated. Leishmania tarentolae (ATCC Strain 30143) axenic promastigote cells were grown in brain heart infusion (BHI) medium and treated with varying concentrations of the new sulfonamide compounds. Light microscopy and viability tests were used to assess the cells with and without treatment. Discussion: A non-water soluble sulfonamide was determined to have 90-96% viability inhibition 24 hours after treatment with 100 μM final concentration. Because Leishmania are also autotrophs for folate precursors, the folic acid pathway was identified as a target for sulfonamide inhibition. When folic acid was added to untreated Leishmania, cell proliferation increased. A water soluble derivative of the inhibitory sulfonamide was synthesized and evaluated, resulting in less viability inhibition with a single dose (approximately 70% viability inhibition after 24 hours with 100 μM final concentration), but additive inhibition with multiple doses of the compound. Results: However, the potential mechanism of inhibition was different between the water-soluble and non-water soluble sulfonamides. The inhibitory effects and potential pathways of inhibition indicate that these compounds may be new treatments for this disease.

Helicobacter pylori (H. pylori) is the only unique microorganism that has been linked to cancer. Although many therapeutic lines have been modified we are still lacking with the successful formulation to treat and manage the infection. Later, probiotics have been introduced as an alternative increasing the efficacy of antimicrobial agents. Probiotics include several microorganisms, mostly Lactobacillus which can be listed as termination of living microorganisms, which, upon ingestion in certain numbers, exert health benefits beyond inherent basic nutrition. To our knowledge, various mechanisms including strengthening gut barrier function, antimicrobial substances, competing for adhesion sites and inducing specific immune responses are which probiotics can serve as antimicrobial agents. Of course, there are some unknown mechanisms of action which should be discovered in close future. Many clinical trials reported that administration of probiotics can reduce the side effects of H. pylori eradication treatment, also increase tolerability, and even increases the efficacy. Taking together, we can assume that the probiotics cannot stand as an alternative to the current antibiotics to eliminate the H. pylori infection. The likely role of probiotics in optimistic view can be an adjuvant in therapeutic regimens against H. pylori. In conclusion, the use of probiotics appears promising only as an adjuvant for the current H. pylori eradication treatment, though it still requires optimization.