Anti-Infective Agents - Volume 14, Issue 2, 2016

Background: Bactericidal/permeability-increasing protein (BPI) is a nat-ural cationic protein, which is stored in the polymorphonuclear leucocyte granules. It exerts anti-infective actions through damaging bacterial membranes, neutralizing microbial endotoxins, and promoting phagocytosis of gram-negative bacteria. Con-sequently, its role in sepsis initially raised much hope in infection control. On the other hand, patients with liver cirrhosis present an important risk of sepsis induced by gram-negative microorganism, especially in advanced stages. Methods: MEDLINE was searched for terms including BPI, endotoxins, lipopoly-saccharides, lipopolysaccharide-binding protein, AND sepsis OR liver cirrhosis. Be-sides, trials addressing clinical BPI implication were retrieved and analyzed. Results: Endotoxemia is frequently elevated in sepsis, in alcoholic liver disease, and in liver cirrhosis. BPI expression is higher in liver cirrhosis patients than in healthy individuals, with a significant increase in patients who present a more severe disease. Contrariwise, most clinical studies failed to show any substantial role of BPI in treating sepsis. Conclusion: This review describes the role of BPI and some other proteins involved in sepsis, with a special focus on patients with alcoholic liver diseases. It outlines their mechanisms, indicates alterations associated with their deficiency, and explains obstacles that restrained their therapeutic use.

Organized jointly by the European Confederation of Medical Mycology (ECMM) and the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer (IDGEORTC), Trends in Medical Mycology (TIMM) has be-come the essential global forum to discuss the most important advances and research find-ings in mycology from basic science to clinical and laboratory research. TIMM-7 was the seventh of this series of biennial international meetings for physicians and scientists with interests in medical mycology. Delegates heard expert presentations on a range of topics, but antifungal drug resistance was a key concern for the meeting in light of the threat posed to the health and survival of seriously ill, immunocompromized patients.

Vibrio cholerae is a Gram-negative bacterium and causative agent of cho-lera, which is a severe gastrointestinal disease and a global public health concern. Repletion and antimicrobial drug therapies are necessary for efficacious treatment of severe cases of cholera. In situations where proper sanitation and repletion therapy are unavailable and multidrug resistant V. cholerae variants are present, alternative means of therapy are indicated. Towards this, comparative genomic analyses bet-ween virulent versus non-virulent serotypes of V. cholerae have been useful in iden-tifying new cellular targets for the development of new chemotherapies for cholera. This review article explores these new avenues for cholera treatments and sum-marizes these novel putative drug targets.

The complement (C) system participates in the immune response against pathogenic microorganisms. C3 protein plays a crucial role because its activation supports the course of the three pathways of the C cascade: the alternative pathway (AP), the classical pathway (CP), and the lectin pathway (LP) leading to the destruction of microorganisms and limitation of the infection. This paper attempts to highlight the role of outer membrane proteins (OMPs) in C components binding, as there are porins able to alter the course of C activation. Additionally, we present molecular methods adapted to C3 activation in human serum upon a contact with Salmonella cells and their OMPs. We demonstrate our achievements by using Salmonella strains as an exemplary microorganism of the public importance. The most severe outcomes of the presence of vital Salmonella rods in human body is sepsis. Therefore, it is desirable to do research on the C evasion mechanisms developed by pathogens, to understand the principles of bacteremia caused by other pathogens. We propose four techniques that may be useful in studying interactions between bacterial surfaces and C components: electrophoretic resolution of OMPs under denaturing and non-denaturing conditions, western blotting, and sandwich ELISA.

Background: There is new information regarding respiratory infection etiologies in Pediatrics. With the ability to test for 20 pathogens with a single nasal swab, we aimed to: 1. Study the relevance of respiratory pathogen testing in the con-text of hospitalized children and the incidence of multiple pathogens or "co-infection." 2. Determine whether patients with multiple pathogens have a longer length of stay (LOS) than those children with a single pathogen. 3. Determine whether children with multiple pathogens have more severe illness—as indicated by oxygen use, antibiotic use, or requirement of critical care—compared to those chil-dren with one pathogen identified. Methods: Electronic medical records of patients who had respiratory pathogen panel (RPP) polymerase chain reaction (PCR) testing during the winter of 2011-2012 at a tertiary care chil-dren’s hospital were reviewed. RPP results, LOS, oxygen use, antibiotic use, and critical care interven-tions were noted. Data were analyzed with Pearson chi-square and Cox proportional hazard regression. Results: 93 RPPs (83%) tested positive for a single pathogen, and 19 RPPs (17%) were positive for multiple pathogens. Patients with co-infections had more severe disease as defined by the requirement of intensive care (p=0.02, OR 3.51, 1.2-9.8). There was no significant difference in oxygen use or antibiotic use between patients with one or more than one pathogen. The co-infection group was hospitalized for a median of 67 hours versus 41 hours for the single pathogen group (p= 0.01). This increased hospital LOS for the co-infection group was also seen in Cox regression analysis (p=0.007). Conclusions: Hospitalized children with multiple pathogens on RPP testing have statistically longer LOS and more severe illness.

A series of novel trifluoromethyl substituted imidazo fused quinolone analogues were prepared, isolated and characterized. The title compounds, thus ob-tained, were synthesized from compound 3. Initially, the nitro group of compound 3 was reduced using Pd/C and hydrazine hydrate afforded the compound 5. The amine 5 was treated with EMME furnished the corresponding imidazo fused quinolines as angular compound 7. The alkylation reaction of 7 with different alkyl halides furnished the corresponding N-alkylated derivatives 9a-h. N-alkylated fluoro quinolones on hydrolysis using 10% LiOH furnished the corresponding carboxylic acid derivatives 10a-h in good yields. All the newly synthesized trifluoromethyl substituted imidazo fused quinolone analogues were further evaluated for their antibacteri-al activity against the four bacterial strains. Among them, two were gram positive i.e., Staphylococcus aureus and Bacillus subtilis bacteria and two were gram negative bacteria i.e., Klebsiella pneumonia and E. coli. Some of the compounds such as 7, 9a, 9d, 9f, 10f and 10g showed good antibacterial activi-ty against all bacterial strains when compared to standard drugs.

Background: Antiviral response rates are highly variable in Hepatitis B chronically infected individuals due to its extensive genetic variability. This genetic inconsistency varies from region to region and highly affects the severity of disease, its progression and treatment outcome. Idea of the existing work is to come across out antiviral response rates of interferon and lamivudine in HBV positive individuals after one year of treatment and their correlation with genotypes in Pakistani isolates. Methods: Sera samples were collected from treated patients and then were subjected to DNA extraction followed by genotyping. Quantification analysis using real time PCR was performed before the treatment, after six months interval and finally in the follow up period of 6 months. Results: Out of total 100 (75% males and 25% females) selected 74 patients [(52/74 (70%) male and 22/74 (30%) females] completed the lamivudine standard therapy (100mg/day) with an end treatment response (ETR) rate of 43/74 (58.1%) while 26 patients were getting interferon-alpha (IFN-α) treatment (5mIU/inj.) showed 4/26 (15.38%) ETR and 12/26 (46.1%), whereas 10/26 (38.4%) were nonresponders. In interferon treated patients, ETR was higher in genotype A, B and C in number of patients respectively 1, 6 and 8. Whereas it was more in genotype D, A, B and F 14, 13, 2, (61.5%, 56.5%, 50% and 25% respectively) after lamivudine treatment. Conclusion: Overall, the treatment response was significantly higher (p-value < 0.05) in patients under 40 years of age. The current study shows a high ETR to antiviral therapy in Pakistan in comparison to other parts of the globe for a defined period of one year.

1,2,3-triazoles linked to bioactive alcohols of natural origin could have great pharmaceutical application as the literature reveals their antifungal, antibacterial, and anti-cancerous properties. These derivatives were synthesized using azide-alkyne cycloaddition strategy and subjected to evaluation for their antibacterial, antiplasmodial and anticancer properties. The drug likeliness was also evaluated by in silico physico-chemical prediction using QikProp version 3.2. The antimicrobial activities were evaluated against Plasmodium falciparum (P. falciparum), Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) strains. The anti-cell proliferative activity was determined against four cancer cell lines (SK-MEL, KB, BT-546 and SK-OV-3). Five compounds (3a, 3c-f) showed antiplasmodial activity against chloroquin sensitive (D6) and chloroquin resistant (W2) strains of P. falciparum. Compound 3a (IC50 = 1.9 μg/mL) against P. falciparum D6 and 3c (IC50 = 2.7 μg/mL) against P. falciparum W2 strains were found as potential antiplasmodial agents. The antibacterial results against two gram negative (E. coli and P. aeruginosa) and one gram positive (S. aureus) strain also indicated the clinical potential of these compounds. Among all, compound 3c containing quinoline ring showed potent antibacterial property with IC50 values of 0.05, 6.23, and 7.4 μg/mL against P. aeruginosa, E. coli and S. aureus strains, respectively. Moreover, compound 3f derived from ferulic acid was found to exhibit promising anticancer activity against all the cancer cell lines used in the study.

Background: New antimalarial drugs are required to fight resistant parasites and plantderived natural products are a robust source for identifying active lead compounds. Stachytarpheta cayennensis (Verbenaceae) is traditionally used in west and central Africa as malaria remedy. Objective: This study was undertaken to evaluate antiplasmodial activity of S. cayennensis leaf fractions and to isolate and identify some active constituents. Method: A dried, powdered batch of S. cayennensis leaf was extracted with hexane, dichloromethane and methanol. The methanol extract was partitioned with ethyl acetate and water. Solvent portions and ethyl acetate column fractions were investigated in early infection in mice, against chloroquine-sensitive (HB3) and chloroquine-resistant (FCM29) P. falciparum. Compounds I, II and III isolated from active fractions were identified based on their spectroscopic data and further evaluated for antioxidant and heme biomineralization inhibitory activity. Results: Column fractions 6-7, 10-11 significantly (P < 0.01) reduced parasitaemia in vivo and in vitro (IC50 < 50 μg/ml). At a dose of 2.5 mg/kg, compounds I - III significantly (P < 0.05) suppressed infection by 54.91 - 88.95 %. Compound III also displayed strong antioxidant effect (EC50 = 0.05 mg/ml) comparable to equivalent concentrations of ascorbic acid (EC50 = 0.03 mg/ml), whereas compound I elicited stronger inhibitory effect (67.93%) on heme biomineralization than compound III (38.67%). The compounds were identified as apigenin (I), stigmasterol glucoside (II) and verbascoside (III). Conclusion: The findings showed that S. cayennensis leaves contain antiplasmodial-active compounds which show potential for further development.

A simple method based on hydrolysis of 2,3-dicyanopyrazinium salts has been used for the synthesis of the corresponding 5-(hetero)aryl-3-cyano-1-ethyl-2(1H)-pyrazinones. Also, the series of novel 1-ethyl-5-(hetero)aryl-1,6-dihydropyrazine-2,3-dicarbonitriles have been obtained through reduction of the same pyrazinium salts with triethylsilane. The obtained compounds proved to be active in micromolar concentrations in vitro against Mycobacterium tuberculosis H37Rv, Mycobacterium avium, Mycobacterium terrae, as well as against rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis. The data for acute in vivo toxicity in mice have been obtained for these compounds which appear to be promising antitubercular agents.