Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 16, Issue 3, 2016

Quinolones and fluoroquinolones are principal weapons against variety of bacterial infections and exert their antibacterial potential by interfering the activities of bacterial enzymes. As these agents are associated with some limitations, an important approach to overcome these major constraints is to prepare covalent derivatives, i.e. prodrugs. Prodrug design has been employed to improve the limitations of these drugs such as less aqueous solubility, poor absorption and distribution, toxicity, disagreeable taste, poor lipophilicity etc and for improving their pharmacological profile. This paper highlights the utility of various prodrug strategies in optimizing the therapeutic index of these antibacterial agents and their recent patents. Some of their prodrugs being utilized at preclinical and clinical levels have also been discussed. Hence, this paper has been prepared to present the significant findings of various research papers that would be helpful in motivating scientific researchers to forward the research in direction of utilization of prodrugs in clinical therapy.

The inadequate benefits of the existing therapies and the new insights into the pathophysiology of inflammatory airway diseases like chronic obstructive pulmonary disease (COPD) and asthma have led to the breakthrough of newer targets and innovative compounds as the treatment alternatives. The enhanced interpretation of immune cell signalling and signal transduction pathways at the molecular level involved in this process allows the selection of new therapeutic targets and designing of new molecules to combat such multifactorial diseases. Pertaining to the marked variability in type of inflammation observed in their disease phenotypes, the blockade of a particular receptor or mediator yielding strong restorative effect in one patient may not be significant to other. Therefore, their management requires the prompt and phenotype specific optimized drug therapies and development of new and improved molecular compounds targeting the immune cell signalling. This whole process including the approval of such compounds as the standard drug therapies is time taking, expensive and complicated task. It ranges from the selection of novel anti-inflammatory drug target to the final approval of biologically active restorative molecules. Grounded on this, the current review gives a comprehensive idea of the basic immunological network involved in these inflammatory airway diseases at the cellular level along with the discussion of their potential therapeutic targets. It also follows brief over viewing of the drug development process generally employed for the exploration of such innovative targets leading to the discovery of novel anti-inflammatory molecules for these inflammatory airway diseases.

Background: Multi-drug resistant P. aeruginosa has been increasing worldwide. Various mechanisms create this cross resistance in this bacterium including, acquisition beta-lactamases and intrinsic mechanisms, such as the presence of multidrug efflux pumps. Generally, multidrug efflux pumps inhibitor is used as a phenotypic method for the detection of active efflux pump systems. Methods: In this study, 100 P. aeruginosa were collected from burn patients. Cefepime and imipenem resistant strains were isolated by disc diffusion agar and MIC. Carbonyl cyanide m-chlorophenyl hydrazone (CCCP), H+ conductor was used to detect activities of multidrug efflux pumps. The multidrug efflux genes of mexA, mexC and mexX were detected by PCR. Results: 87% and 79% of isolates were cefepime and imipenem resistant respectively. Only 18% of cefepime and imipenem resistant strains were inhibited by CCCP. 98% and 97% of isolates harbored mexA and mexC genes, respectively, while all of them harbored mexX. Conclusion: Thus, cross resistance in P. aeruginosa isolates can be obtained by multidrug efflux pump systems. Therefore, the inhibition of multidrug efflux pumps can be very helpful for the treatment of infections caused by multi drug resistant P. aeruginosa.

Background and Purpose: Giardia duodenalis is an intestinal flagellate parasite which spreads all over the world and is considered as a health problem in the most rural and low sanitation areas. Many diagnostic tests have been developed for the detection of Giardia parasite in stool samples but all of them have some disadvantages such as lack of sensitivity and specificity. In search for a simple and accurate test, diagnosis of Giardia infection using dot blot method has been investigated in this work. Materials and Methods: In this descriptive study, 30 stool samples which their infection with Giardia were confirmed by direct examination and formalin ether considered as case group. Thirty stool samples without Giardia infection according to formalin ether examination were also considered as a control group. Giardia cysts were isolated from the stool samples using sucrose method. In order to raise antiserum against Giardia cysts, the purified cysts were then sonicated and injected to a rabbit. A mono specific antiserum against the 66KDa band of Giardia cyst antigen was also prepared. The two antisera were used in the dot blot test. Finally, the sensitivity and specificity of the dot-blot method were estimated by considering formalin ether as the gold standard. Results: When Poly specific antiserum was used, the sensitivity and specificity of the dot blot for detection of Giardia infection were 77% and 64% respectively. However the sensitivity and specificity of this assay were 97% and 64% respectively when monospecific antiserum was used. Conclusion: It seems that dot blot is an easy method for the diagnosis of Giardia especially in the rural areas. However more work is recommended for further development of this test.

Background: A total of 94 lactic acid bacteria (LAB) were isolated from Tunisian artisanal (Ricotta cheese’s whey) and industrial (bactofugate) milk waste, identified and then screened for their antimicrobial activity against some bacteria implicated on nosocomial infections. Objective: Bacterial genera and species identification was performed using molecular tools. The antimicrobial activity was tested against 7 strains of Gram-negative bacteria and 4 strains of Gram-positive bacteria as well as 6 yeasts. Method: The Crude extract was found to have a narrow antimicrobial spectrum on Gram-positive bacteria mainly Listeria monocytogenes. Among the strains which showed antibacterial activity, four were determined to be bacteriocins-producers. They were identified as Lactococcus lactis. Results: Brain Heart Infusion (BHI) Agar was found more adapted than Man, Rogosa and Sharpe (MRS) to investigate the antimicrobial activity of L. actococcus lactis against L. isteria monocytogenes. The genetic determinants encoding the antimicrobial peptides were targeted by specific PCR. Conclusion: All L. lactis bacteriocin producing strains possessed the Nisine Z gene (nisZ) except for one, which contained both Nisine A and Nisine Z genes (nisA and nisZ). They have been identified as antilisterial agentS.

Background: Candida spp. remains the fungal species most commonly associated with biofilm formation. Increase in Candida infections in last decades has almost paralleled the increase and wide spread use of a broad range of medical implant devices mainly in population with impaired host defences. One of the most important characteristics of biofilms is their high level of resistance to antimicrobial drugs. Aims and Objectives: This study was conducted to know the prevalence of different Candida spp. causing blood stream infections and ability to form biofilm and to evaluate the co relation of biofilm with antifungal drug resistance. Material and Methods: The present study was conducted on 12464 blood samples for the identification and speciation of various Candida spp. causing blood stream infection over a period of one year. Antifungal susceptibility was performed as per clinical laboratory standard institute guidelines and biofilm formation was detected by method described by Christensen’s et al. Results: Out of total 12464 blood culture received, 1378 (11.05%) were culture positive rest and among culture positive 100 (7.25%) Candida isolates were recovered. C. tropicalis was the commonest (43%) species followed by C. albicans (41%), C. krusei (9%) and C. parapsilosis (7%). A total of 41 Candida isolates were biofilm producers and rest 59 isolates were non-biofilm producers. Conclusion: A changing trend of increased prevalence of non albicans Candida spp. was observed which were resistant to commonly used antifungal fluconazole. Multi drug resistance was more common in biofilm forming Candida isolates.

Background: The human immune system can be impaired due to lack of adherence to treatment among HIV positive patients. This is reflected in lower levels of CD4 count and incomplete viral suppression leading to the disease's progression and increased risks of opportunistic infections. Little is known about adherence to antiretroviral therapy (ART) and Tuberculosis (TB) treatment and barriers to ART adherence faced by prisoners. Therefore, we conducted a study to evaluate adherence to ART, treatment of latent TB infection (LTBI), and TB treatment and barriers of ART adherence in the Great Tehran Prison in 2014. Materials and Methods: We conducted a study to evaluate adherence to ART, latent TB infection treatment, and TB treatment via Directly Observed Therapy (DOT) among HIV positive patients in the Great Tehran Prison in 2014. Furthermore, we examined the barriers of adherence to ART through focus group discussions (FGDs) with 22 people living with HIV in the prison. Results: The mean of adherence to ART, latent TB infection treatment, and TB treatment were 93.3%, 92.7% and 93.3%, respectively. Addiction, negative drug reactions, bad experiences with staffs, and psychosocial and nutritional problems were cited as the most common barriers to adherence. Conclusion: It is recommended to implement DOT for ART in Iranian prisons. In addition, through removing the barriers and implementation of DOT for ART, HIV positive prisoners can achieve a complete adherence.

Background: Lead compounds that target tubulin are being developed as agents against the human malaria parasite, Plasmodium falciparum. It is important to define the binding sites of these molecules on the tubulin dimer: Taxol, Vinca domains or novel binding pockets; however, extraction of native parasite tubulin is difficult. Objective: This report aims to develop assays that allow the rapid assessment of binding sites of compounds on the tubulin dimer. Method: We have developed a simple growth assay, using a combination of two anti-microtubule drugs that have overlapping binding sites, to study whether the two drugs act in synergistic, antagonistic or neutral manner. Additionally, Molecular docking was used to predict the binding sites of the drugs. Results: The combination assay shows antagonistic interactions between drugs having overlapping binding sites. In contrast, drugs that do not bind to overlapping sites show no interactions or synergism in this combination assay. Molecular docking predictions show that indeed, drugs with antagonistic interactions in the growth assay do bind to overlapping sites. Conclusion: These two assays can be a simple preliminary screen for the binding sites of novel anti-tubulin compounds being developed for malaria therapeutics.