Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 19, Issue 4, 2019

Today schistosomiasis, caused mainly by the three major schistosome species (S. mansoni, S. haematobium and S. japonicum), has for many decades and still continues to be on a rapid and swift rise globally, claiming thousands of lives every year and leaving 800 million people at the risk of infection. Due to the high prevalence of this disease and the steady increase in the infection rates, praziquantel (PZQ) remains the only effective drug against this acute disease although it has no effect on the juvenile schistosome parasite. However, no significant approaches have been made in recent years in the discovery of new or alternative drugs and unfortunately, resistance to this drug has been reported in some parts of the world. Therefore, it is imperative to develop a new drug for this debilitating disease. In this review, a brief history of past, present, and new promising anti-schistosomal drugs is presented.

Acinetobacter baumannii (A. baumannii) is an important opportunistic pathogen that causes major public health concerns, especially in hospitalized patients due to acquisition of resistant genes. The aim of this study was to systematically review the published data on the prevalence and dispersion of metallo-β-lactamases (MBLs) genes in A. baumannii in different provinces of Iran and provide an overall prevalence rate using meta-analysis. All available national and international databanks from 2011 to 2017 were searched to find published studies. Quality of studies was assessed by STROBE. Due to the fact that a significant heterogeneity was observed, the random effects model was used to combine the results. Statistical analysis was performed by comprehensive meta-analysis (CMA) V2 software. Out of 78 articles, 28 were extracted based on certain inclusion and exclusion criteria. Most of the A. baumannii isolates were obtained from intensive care unit (ICU) ward of hospitals. Based on phenotypic and molecular detection tests, pooled prevalence of all MBLs was 58%, and blaVIM, blaIMP, and blaSPM-1 genes were estimated to be at 10.5, 6, and 5%, respectively. Based on the results, further attention should be given to report MBL genes in A. baumannii based on molecular detection rather than the phenotypic one. Furthermore, more effort should be focused on ICU sections in order to avoid the distribution of resistant genes.

Upon viral infection, the interferon (IFN) system triggers potent antiviral mechanisms limiting viral growth and spread. Hence, to sustain their infection, viruses evolved efficient counteracting strategies to evade IFN control. Ebola virus (EBOV), member of the family Filoviridae, is one of the most virulent and deadly pathogen ever faced by humans. The etiological agent of the Ebola Virus Disease (EVD), EBOV can be undoubtedly considered the perfect example of a powerful inhibitor of the host organism immune response activation. Particularly, the efficacious suppression of the IFN cascade contributes to disease progression and severity. Among the EBOVencoded proteins, the Viral Proteins 35 (VP35) and 24 (VP24) are responsible for the EBOV extreme virulence, representing the core of such inhibitory function through which EBOV determines its very effective shield to the cellular immune defenses. VP35 inhibits the activation of the cascade leading to IFN production, while VP24 inhibits the activation of the IFN-stimulated genes. A number of studies demonstrated that both VP35 and VP24 is validated target for drug development. Insights into the structural characteristics of VP35 and VP24 domains revealed crucial pockets exploitable for drug development. Considered the lack of therapy for EVD, restoring the immune activation is a promising approach for drug development. In the present review, we summarize the importance of VP35 and VP24 proteins in counteracting the host IFN cellular response and discuss their potential as druggable viral targets as a promising approach toward attenuation of EBOV virulence.

The introduction of more efficient antiviral drugs are common cause drug-induced acute kidney injury (AKI). The true prevalence of antiviral drugs induced nephrotoxicity is hardly determined. It causes AKI by many mechanisms including acute tubular necrosis (ATN), allergic interstitial nephritis (AIN), and crystal nephropathy. ATN has been described with a few kinds of antiviral drugs such as cidofovir, adefovir and tenofovir with unique effects on transporter defects, apoptosis, and mitochondrial injury. AIN from atazanavir is a rapid onset of AKI and usually nonoliguric but dialytic therapy are needed because of severity. Additionally, crystal nephropathy from acyclovir, indinavir, and foscarnet can cause AKI due to intratubular obstruction. In this article, the mechanisms of antiviral drug-induced AKI were reviewed and strategies for preventing AKI were mentioned.

Background: Staphylococcus aureus is one of the important causes of clinical infections that can be more destructive by its antibiotic resistant strains. Objective: This study aimed to determine the antibiotic susceptibility pattern and distribution of mecA and coa genes in clinical isolates of S. aureus. Methods: Two hundred seventy-three specimens suspected to S. aureus were taken from hospitals of Ahvaz, southwest of Iran. Isolates were identified by standard microbiologic tests and confirmed by the molecular method. Antimicrobial susceptibility testing was carried out by disk diffusion method. The presence of mecA and coa genes was determined by PCR method. Results: Of a total of 200 isolates which were tested for coagulase tube test, 143 (71.5%) showed coagulase positive, and 57 (28.5%) showed a coagulase-negative reaction. Antibacterial susceptibility pattern of 200 S. aureus isolates showed the highest and lowest susceptibility rate to linezolid (98%) and ciprofloxacin (42%), respectively. The prevalence of methicillin-resistant S. aureus (MRSA) by detection of mecA gene was estimated as 47.5 % (95/200), of which the rate of MRSA in coagulase positive and negative isolates was 35% (50/143), and 65% (45/57), respectively. Meanwhile, coa gene was detected in 100% of coagulase positive and 28.1% of coagulasenegative isolates. Conclusion: The results of this study showed that the number of atypical CNSA in our area is high. Since the coagulase test is an essential test for diagnosis of S. aureus, our findings regarding the emergence of CNSA are a warning about the misdiagnosis and selection of appropriate treatment approach for S. aureus isolates.

Background: 1.2-2.0 million cases of leishmaniasis occur annually throughout the world. The available drugs like Amphotericin B, antimonials and miltefosine are unable to fulfill the need due to less effectiveness, high toxicity, resistance, high cost and complex route of administration. Leishmania survives inside the macrophages through different evasion mechanisms; one of that is activation of its trypanothione reductase enzyme which neutralizes the reactive oxygen species generated inside the macrophages to kill the parasites. This enzyme is unique and absent in human, therefore in this study I targeted it for screening of new inhibitors to fight against leishmaniasis. Methods: Homology modeling of Leishmania major trypanothione reductase was performed using Phyre2 server. The homology based modelled protein was validated with PROCHECK analysis. Ligplot analysis was performed to predict the active residues inside the binding pocket. Further, virtual screening of ligand library containing 113 ligands from PubChem Bioassay was performed against the target using AutoDock Vina Tool. Results: Top five ligands showed best binding affinity. The molecule having PubChem CID: 10553746 showed highest binding affinity of -11.3 kcal/mol. Over all this molecule showed highest binding affinity and moderate number of hydrogen bonds. Hopefully, this molecule will be able to block the activity of target enzyme, trypanothione reductase of Leishmania major effectively and may work as new molecules to fight against cutaneous leishmanaisis. Conclusion: This study will help the researchers to identify the new molecules which can block the activity of leishmanial-trypanothione reductase, a novel enzyme of trypanosomatids. These screened inhibitors may also be effective not only in leishmaniasis but also other trypanosomatid-mediated infectious diseases.

Background: High resistance to common antibiotics has become a huge global dilemma in eradicating Helicobacter Pylori infection in both children and adults. The great concern is about the resistance to different classes of antibiotics especially Clarithromycin because of its widespread use. Objectives: The present survey aimed to assess the resistance rate to Clarithromycin in Helicobacter Pylori isolated in patients aged less than 15 years as compared to patients older than 15 years of age. Methods: In this cross-sectional study, total 72 patients with upper gastrointestinal symptoms requiring diagnostic endoscopy referred to Rasoul-e-Akram Hospital in Tehran during one year (August 2015 to August 2016). Helicobacter Pylori infection was diagnosed in patients using the Rapid Urease Test. The antibiotics resistance was detected in genomes using the real-time polymerase chain reaction (PCR) on 23S rRNA gene. Results: In total 72 patients, 36 cases aged less than or equal to 15 years and 36 patients were older than 15 years. Of all patients in this study, 17 cases were detected with gene mutations or polymorphisms related to resistance to Clarithromycin. Overall prevalence rate of resistance was reported 23.61%. Three polymorphisms on 23S rRNA gene including A2142G, A2142C, and A2143G were revealed in 47.1%, 5.9%, and 47.1% of patients, respectively. The bacterial resistance to Clarithromycin was observed more prevalent in patients that aged older than 15 years compared to patients younger than 15 years of age. Also, frequent consumption of any type of antibiotics was significantly associated with the higher resistance of bacterium to Clarithromycin. Conclusion: The results of our study regarding the resistance of Helicobacter Pylori to Clarithromycin were similar to findings of other studies around the world. But, the Clarithromycin resistance rate was reported higher in patients older than 15 years of age and those patients who repeatedly received different types of antibiotics regardless of their age. Of all mutations in bacterial genome, the prominent mutations responsible for bacterial resistance to Clarithromycin included A2142C, A2142G, and A2143G nucleotide polymorphism on 23S rRNA gene.

Background: Saliva is a very important complex biological oral fluid .Antioxidants are present in all body fluids. Uric acid, albumin and vitamins are some of the non- enzymatic molecular antioxidants. Alkaline phosphatase is related to cell injury and death. Objectives: The aim of this study was the evaluation of salivary alkaline phosphatase and albumin level in HIV positive patients in comparison to healthy control group. Methods: Case groups were 49 HIV positive subjects, compared with 49 healthy control group. Oral clinical examination was carried out. Five ml unstimulated whole saliva was collected during 5 min with the Navazesh method. Alkaline phosphatase was determined by spectrophotometric assay. Albumin was assessed by the nephelometric method. Results: The results of this study showed significantly lower salivary albumin in the case group in comparison to healthy control group (p= 0.001). HIV positive group had greater alkaline phosphatase than the healthy control group. However, this difference was not statistically significant (p=0.458). Conclusion: Salivary albumin level was significantly decreased and salivary alkaline phosphatase level slightly increased in HIV positive patients in comparison to healthy control group. All of the HIV infected patients were in early phase of HIV infection with normal immune status. More research is needed to estimate these enzymes changes in late phase of HIV infection and AIDS step.

Background: Pneumonias are the most frequent infectious diseases, characterized by a high prevalence especially among children and adults at risk. The socio-economic impact caused by Streptococcus pneumoniae is evaluated in terms of morbidity, death rate and hospitalizations. Objective: The aim of the study was to demonstrate the potential economic advantages by implementation of an active anti-pneumococcal 13-valent vaccine strategy in Campania region (Southern Italy) in two different categories of subjects, children (aged 0-12), and adults (aged 50- 79) at risk (hypertension, nephropathies, COPD and heart diseases). Methods: Vaccination costs were compared with costs necessary to treat avoidable diseases in the presence and absence of a vaccination program. Results: Offering anti-pneumococcal 13-valent vaccine to the paediatric population was quantified as saving one million euros for Italian national health service in two years. In addition, offering anti-pneumococcal vaccine to adults at risk would generate a return of around 29 million euros. Conclusion: In both cases, offering anti-pneumococcal 13-valent vaccine was proven to be a helpful political health strategy, not only in consideration of a reduction of cases but also in view of the favourable economic impacts.

Objectives: The most common parasites responsible for fascioliasis are F. hepatica and F. gigantica. Fascioliasis is an important problem in terms of health and economics. The western part of Iran is one of the major hubs of animal husbandry and the prevalence of fascioliasis is high. The aim of the current study was to determine the Fasciola spp. present in the western part of Iran. In the present study, 45 samples were collected from slaughterhouses in three provinces in the western part of Iran, including Ilam, Lorestan and Kermanshah. Methods: The flukes were detected using morphological methods and the DNA of all samples was extracted. The ribosomal internal transcribed spacer (ITS1) was identified by PCR and PCR-RFLP techniques using the Rsa1 restriction enzyme. Then, 15% of the samples were sequenced. Results: Based on their ITS1 sequence, all samples showed 700 bp bands. The results of sequencing showed a similarity of 99% to 100% across samples. Using the Rsa1 restriction enzyme, all samples produced three distinct bands (60 bp, 100 bp, and 360 bp). These results demonstrated that the most common fasciola in the western part of Iran in sheep and cattle is F. hepatica. Conclusion: The results of the present study showed that only the species F. hepatica is parasitizing livestock in the western part of Iran. Further studies using new molecular markers for more accurate identification of fasciola-causing species will be useful in the control and prevention of fascioliasis.

Background: Intrathoracic Lymphadenopathy (ITLN) in Human Immunodeficiency Virus (HIV) infected patients may have various etiologies and prognoses. Etiologies of ITLN can be distinguished based on the distribution of enlarged lymph nodes. Sometimes tuberculosis (TB) is the first sign of underlying HIV infection. Objectives: We sought to determine ITLN distribution and associated pulmonary findings in TB/HIV co-infection using Computed Tomography (CT) scan. Methods: In this retrospective, observational, cross-sectional study, chest CT scans of 52 patients with TB/HIV co-infection were assessed for enlarged intrathoracic lymph nodes (>10 mm in short axis diameter), lymphadenopathy (LAP) distribution, calcification, conglomeration, the presence of hypodense center and associated pulmonary abnormalities. LAP distribution was compared in TB/HIV co-infection with isolated TB infection. Results: Mediastinal and/or hilar LAP were seen in 53.8% of TB/HIV co-infection patients. In all cases, LAP was multistational. The most frequent stations were right lower paratracheal and subcarinal stations. Lymph node conglomeration, hypodense center and calcification were noted in 25%, 21.4% and 3.5% of patients, respectively. LAP distribution was the same as that in patients with isolated TB infection except for the right hilar, right upper paratracheal and prevascular stations. All patients with mediastinal and/or hilar adenopathy had associated pulmonary abnormalities. Conclusion: All patients with TB/HIV co-infection and mediastinal and/or hilar adenopathy had associated pulmonary abnormalities. Superior mediastinal lymph nodes were less commonly affected in TB/HIV co-infection than isolated TB.

Background: The increasing prevalence of antibiotic resistant bacteria has raised an urgent need for substitute remedies. Antimicrobial peptides (AMPs) are considered promising candidates to address infections by multidrug-resistant bacteria through new mechanisms of action that require a careful evaluation of their performance. Objective: Identification of effective AMPs against Neisseria meningitidis, which represents a pathogen of great public health importance worldwide that is intrinsically resistant to some AMPs, such as polymyxin B. Methods: A cationic 11-residue peptide (KLKLLLLLKLK), referred to as poly-Leu, was synthesized and its antimeningococcal activity was compared to cecropin A and poly-P (KLKPPPPPKLK) through a variety of assays. Flow cytometry was used to measure propidium iodide uptake by N. meningitidis serotype B as an indicator of the effectiveness of each peptide when added to cultures at different concentrations. Results: The addition of the poly-Leu peptide led to a 90.3% uptake of the dye with an EC50 value of 7.9 μg mL-1. In contrast, uptake was <10% in cells grown in the absence of peptides or with an identical concentration of cecropin and poly-Pro peptides. Electron micrographs indicated that the integrity of the cellular wall and internal membrane was impacted in relation to peptide concentrations, which was confirmed by the detection of released alkaline phosphatase from the periplasmic space due to disruption of the external membrane. Conclusion: Poly-Leu peptide demonstrated definitive antimicrobial activity against N. meningitidis.

Background: The increasing incidence of invasive forms of candidiasis and resistance to antifungal therapy leads us to seek new and more effective antifungal compounds. Objective: To investigate the antifungal activity and toxicity as well as to evaluate the potential targets of 2- cyclohexylidenhydrazo-4-phenyl-thiazole (CPT) in Candida albicans. Methods: The antifungal activity of CPT against the survival of C. albicans was investigated in Caenorhabditis elegans. Additionally, we determined the effect of CPT on the inhibition of C. albicans adhesion capacity to buccal epithelial cells (BECs), the toxicity of CPT in mammalian cells, and the potential targets of CPT in C. albicans. Results: CPT exhibited a minimum inhibitory concentration (MIC) value of 0.4-1.9 μg/mL. Furthermore, CPT at high concentrations (>60 x MIC) showed no or low toxicity in HepG2 cells and <1% haemolysis in human erythrocytes. In addition, CPT decreased the adhesion capacity of yeasts to the BECs and prolonged the survival of C. elegans infected with C. albicans. Analysis of CPT-treated cells showed that their cell wall was thinner than that of untreated cells, especially the glucan layer. We found that there was a significantly lower quantity of 1,3-β-D-glucan present in CPT-treated cells than that in untreated cells. Assays performed on several mutant strains showed that the MIC value of CPT was high for its antifungal activity on yeasts with defective 1,3-β-glucan synthase. Conclusion: In conclusion, CPT appears to target the cell wall of C. albicans, exhibits low toxicity in mammalian cells, and prolongs the survival of C. elegans infected with C. albicans.