Anti-Infective Agents - Volume 16, Issue 2, 2018

Tuberculosis, an ancient infectious disease caused by Mycobacterium tuberculosis, ranks as one of the top ten killers worldwide. The limited number of validated targets and scarce therapeutic options demand that renewed efforts should be made to identify tuberculosis drugs with novel mechanisms of action. To this end, mycobacterial DNA might represent a potential target for the development of effective anti-tubercular compounds. In particular, the minor groove of DNA offers an important recognition site for small-molecules that can be programmed to bind to this region in a sequence-selective manner to disrupt mycobacterial transcription factors activity and ultimately cause bacterial cell death. This review describes the structural features of the DNA-minor groove, the requirements for small molecules to bind to this site and the remarkable biophysical and antibacterial properties of DNA-minor groove binding agents, including netropsin, distamycin and their poly-heterocyclic analogues, diamidines, benzimidazole-containing molecules, duocarmycins and pyrrolo[2,1-c][1,4]benzodiazepines (PBDs). Furthermore, the ability of selected heterocyclic-polyamides and PBDs to significantly inhibit the growth of pathogenic, slow-growing M. tuberculosis and other non-pathogenic mycobacterial strains is highlighted. In summary, DNA-minor groove binding agents may serve as molecular scaffolds for the design of highly efficient probes to treat M. tuberculosis infections.

Human cytomegalovirus (HCMV) is a beta herpesvirus that inflicts an active infection in the fetus and immunosuppressive patients. The virus encodes many proteins that work together with cellular factors to achieve virus replication. In addition to vaccines, antiviral drugs can be deployed to manipulate how the virus replicates and minimize its pathogenicity. The five antiviral drugs approved by the Food and Drug Administration (FDA) have shown adverse reactions and the antiviral drug resistance were reported. Hence, this warrants the need for urgent development of a novel antiviral drug. Detailed understanding of the virus replication steps and how cellular signals interact with these steps will be key for pharmacological developments of for anti HCMV drugs. This review summarized all the drugs that target the virus proteins and cell signals that mediate CMV replication.

Background: Despite recent advances in burns management and antimicrobial chemotherapy, infection continues to be a tricky in the burns. Treatment of a burn infection especially in case of multi-drug resistant Pseudomonas aeruginosa is a big challenge in clinics and needs novel strategies. Miscarriage of the current treatment strategies to control several cases of burns infections, the systemic and local toxicity that are produced by many topical antibiotics (especially in children), and the delay of healing caused by several antiseptics, make a strong motive to find effective and safe products. Aim: This study aimed to investigate the in vitro activity of different concentration of date vinegar against P. aeruginosa in comparison to the ciprofloxacin, one of the antibiotics used in the treatment of burns infection by using disk diffusion method and agar dilution MICs assay. Results and Conclusion: The disk diffusion method revealed that mean inhibition zone of date vinegar at 100%, 50%, 20%, 10% and 5% were (50.9 ±0.27) mm, (30.5 ±0.24) mm, (25.9 ±0.29) mm, (18.3±0.22) mm, and (9.2±0.25) mm respectively while ciprofloxacin has mean inhibition zone (8.95 ±2.25) mm and MICs (1.25%). So the conclusion was that date vinegar exerted a good in vitro antimicrobial activity against all tested isolates.

Background: Multidrug Resistance (MDR) of microorganisms is the biggest pharmacological challenge, despite plenty of modern antibiotics. Obviously, new classes of antimicrobial drugs against MDR pathogens need to be developed. Objective: This work aimed to investigate the antibacterial properties of the novel copper-based complex - bisimidazoles - (1,10) phenanthroline cuprum (II) dichloride - [CuPhenIm2]Cl2. Material & Methods: The complex - bisimidazoles-(1,10)phenanthroline cuprum (II) dichloride - [Cu- Phen-Im2]Cl2 was synthetized for the experiment. The structure was identified by elemental analysis and IR spectroscopy. The antibacterial properties of the copper complex were investigated by agar diffusion and serial dilution methods with the following bacteria strains Staphylococcus haemolyticus (ATCC 29970), Staphylococcus aureus (ATCC 25923), Proteus vulgaris (ATCC 13315), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and Mycobacterium bovis (Valle). Antituberculosis activity test included evaluation of bacterial growth on Lowenstein Jensen media with a serial dilution of copper complex, within an observation period of 90 days. Results: The prospect copper complex showed significant antibacterial activity. The most susceptible to copper action were strains of S.haemolyticus and S.aureus. The bisimidazoles - (1,10) phenanthroline cuprum (II) dichloride revealed moderate bactericidal action against Mycobacteria bovis. Conclusion: Most of the tested bacterial pathogens were highly susceptible to the novel copper substance. A detailed assessment of the biological action in in vivo is further required.

Introduction: A series of (R)-(-)-4-Phenyl-2 oxazolidinone based azetidinones (4a-i) were synthesized from the reaction of (2-Oxo-4-phenyl-oxazolidin-3-yl) acetic acid with aromatic imines (3a-i) in the presence of Thionyl chloride and Triethylamine as a base. Methods: The transformation proceeds through the formation of acid chloride to ketene which finally forms the azetidinones through [2+2] cycloaddition with aromatic imines. Products obtained were screened to evaluate their antibacterial activity with respect to known bacteria like Escherichia Coli (E. Coli) and Bacillus subtilis. Results and Conclusion: In most of the cases, azetidinones were found to exhibit superior antimicrobial properties than oxazolidinones. They were found to be a good inhibitor of gram-positive and gramnegative bacteria. Enhancement of antibacterial property can be attributed to the presence of azetidinone ring and hydrophobic alkyl side chain in the scaffolds.

Introduction: When environment polluted by complex petrochemical contaminants then prospective for biological treatment is needed. Methods: Biosurfactants exhibit biodegradability and anti-microbial properties hence efficacy of production and kinetics of in situ rhamnolipid production by Pseudomonas aeruginosa and lipopeptide production by Bacillus subtilis was carried out in a batch process. The need of the specific growth rate on carbon, nitrogen and phosphorous substrates was expected to monitor using Logistic, Monod, Moser and Contois type kinetic equation models. Impact of several bioprocess factors and optimization of control factors were studied. Results and Discussion: The simulation results show, Contois type model was better model than monod equation. Contois growth model says that bio mass rate depends upon the concentrations of substrate and biomass being inhibited at high concentrations of the biomass predicts, bio surfactant formation lowered with the high biomass concentration. Conclusion: The Luedeking Piret constants were calculated for rahamnolipid and lipopeptide production bearing in mind the cell survival maintenance from carbon, nitrogenand phosphorous substrates consumption. Assessed factors of this model specify that the formation of Rhamnolipid and lipopeptide was typically growth-associated.

Background: Two series of Guanidinyl benzothiazole and benzothiazole diamide derivatives were synthesized and screened for their anti-mycobacterial activity and cytotoxicity on cancer cell lines. Methods: The anti-mycobacterium study indicates that all the synthesized benzothiazole compounds were appreciably active and some of the compounds have MIC values lower than the standard drugs. Benzothiazoleguanidinyl derivatives (13a, 13b and 13f) showed the excellent activity with MIC values 1.6 μg/mL. The guanidinyl group and electron donating group present in the molecule interacts with the microorganism and arrest the further growth, indicating excellent activity by these compounds. These benzothiazole derivatives were also tested for cytotoxicity against MCF-7 and KB Mouth cell lines by MTT assay and they were found to be moderately active. Results: For the KB-Mouth cell lines, diamide compounds (9a-9h) have remarkable activity and they showed IC50 values at 10 μg/mL. Compared to benzothiazole diamides, Benzothiazole guanidinyl compounds selectively acted as a good anti-mycobacterium agent. Conclusion: In order to rationalize the in-vitro anti-tuberculosis activity, we carried out molecular docking studies with enoyl acyl carrier reductase (InhA) of M. tuberculosis and they exhibited remarkable docking scores from -5.85 to -9.27, which was comparable with the positive control Isoniazid (INH) with -6.61 as the docking score and showed less affinity towards the DprE1 protien.

Background: The prevalence of pulmonary tuberculosis infections had increased among the type 2 Diabetes Mellitus (DM) patients in India, although the biological basis underlying this susceptibility remains poorly characterized. Based on the symptom's, chest X-rays and their correlation with clinical and diagnostic parameters, we had suspected diabetic-tuberculosis co-infections. As Chest XRay plays a vital role in the identification of pulmonary tuberculosis infections, we emphasized more on it. Chest X-ray features included were; (infiltrate, cavitation, miliary shadows, pleural effusion, mediastinal lymphadenopathy and extent of lesions) such features were analyzed to identify associations with biological/clinical parameters through univariate and multivariate logistic regression. Methods: The study was carried out in diabetic type 2 patients suspected with pulmonary tuberculosis infections, Warangal, India. Spoligotyping was used for identification, detection and characterization of M. tuberculosis complex bacteria in clinical samples. This method is based on polymerase chain reaction (PCR) amplification of a highly polymorphic direct repeat locus in the M. tuberculosis genome. It is helpful in detecting causative bacteria and in providing epidemiologic information on genotyping strain identities. Results: Based on the chest X-Ray of 200 diabetic patients suspected with pulmonary infections, we found 26 infiltrates, 30 cavitation, 28 miliary shadows, 35 pleural effusion, 46 mediastinal lymphadenopathy and 35 were confirmed for the extent of lesions, which supported us to further screen for pulmonary tuberculosis of 200 subjects tested, 113 were males, 85 were females and 2 were children. All 200 subjects were tested for pulmonary tuberculosis, 36 were positive by smear microscopy and 20 were culture positive. Phenotypic and genotypic variations were found for all the 20 identified clinical isolates, by conventional and molecular methods of 20 clinical isolates, 4 MDR-TB were identified based on the Drug Susceptibility Test for first-line drugs. Of 20 clinical isolates, we took 10 clinical isolates (4-were MDR-TB and 6- were MTB) and 1- was control sample of H37RV used for spoligotyping and showed different patterns Bejing (1) and Lineages of East Asian, of family EA13(2) and Lineages of Indo-Oceanic, of family LAM1(1) and Lineages of Euro-American and 6 were found to be MTB of family 33(2) and Lineages of Indo-Oceanic, of family CAS(4) and Lineages of Un-known family. CAS (Central Asian) of M.tuberculosis strains showed more prevailing spoligotype pattern in Diabetic Pulmonary Tuberculosis patients. Conclusion: Implementing such a method in clinical settings would be useful in surveillance of tuberculosis transmission and in interventions to prevent further spread of this disease among the Diabetic Pulmonary Tuberculosis co-infections.

Background: Glycyrrhiza glabra (liquorice) has been extensively used since ancient Egypt, Greek and Roman, and is an important herb in traditional Chinese medicine. Its major compound, Glycyrrhizin (GL) possesses multiple pharmacological activities, such as anti-virus waiting for exploration indepth. Objective: The aim of this research is determining the antiviral mechanisms of Stronger Neo-Minophafen C (SNMC), an established formulation of compound GL based on Interferon (IFN) system, an important cytokine family best known for its antiviral ability. Methods: Four cell lines, A549, Hela, SMMC-7721 and TC-1, were recruited. The relative cell viability (RCV) was measured with 3(4, 5 dimethylthiazol) 2, 5 diphenyltetrazolium bromide (MTT). The gene transcription of key elements on IFN system, such as IFN-β1, IRF3 and ISG15 were evaluated using realtime RT-PCR. The expressions of key enzymes on IFN system were measured by Western blot. The concentrations of IFN-γ and IRF1, representative members of type II interferon, were detected by ELISA. Results: SNMC reduces RCV with concurrent induction of antiviral genes majorly belong to type I IFN pathway, focusing on IRF3-IFN-β1- ISG15 axis. The expression of IFN-β1, IRF3 and ISG15 genes in A549 and Hela cells peak at 12 h post-SNMC incubation, in a time- and dosage- dependent manner. The expression of IFN-β1 protein reaches a peak at 24 h in A549 and SMMC-7721 cells, and peaks at 48 h in Hela and TC-1 cells. The expression of ISG15 reaches a peak at 24 h in A549, Hela and TC-1 cells, and at 48 h in SNMC-7721 cells. The expression of Mx reaches a peak at 24 h in A549 and Hela cells, and at 48 h in SMMC-7721 and TC-1 cells. However, SNMC could not induce the expression of type II IFN signal pathway. Conclusion: We demonstrated that SNMC can induce the expression of important anti-viral genes in type I interferon pathway and indicate the existence of a key pathway response for the anti-viral effects of SNMC.

Background: Fascioliasis is a neglected tropical disease that affects poor people from poor and developing countries. In the world, it has been estimated that at least 2.6 million people are affected with this disease. The International agency for Research on Cancer, states that O. viverrini and C. sinensis, also liver flukes, are considered as definitive causes of cholangiocarcinoma. However, fascioliasis caused by F. hepatica has not been associated with cancer to date. There are not any known causative associations between this parasite and liver cancer (cholangiocarcinoma). Methods: Chine Hamster Ovary (CHO) cells were treated with F. haepatica extracts and cell proliferation was assessed by using the indirect method for estimating cell number based on the mitochondrial activity with MTS cell proliferation reagent. Results: We observed unexpected death of these cells when treated with F. haepatica extracts. Conclusion: We now hypothesize that this parasite could be used as a medically-important trematode pathogen in cancer therapy.