Ehrlich II –2nd World Conference on Magic Bullets

Background: Tetracyclines (TCs) are large group of medically-important antibiotics with a common basic structure of four linearly fused six-membered rings. They are produced by several genera from the order Actinobacteria; some examples are tetracycline, chlortetracycline, oxytetracycine, and demethylchlortetracycline, synthesized by the type II polyketide synthase (PKS) multi-enzyme complexes. A number of potent antibacterial TCs have been generated using a semi-synthetic approach such as minocycline, doxycycine and novel tigecyclin. TCs act at the ribosomal level interfere bacterial protein synthesis. They were amongst the first broad-spectrum antibiotics and their intensive use led to widespread microbial resistance. A small group of tetracycline analogs has recently been identified that do not target bacterial ribosome. Instead, they have bactericidal rather than bacteriostatic activity, and are active even against the tetracycline-resistant strains.

Methods: The objective of our work was to clone, sequence and characterize a novel gene cluster encoding an unusual TC antibiotic.

Results: Consistently with the chemical structure of the antibiotic, the cluster encodes genes for a typical minimal PKS (KSα, KSβ and ACP), three genes involved in the cyclisation/aromatisation process, methyltransferases, one aminotransferase, oxygenases, a ketoreductase, an acyl-CoA ligase, a drug resistance transporter and a transcriptional regulator were identified. The application of biosynthetic engineering methods in combination with well-established semi-synthetic approaches will be presented.

Conclusions: The unusual structure of this tetracycline analog provides an opportunity for development of new tetracycline molecules.
References:

PETKOVIĆ, H, HUNTER, IS., RASPOR, P. Engineering of polyketide synthases : how close are we to the reality? Acta microbiol. immunol. Hung., 2002, vol. 49, no. 4, p.. 493-500.

PETKOVIĆ, H, CULLUM, J, HRANUELI, D, HUNTER, IS., PERIĆ-CONCHA, N, PIGAC, J, THAMCHAIPENET, A, VUJAKLIJA, D, LONG, Paul F. Genetics of Streptomyces rimosus, the oxytetracycline producer. Microbiol. mol. biol. rev., 2006, vol. 70, no. 3, p.. 704-728.

Prokinetic Effect Of Erythromycin: The Benefit Of A Common Side Effect PETRAKIS IE, GRISBOLAKI EE University Hospital of Herakleion Crete, Greece, Department of General Surgery Background: Erythromycin was firstly introduced in the clinical practice in 1950 as antibiotic. The prokinetic activity of erythromycin was discovered in the 1980's as an adverse effect of the drug. Since then erythromycin has been used in patients with chronic functional pseudo-obstruction, gastro-oesophageal reflux post-operative intestinal dysmotility, gastroparesis secondary to diabetes, hyperglycaemia and scleroderma and after surgical vagotomy. Its use as a prokinetic agent has also been extended to preterm infants with gastrointestinal dysmotility and feeding intolerance and more recently within the context of critically ill patients. It is effective as a prokinetic drug on gastroparesis related to acute pain-related stress and when given prior to elective surgery has been shown to improve gastric motility. However, the aim of the present study was to investigate whether Erythromycin accelerates the delayed gastric emptying of solids and hypertonic liquids induced by hyperglycemic conditions. Methods: Twelve healthy subjects ate standard radiolabelled solid and hypertonic liquid meals. Gastric emptying was measured by scintigraphy during normoglycemia (5-8.9 mmol/L glucose) and hyperglycemia induced by intravenous glucose (16-19 mmol/L glucose) after administration of placebo or 200 mg of erythromycin intravenously. Emptying was measured randomly on 4 different days. Results: Administration of erythromycin during normoglycemia or induced hyperglycemia compared with placebo, accelerated the gastric emptying of the solid meal while gastric emptying of the hypertonic liquid was reduced. Eythromycin versus placebo significantly reduced the lag-phase duration, The lag-phase duration was significantly increased (17.5 +/- 5.5 min, and 7.2 +/- 4.5 min vs 10.5 +/- 3.4 min, and 3.5 +/- 2.5 min, respectively, P < 0.0001) as were the overall T1/2 (gastric emptying time of the half meal) (52.5 +/- 13 min and 24.5 +/- 5.5 min vs 42 +/- 10.5 min, and 16 +/- 6 min, respectively, P < 0.0001) and the percentage of liquid meal retained in the stomach at 60 and 100 min postprandially (P < 0.001). Gastric emptying of the half meal, and the percentage of meal retained in the stomach 120 min postprandially Conclusions: The erythromycin-induced effect on gastric emptying of solids and hypertonic liquids is related to the plasma glucose level. Erythromycin accelerates gastric emptying rate of both solids and hypertonic liquids in both conditions, either in normoglycaemia or hyperglycaemia	Combinatorial Nanobiotechnology – A Paradigm Shift in Chemistry and Material Science PETRENKO VA Department of Pathobiology, Auburn University, Auburn, AL 36849, U.S.A. Background: The more than 20-year evolution of phage display has dramatically affected the potential of this technique amid other bioengineering methods. The marriage of combinatorial chemistry and biological selection has been very powerful changing the methodology of biochemical research by allowing selection simultaneously among billions of genetic species in one test tube. Genetically driven phage nanobiotechnology has allowed development of libraries of diverse nanostructures expressed on the phage surface providing a rich resource of diagnostic, detection and pharmaceutical probes. Methods: Phage engineering, which is based on natural mechanisms of selection, amplification and self-assembly, allows directed nano-fabrication of bioselective materials with possible applications in gene/drug-delivery, biosensors, nanoelectronics, biosorbents, and other areas of medicine, technology, and environmental monitoring. In particular, landscape phage expressing tumor-specific peptides fused to all copies of the major coat protein pVIII can be converted easily into gene-encapsulating particles or drug-loaded vesicles that acquire the ability to recognize the same receptors, cells, tissues and organs that have been used for selection of the precisely targeted phage. The fusion major coat protein constitutes 98% of the total protein mass of the virion — a purity hardly attainable in normal synthetic and bioengineering procedures. As a normal intestinal parasite, phage and its components are not toxic and have already been tested for safety in preclinical and clinical trials. All these unique characteristics of phage commend it very well as a very promising nanomaterial for a variety of medical and technical applications. To illustrate the concept, the author will present the data obtained in his research group and collaborative research. Results: This presentation focuses on the progress made in the development of these new nanomaterials and discusses the prospects of using phage as a bioselectable molecular recognition interface in medical and technical devices based on the experience of the author in this area. Conclusions: Phage display evolved into a discipline of material science presenting phage not only as an instrument for peptide and antibody discovery, but also as a prospective nanomaterial that can be easily tailored using routine genetic engineering manipulations. This merge of phage display technologies with nanotechnology during the last several years is very promising and has already shown its vitality and productivity contributing vigorously to different areas of medicine and technology, such as medical diagnostics and monitoring, molecular imaging, targeted drug and gene delivery, vaccine development, as well as bone and tissue repair.
Magic bullet or magic diet: The need for further understanding in sport performance enhancements PETROCZI A^1, NAUGHTON D.P^1 ^1School of Life Sciences, Kingston University, London KT1 2EE. Background: Translational nutrition embodies the use of dietary components to effect a therapeutic end point commonly associated with medicinal intervention. For example, recent advances have been made in the study of dietary chelators for treating neurodegenerative diseases via dissolution of plaques and by formation of anti-oxidnat enzyme mimetics. Further work has posited dietary components as regulators of gene product formation to enhance key protective enzymes such as superoxide dismutase. However, many scienticfic studies have focussed on individual components of diet (e.g. anti-oxidants) with little or scant regard for the entire profile of a foodstuff. In this era of multiple advance in integrative translation nutrition, further emphasis on the informed decision making regarding function nutrition is warranted. The aim of this study is to deconvolute decision making rationale versus practice for functional nutrition use in elite athletes. Methods: The 'UK Sport 2005 Drug Free Survey' data (n = 874 adult and n = 403 youth elite athletes) were re-analysed using association [chi-square] and 'strength of association' tests [phi] to show the proportion of informed choices and to unveil incongruencies between self-reported supplement use and the underlying motives. Results: Participants reported supplement use for performance enhancing and health maintenance reasons. Of the 30 possible associations between supplements and reasons, 11 were predictable in the first and 10 in the latter category from literature precedents, In the adult athlete population, only 8/11 were evidenced and these were not strong (phi < .7). The best associations were for the ability to train longer and maintaining strength with creatine and whey protein. Associations with health maintenance motives were found in 8/10 test pairs, however only weak associations exist. Of these, 4 were associated with avoidance of sickness (iron, multivitamin, vitamin C and Echinacea). Similar results were found among young elite athletes, where supplements were taken for performance enhancing reasons. No agreement was observed between athletes’ rationale and behaviour except for creatine. Conclusions: These results suggest that a lack of understanding exists in supplement use. There is an urgent need to provide accurate information which will help athletes make informed choices about the use of supplements.	MRI monitoring of blood brain barrier alterations in inflammatory lesions of Multiple Sclerosis: Tools to evaluate disease activity, efficacy of treatments and to develop new therapeutic strategies PETRY KG, BOIZIAU C, BROCHET B, DOUSSET V EA2966 Neurobiology of myelin disorders, University of Bordeaux 2, 146, rue Léo-Saignat, 33076 BORDEAUX – France Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Since 1999 we have pioneered a new approach of cellular and molecular imaging in vivo in application to MS. In an experimental animal model of MS we have monitored in vivo by Magnetic Resonance Imaging (MRI) the infiltration of the CNS by inflammatory blood cells (monocytes, T cells) labelled with iron nanoparticles as contrast agent in comparison to Gadolinium enhanced rupture of the blood brain barrier (BBB), and we have transferred this innovative approach for the first time to clinical research in MS patients. In experimental work and MS, this new approach has been validated as helpful tool to characterize acute inflammation and active inflammatory lesions, to predict the severity of disease development and to monitor the efficacy of immunomodulatory treatment strategies. Ongoing experimental work aims to identify molecular alterations at the BBB that occur at early stages in EAE rats, by phage display screening in CNS characterized by macrophage infiltrates with MRI. We further develop a strategy by using the MRI cell marker and peptide-ligand binding approach to inflammatory lesions sites for transport of therapeutic compounds into the lesion sites and their local liberation under the control of MRI.
Is there a magic bullet in antiviral therapy? PEUSCHEL KE Hopital psychiatrique de Prefargier, 2000 Marin/NE, Switzerland Antiviral therapy has been highly specific and tailored typically to treat one strain of a virus, but has also been problematic because viruses escape targeted therapy by mutation. This has been of increasing importance for example in the treatment of globally spreading viral infections like the HIV-infection, hepatitis C and other viral infections. An antiviral treatment that would fulfill the requirements of a magic bullet would however need to have a different type of target, and it is proposed that this target has to be the immune system itself, in the sense of a treatment that enhances the ability of the immune system to ward off viral infections independent of the viral genome. A mechanism of such a therapy has been described, where the target is the beta-receptor on cells of the immune system, and as a consequence, the cAMP-PKA pathway that inactivates and disables cells of the immune system. The mechanism is therefore an immunoactivation via inhibition of an inhibitory stress-related cellular pathway activated by beta-receptors. Various experiments have shown that this mechanism diminishes viral titers of different viruses and this has also been demonstrated in virus-infected patients treated with selected beta-blockers like propranolol. Beta-blockers used for such a therapy may need to have special properties like efficient penetration of the blood-brain barrier, they should be highly lipophilic and non-selective for beta-receptors.	A Cost-Benefit Approach to Sample Size Determination for Clinical Trials with Binary Responses PEZESHK H^1, NEMATOLLAHI N^2 and MAROUFY V^3 ^1School of Mathematics, Statistics and Computer Science and Center of Excellence in Biomathematics University of Tehran, Tehran, Iran ^2,3Department of Statistics, Allameh Tabatabaie University, Tehran, Iran The determination of sample size is an important issue in designing any trial. Particularly it is of key importance in medical studies. Many authors have looked at the problem and many papers have been written to discuss the problem form both the frequentist and Bayesian standpoints. In the frequentist approach sample sizes are usually determined either from power and size calculations or from formulae based on confidence interval widths. In the fully Bayesian (or decision theoretic) approach, as in this work, the sample sizes are determined by maximizing expected net benefit. In this work we discuss a decision theoretic or fully Bayesian approach to the sample size question in clinical trials with binary responses. Data are assumed to come from two binomial distributions for which p1 and p2 are the probabilities of favourable outcomes for each individual in group i, (i=1, 2). To describe our prior knowledge about (p1, p2), we assume that it has a joint density. With a binomial likelihood it is mathematically convenient, and often reasonably realistic, to make the assumption that (p1, p2) has a Dirichlet distribution. The parameter of interest is p= p1-p2. The optimal size of the trial is obtained by maximizing the expected net benefit function which is the expected benefit of conducting the trial minus the cost of it.
Metals as Endocrine Disruptors in Women's Reproduction: Assessment of Effect and Mechanism of Action in Different Steroidogenic Cells PIASEK M^1, HENSON MC^2, CHEDRESE PJ^3 ^1Institute for Medical Research and Occupational Health, Zagreb, HR, Croatia; ^2Purdue University Calumet, Hammond, IN, USA; ^3University of Saskatchewan, Saskatoon, CA, Canada. Background: The polluted environment contains a mixture of reproductive toxicants that includes metals and metalloids. The emerging evidence exists that cadmium, lead, arsenic, mercury and the others can act as endocrine disrupting chemicals in mammals. They can alter ovarian and/or placental steroidogenesis and thus affect ovarian cyclicity, the maintenance of pregnancy, and embryo/foetal development. A better understanding of the endocrine disrupting potential of metal exposure bears great clinical relevance, as metals constitute an important part of our ecosystem and lifestyle, the production and use of which is unlikely to be discontinued in the foreseeable future. Methods: We conducted complementary research on cadmium-related steroid disruption using different experimental paradigms. Human placentas were used for ex vivo (epidemiological) and in vitro studies of cadmium effect(s) on placental progesterone production. In experiments on laboratory rats in vivo and in vitro and in the stable porcine granulosa cell line JC-410, steroidogenesis was assessed in placental and ovarian steroidogenic cells. Results: In either human or rodent placenta and in ovary, increased cadmium concentrations in steroidogenic tissue were accompanied by decreased progesterone production. Direct cadmium effects on specific components of the steroidogenic pathway were found. This includes two sites of action: the low-density lipoprotein-cholesterol receptor and P450 side chain cleavage enzyme. In cultured porcine granulosa cells, cadmium stimulated ovarian progesterone synthesis through a mechanisms involving activation of P450 side chain cleavage gene expression. Conclusions: 1) Cadmium has the potential to disrupt steroidogenesis in human placenta. 2) Cadmium may display paradoxical dual effects in the ovary; depending on the exposure level, it may either inhibit or enhance/mimic the biosynthesis of progesterone and oestrogen, and act as xenoestrogen (metalloestrogen). 3) Sites of cadmium direct effects on specific components of the steroid biosynthetic pathway are multifaceted and it is possible that cadmium’s effects are “tissue-specific” in different steroidogenic cells.	Cardiological medicines: allowed and prohibited pharmacological helping for athletes PILKOWSKI SM^1, POKRYWKA A^2, KWIATKOWSKA D^2,.MAMCARZ A^1 ^1 III Department of Internal Medicine and Cardiology, II Medical Faculty of Warsaw Medical University, Warsaw, Poland ^2 Department of Anti-Doping Research, Institute of Sport, Warsaw, Poland Background: Cardiological medicines are recommended athletes with medical indications by doctors working in a Center of Sport Medicine in Warsaw, Poland. There is almost two hundred consultations a year. The Therapeutic Use Exemption (TUE) allows athletes to use substances and methods banned by World Anti-Dopnig Agency (WADA). Diuretics are prohibited for sportsmen at all time ( in and out of competitions). B-blockers are not allowed only in a particular sports (for example: ski jumps, snowboard or aerial and car sports) .On the other hand l-blockers or cardioprotecitve substances like a trimetazidine are not yet present on the WADA list of prohibited substances. Methods: Department of Anti-Doping Research of Institute of Sport in Warsaw, Poland (WADA accreditation since 2004) had been analyzed 6210 urine samples of Polish athletes since 2005 to 2007. This material has been tested retrospectively in direction of finding diuretics, b-blockers and their metabolites, l-blockers and cardioprotective substance - trimetazidine. Results: -diuretics were found in 7 samples -b-blocker – only one case -l-blocker –buflomedil was present in 6 athlete’s samples (all cycling riders in competition) -trimetazidine was found in 34 samples from various discipline of sport: Strength discipline: trimetazydine was often found (n=27) 13 cases - cycling riders 7 cases – athletics 4 cases – triathlon 2 cases -canoeing 2 cases – swimming Then in the forces (n=7): 3 cases - weigh-lifting 3 cases - football 1 case - judo Conclusions: 1. The use of diuretics and b-blockers by athletes is the occasional phenomenon in Poland compared to the use of other banned substances such as anabolic steroids. 2. Trimetazidine and buflomedil are used as allowed pharmacological helping for athletes in Poland 3. There is no objective evidence of clinical trials of trimetazidine and buflomedil use in improving the physical capacity at the athletes. 4. The use of trimetazidine and buflomedil in enhancing the capacity of physical athletes, wakes up ethical doubts but is not prohibited.
Psychotomimetic action of ketamine and MK-801: Behavioral, Network and Cellular Features PINAULT D INSERM U666, Faculté de Médecine, ULP, Strasbourg, France Cognitive dysfunction, hallucination and delusion are typical disorders that are diagnosed in schizophrenic patients and that can be induced in humans following the administration of a single non-anesthetic dose of ketamine, a non-competitive NMDAr antagonist. What is the impact of a similar single injection of ketamine in the EEG of rodents? And what is the direct effect of ketamine in cortical networks? In awaked adult rats, a single subcutaneous injection of ketamine (<5 mg/kg) induces persistent aberrant gamma frequency (30-80Hz) oscillations (increased power and intrinsic frequency) in the frontoparietal cortex and a concomitant ataxic behaviour. EEG recordings performed in deeply anesthetized rats demonstrated that these pathophysiological gamma oscillations are not caused by abnormal motor activity. Neither are they dependent on conscious sensorimotor processing. Local application of ketamine produces a cortical focus of persistent aberrant gamma oscillations, which progressively spread to adjacent networks. Furthermore, ketamine significantly increases the synchrony of basal gamma oscillations between two highly and not between two weakly interconnected structures. Juxtacellular recordings combined with EEG recordings have revealed that aberrant gamma oscillations are associated with a significant increase in the firing rate in the majority of glutamatergic corticofugal and thalamocortical neurons. Our findings suggest that ketamine-induced persistent gamma hypersynchrony is an aberrant network noise that might set out of control the spatiotemporal patterning of inputs in cortical-related networks, which would impair top-down processing. A persistent decrease or annihilation of the signal/noise ratio of the cognition-related transient gamma synchrony might cause cognitive dysfunction, acute psychosis and exacerbate schizophrenia symptoms. Therefore, this persistent aberrant gamma noise may be a potential neurophysiological marker of psychoses. INSERM and ULP support.	Targeting the Tumor Microenvironment as a Modality to Combat Cancer – Effect of Halofuginone PINES M Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel Background: Most solid tumors comprise neoplastic and non-neoplastic cells plus extracellular matrix (ECM) components. This cellular microenvironment favors tumor development, and the ECM–stromal cell interactions contribute to the neoplastic phenotype. The tumor–dependent conversion of fibroblasts to myofibroblasts, mediated by transforming growth factor-beta (TGF), results in overproduction of ECM proteins. Thus, the fibroblast-to-myofibroblast transition has emerged as a viable target for pharmacological intervention. Halofuginone, an analog of the plant alkaloid febrifugine, inhibits Smad3 phosphorylation downstream of the TGF signaling. In pre-clinical and clinical studies halofuginone prevented new, and stimulated resolution of pre-existing fibrosis in which excess of ECM hallmarks the disease. Methods: Xenografts were established by implanting various human tumor cells –subcutaneously or orthotopically – into nude mice. Tumor size was evaluated directly or by NMR micro-imaging. Gene expression and protein synthesis were evaluated by in situ hybridization and immunohistochemistry, respectively. Results: Halofuginone, however administered and irrespective of cancer type, inhibited smad3 phosphorylation, resulting in inhibition of the fibroblast-to-myofibroblast transition, reduction in ECM production and reduction in angiogenesis resulted in inhibition of tumor growth. In prostate cancer xenografts representing various phenotypes of the disease, halofuginone inhibited tumor progression in correlation with reduction of plasma prostate-specific antigen. Halofuginone is ideal for combination therapy because of its unique mode of action and the dissimilarity of its targets from those of the conventional chemotherapies. In various xenografts, halofuginone synergizes with chemotherapy and reduces the need for high doses of toxic compounds, and thereby can reduce cancer patients’ treatment burden without impairing treatment efficacy. Halofuginone is now undergoing clinical trials. Conclusions: The TGF signaling cascade is shared by myofibroblasts in wound healing, fibrosis and cancer. In fibrosis where the myofibroblasts are the major participant halofuginone can be used alone; in cancer it should be considered in combination with other therapies that affect tumors via different modalities.
Anabolic Androgenic Steroids (AAS) Elicit Aggression by Selectively Decreasing Neurosteroid Biosynthesis in Corticolimbic Glutamatergic Neurons PINNA G, PIBIRI F, NELSON M, AGIS-BALBOA RC The Psychiatric Institute, Dept. Psychiatry, College of Medicine, UIC, Chicago, IL, USA Background: AAS abuse is a serious problem among adolescents, elderly subjects, and military personnel. AAS increase sex drive and mental acuity but have remarkable physical and behavioral side effects, including irritability, aggression, and depression. The molecular mechanisms and neuronal circuitry underlying these symptoms are largely unknown. Protracted testosterone propionate (TP) administration in mice induces aggression accompanied by a decrease in brain allopregnanolone (Allo) content. Allo is a neurosteroid that positively and allosterically modulates GABAA receptor function. In the brain, Allo is synthesized from progesterone by the sequential action of 5α-reductase type I (5α-RI) and 3α-hydroxysteroid dehydrogenase (3α-HSD). 5α-RI and 3α-HSD colocalize in cortical, hippocampal, and olfactory bulb glutamatergic neurons and in output neurons of the basolateral amygdala (BLA), thalamus, and striatum. Methods: To study the alterations of selective neuronal circuitry in AAS abuse, we established a mouse model of AAS-induced aggression. Using GC-MS, we studied whether TP, in doses that induce aggression, selectively downregulates Allo in a structure-specific manner. Using immunohistochemistry, quantitative nested RT-PCR, and Western blot, we studied whether TP decreases corticolimbic Allo levels by downregulation of 5α-RI mRNA and protein expression. We used local microinfusions of the selective brain steroidogenic stimulant (SBSS), S-norfluoxetine (S-NFLX), to upregulate Allo and decrease aggression. Results: Treatment of mice with TP reduces 5-RI expression in selected glutamatergic pyramidal neurons of the cortex, hippocampal CA3, and BLA and in granular cells of the dentate gyrus, which results in a decrease of Allo content. In contrast, 5α-RI mRNA expression fails to change in the striatum medium spiny neurons and reticular thalamic nucleus neurons, which are GABAergic. A bilateral microinfusion of S-NFLX in the BLA decreased TP-induced aggression by upregulation of Allo levels. Conclusions: TP-induced aggression is associated with an impairment of Allo biosynthesis in specific corticolimbic glutamatergic neurons. These results may help in the design of therapeutics to limit the adverse effects of AAS abuse.	IL-12 receptor expression and function on human lung adenocarcinoma: identification of a new potential therapeutic target AIROLDI I^1, DI CARLO E^2, COCCO C^1, CACI E^1, CILLI M^3, SORRENTINO C^2, SOZZI G^4, FERRINI S^3, ROSINI S^5, GALIETTA L^1, RIBATTI D^6 and PISTOIA V^1 ^1G. Gaslini Institute, Genova, Italy, ^2G. d'Annunzio" University Chieti, Italy, ^3Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy, ^4Fondazione IRCCS Istituto Nazionale Tumori, Italy, ^5SS Annunziata” Hospital, Chieti, ^6University of Bari, Bari, Italy Background: Non small cell lung cancer (NSCLC) is a leading cause of cancer death. We have shown that mice lacking expression of the β2 chain of the interleukin-12 receptor (IL-12Rβ2 KO mice) develop spontaneously lung adenocarcinomas or bronchioalveolar carcinomas. Here we have investigated i) IL-12R2 expression in human primary lung adenocarcinomas and normal bronchial epithelial cells (NBEC), and ii) the direct activity of IL-12 on NSCLC cells and the mechanisms involved. Methods: Lung adenocarcinoma tissues obtained at diagnosis from seventy untreated patients were studied for IL-12Rβ2 expression by immunohistochemistry. Stage I lung adenocarcinomas showed significantly (P=0.012) higher frequency of IL-12R2^+ samples than stage II/III tumors. Calu6 NSCLC cells were next transfected with IL-12R2 containing plasmid (Calu6/β2), while NBEC cells were expanded from lung specimens of non neoplastic origin. In vitro IL-12 activity on Calu6/β2 or NBEC was investigated by flow cytometry, ELISA and chorioallantoic membrane assay. Severe combined immune deficienty (SCID)/ non obese diabetic (NOD) mice were inoculated with Calu6/β2 cells subcutaneously or orthotopically and treated with human recombinant (hr) IL-12. Explanted tumors were studied by polymerase chain reaction (PCR) array and immunohistochemistry. Results: IL-12 treatment of Calu6/β2 cells inhibited IL-6 production and angiogenesis in vitro. Tumors formed by Calu6/2 cells in SCID/NOD mice were significantly smaller following hrIL-12 vs PBS treatment due to inhibition of angiogenesis. NBEC expressed functional IL-12R and IL-12 damped the release of cytokines involved in tumor progression. Conclusions: 1) IL-12 inhibits directly the growth of human lung adenocarcinoma and targets the adjacent NBEC, 2) IL-12R2 on primary lung adenocarcinoma may represent a new therapeutic target, and 3) clinical trials investigating hrIL-12 activity in lung adenocarcinoma patients appear feasible.
In Search of the Magic Bullets: Discovery of RN5 and its Structural Modifications for Targeting Selectively 1 Adrenoceptors PITTALA’ V^1, SALERNO L^1, MODICA M^1, SIRACUSA MA^1, ROMEO G^1 ^1Università di Catania, Catania, Italy. Background: Alfa1 adrenoceptors (1-ARs), further subdivided into 1A, 1B, and 1D subtypes, are therapeutically relevant because represent pharmacological targets for a number of drugs currently used in the treatment of two widely occurring diseases, hypertension and benign prostatic hyperplasia (BPH). Aims: 1) To develop new ligands highly selective towards 1-ARs with respect to 5-HT1A serotonin and dopaminergic D1 and D2 receptors. 2) To develop selective ligands with respect to the different 1-AR subtypes to finally clarify the pharmacological profile of each receptor type and subtype. Methods: Design and synthesis of pharmaceutically active molecules, Molecular modeling studies and pharmacological assays. Synthesis of radiolabelled 3-[2-[4-(2-[^11C]methoxyphenyl)piperazin-1-yl]ethyl]pyrimido[5,4-b]indole-2,4-dione, [^11C]RN5, for positron emission tomography (PET) studies on 1-ARs. Results: In this general overview of our twenty years research on adrenergic receptors, example of the most relevant medicinal chemistry results achieved are given. In the two last decades, we have been involved in the development of new selective 1-AR ligands characterized by a planar tricyclic or bicyclic system coupled to a pharmacophoric phenylpiperazine (PP) moiety. Among more than one hundred synthesized ligands, 3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]pyrimido[5,4-b]indole-2,4-dione, RN5 is one of the most representative example of such ligands. Nowdays, this compound is sold and commonly used as standard reference ligand for 1-ARs. A number of RN5 analogues were subsequently synthesized and even more selective 1-AR and high affinity ligands were identified with respect to other related receptors. Moreover, some interesting subtype selective ligands were designed and synthesized. Chemistry, structure-activity relationships, molecular modeling studies, and pharmacological results of these 1-AR ligands will be discussed. Conclusions: 1) RN5 is one of the most representative ligands discovered. 2) [^11C]RN5 radioligand was synthesized and in vivo PET biodistribution of 1-ARs was studied. 3) A number of RN5 analogues with improved profile were synthesized. 4) Moreover, some subtype selective ligands were identified.	Emergence of Colistin Resistance during Therapy of Infections by Multi-drug Resistant Gram Negative Pathogens in the Critically Ill PLACHOURAS D^1, KONTOPIDOU FV^1, GALANI I^1, KORATZANIS E^1, PONTIKIS K^2, ARMAGANIDIS A^2, GIAMARELLOU H^1 ^14^th Department of Internal Medicine and ^22^nd Department of Critical Care, Medical School, University of Athens, Greece Background:  Selective pressure due to colistin (Col) may result in emergence of Col resistance among multi-drug resistant gram negative bacteria (MDR-GNB), jeopardizing treatment choices in the ICU.  The aim of this study was to present the emergence of Col resistant (ColR) MDR-GNB isolated from ICU patients in association with exposure to Col. Methods:  The study was performed in a 12-bed University General ICU from November 2003 to December 2006.  Empirical antimicrobial treatment was guided by weekly active surveillance of patients’ floras.  All specimens were cultured in MacConkey agar plates containing antibiotics in order to focus on resistant pathogen detection.  ColR was defined by Etest according to BSAC breakpoints (>4ìg/ml).  Epidemiological typing was performed by Rep-PCR in the fist sensitive and the first ColR isolate from each patient. Results: 152 patients were included in the study. Patients were colonized by K.pneumoniae (54%), P.aeruginosa (57%), A.baummanni (75%), Enterobacter spp (17%), E.coli (28%) and S.maltophilia (30%) while ColR strains were 37%, 4.5%, 2.5%, 4%, 7.3% and 44% respectively. Among patients colonized with at least one ColR strain, 95% had been exposed to Col while among patients who had been exposed to Col, 66% developed at least one ColR strain.  Epidemiological typing demonstrated 20 distinct clones of ColR K.pneumoniae isolated from 30 patients. The median duration of exposure to Col, for patients that were colonized or infected by distinct ColR K.pneumoniae clone during their hospitalization was 18 days. Epidemiological typing showed that there was horizontal transmission of the resistant clone among co-hospitalized patients. 18.5% of patients were also colonized with an intrinsically ColR enterobacteriacae; among them 93% had been exposed to Col (p<0.01, OR:11.66). Conclusions:  1) Unnecessary and/or prolonged (>2weeks) Col administration is associated with colonization of ColR MDR-GNB 2) Both endogenous acquisition and horizontal transmission are responsible for the spread of Col resistance in the ICU environment under selective pressure.
Silencing Cell-Cell Communication: The New Bullets in Anti-Infectives PLOTKIN BJ^1, KONAKLIEVA MI,^2 GREEN JM^1 Midwestern University, Downers Grove Illinois, U.S.A.; American University, Washington, D.C., U.S.A Background: At least two lines of communication occur in the host: bacterial cell-cell communication (quorum sensing) and cross-kingdom communication, i.e., host hormones functioning as molecular signal mimics. Both forms of chemical communication can affect phenotypic expression of virulence factors and antimicrobial susceptibility. Currently, focus is on design of quorum sensing autoinducer analogs. However, cross-kingdom communication presents a particularly intriguing line of communication, with evolutionary origins of some host hormones hypothesized as microbial. To determine their putative role as inter-kingdom communication molecules, the effect of insulin and dehydroepiandrosterone (DHEA) on phenotypic expression was assessed. Methods: Staphylococcus aureus 29523 grown with DHEA (0.1, 0.5, 1.0, 5.0 mM) was tested for susceptibility to Triton X-100, lysozyme, -defensin and vancomycin. r-Insulin’s (Humulin) role as a microbial insulin mimic was tested in Escherichia coli’ K12 by measuring the effect of insulin (2-400 U/ml) on E. coli adherence, biofilm production and chemotaxis, using standard methodology. Results: S. aureus exposure to DHEA resulted in increased carotinoid levels which correlated with increased resistance to Triton-X100, lysozyme, -defensin and vancomycin. Exposure of E. coli to r-insulin affects E. coli behavior. Insulin alone is a chemo-repellent. However, with glucose insulin enhances glucose chemoattraction, adherence (glass, plastic and latex) and biofilm formation as compared to sugar alone. Conclusion: 1) DHEA enhances carotenoid synthesis and resistance to cell-wall active agents. 2) r-Insulin in the absence of glucose disperses populations in nutritionally impoverished environments; however, with glucose present insulin enhances population density through biofilm formation. 3) It is possible that in some cases inter-kingdom signaling molecules may provide an alternative signaling pathway that will need consideration along with more traditional quorum autoinducers if analogs of this class of compounds will have broad utility as anti-infectives.	Treating fungal infections with CYP53A15 inhibitors PODOBNIK B^a,b, STOJAN J^c, .LAH L^b, KRAŠEVEC N^b, KOMEL R^b,c ^aLek Pharmaceuticals d.d., Verovškova 57, SI-1000 Ljubljana, Slovenia; ^bNational Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia; ^cFaculty of Medicine, University of Ljubljana, Institute of Biochemistry, Vrazov trg 2, SI-1000 Ljubljana, Slovenia Our in vitro and in vivo studies suggest that targeting CYP53A15 could help treat fungal infections. In vitro, four phenolic compounds (isoeugenol, eugenol, vanillin and thymol) that play a role in plant resistance to fungal infection inhibited CYP53A15. Inhibition of CYP53A15 leads to increased intracellular levels of benzoic acid, which impedes fungal growth. In vivo, three of these compounds inhibited Cochliobolus lunatus growth. Next steps include solving the X-ray crystal structure of the CYP53A15 active site. Ref. CYP53A15 of Cochliobolus lunatus - a target for natural antifungal compounds, J. Med. Chem.; published online May 28, 2008; doi:10.1021/jm800030e
Status and antibiotic sensitivity profile of Salmonella enterica during 2001-2007 at Tribhuvan University Teaching Hospital - a tertiary health care centre of Nepal POKHREL BM^1, DAHAL RK^1 , KHADGA PK^1, KOIRALA J^2 ^1Institute of Medicine, Kathmandu, Nepal, ^2School of Medicine, Southern Illinois University,Springfield,IL,UnitedStates Background: Enteric fever is a common problem in Nepal. In view to determine the trends of Salmonellae causing bacteremia/septicemia and to determine the antimicrobial susceptibility profile of these organisms, a retrospective study was carried out during 2001 to 2007 at Tribhuvan University Teaching Hospital, a tertiary care health centre inNepal. Methods: During 2001-2007, 41408 blood culture samples from the patients clinically suspected of enteric fever were received at Department of Microbiology,Tribhuvan University Teaching Hospital, Katmandu, Nepal. These samples were cultured and isolates were identified then subjected for antibiotic sensitivity testing as described by American Society for Microbiology (ASM). Results: Approximately 13% blood culture samples showed growth positive. Of which about 10% were Salmonella enterica serotype Typhi and Paratyphi-A. Three percentage of isolates included Staphylococcus aureus, E.coli, Klebsiella pneumoniae, Pseudomonas spp, Viridans Streptococci, Acinetobacter calcoaceticus, Citrobacter spp, Enterobacter spp and Streptococcus faecalis. Among 4013 Salmonella isolates, 6.5% were resistant to at least two groups of antibiotics. Almost equal percentage of both salmonella enterica serotype Typhi and Paratyphi-A isolates were found to be multi drug resistant (MDR). Many of the multi drug resistance Salmonellae were resistant to ampicillin, ciprofloxacin, co-trimoxazole and chloramphenicol. Conclusion: There is increasing trends of Multi drug resistant Salmonellae over the years, therefore It is felt that the cause of resistance should be investigated.	N-Oleoyl-Dopamine: A Potential Novel Deliverer of Dopamine to the Brain POKORSKI M, ZAJAC D, REKAWEK A. Department of Respiratory Research, Medical Research Center, Polish Academy of Sciences, Warsaw, Poland Background: N-oleoyl-dopamine (OLDA) is the most biologically active N-acylated dopamine, a member of a new class of lipid compounds, termed dopamides. The compounds are a condensation product of dopamine (DA) and a polyunsaturated free fatty acid chain. We hypothesized that a lipophilic OLDA could serve as a carrier of DA into the biomembranes of neural cells, the target site of cellular signaling. DA has a well defined role of a major neurotransmitter in both the brain and the carotid body; the latter is an organ of neural crest origin that generates the hypoxic ventilatory response. Aims: 1) To study the uptake of radiolabeled N-OLDA by the brain, a barrier-equipped, and the carotid body, a non-barrier- equipped organ, and to compare it with that of radiolabeled DA alone. 2) To study the effect of N-OLDA on the hypoxic respiratory response. 3) To ascertain dopaminergic mediation in N-OLDA respiratory effects. Methods: The study included a total of 28 anesthetized Wistar rats, weight: 180-340 g. One group, 22 rats, received intracarotid injections of 0.3 ml [^3H]N-OLDA dissolved in DMSO, 1.33 µCi/ml and 1 ml [^3H]DA dissolved in NaCl, 10 µCi/ml. The ^3H radioactivity was measured by a scintillation counter. The rats of the other group were paralyzed, ventilated, and respiratory neural output was recorded from the integrated phrenic nerve activity. The ventilatory response to 14 and 11% O2 in N2 was taken at baseline, after OLDA-20 mg/kg, ip, and then after a DA D2 receptor antagonism by Haloperidol-300 µg/kg, iv. Results: OLDA was taken up by both neural tissues studied. The regional brain uptake of [^3H]N-OLDA was ~6% and the carotid body uptake was ~30% of the entire radioactivity injected, both being 3-4-fold greater than those of [^3H]DA alone in respective tissues (P<0.01). The peak stimulatory hypoxic respiratory response was diminished by OLDA by ~20 and 45% during the responses to 14 and 11% hypoxia, respectively. The inhibitory effect of N-OLDA was abolished by pretreatment with Haloperidol. Conclusions: 1) OLDA has an inhibitory, DA-like effect on the hypoxic chemoreflex. 2) OLDA is incorporated into DA-mediated signal transduction in neural tissues. 2) OLDA may serve as a carrier of DA into neural tissue. 3) OLDA's potential to stabilize DA molecule in biomembranes may give rise to its sustained action, as opposed to the fleeting effects of DA proper.
The Use of Regulatory RNA Molecules as a Novel Treatment Strategy for Cardiac Diseases - RNA as a Magic Bullet ? POLLER W Charité – Universitätsmedizin Berlin, Charité Centrum 11 (Cardiovascular Medicine) The current status and challenges of RNA interference (RNAi) and microRNA modulation strategies for the treatment of myocardial disorders are discussed and related to the classical gene therapeutic approaches of the past decade. We summarize the key issues of current vector technologies which determine if they may be suitable for clinical translation of experimental RNAi or microRNA therapeutic protocols. We then present and discuss examples dealing with the potential of cardiac RNAi therapy. First, an approach to block a key early step in the pathogenesis of a virus-induced cardiomyopathy by RNAi targeting of a cellular receptor for cardiopathogenic viruses. Second, an approach to improve cardiac function by RNAi targeting of late pathway of heart failure pathogenesis common to myocardial disorders of multiple etiologies. This strategy is directed at myocardial Ca2+ homeostasis which is disturbed in heart failure due to coronary heart disease, heart valve dysfunction, cardiac inflammation, or genetic defects. Whereas the first type of strategies (directed at early pathogenesis) need to be tailor-made for each different type of pathomechanism, the second type (targeting late common pathways) has a much broader range of application. This advantage of the second type of approaches is of key importance since enormous efforts need to be undertaken before any regulatory RNA therapy enters the stage of possible clinical translation. If then the number of patients eligible for this protocol is large, the actual transformation of the experimental therapy into a new therapeutic option of clinical importance is far more likely to occur.	Modern quantum chemical descriptors for QSAR/QSPR POPELIER PLA^1, HARDING A^1 and ROY K^2 ^1MIB, Univ.of Manchester, 131 Princess Str., Manchester M1 7DN, Great Britain; ^2Drug Theoretics and Cheminformatics Lab, Dept. of Pharm. Techn., Jadavpur University, Kolkata 700 032, India Background: The current availability of cheap computing power enables solving the Schrödinger equation for congeneric drug-sized molecules. Modern ab initio methods yield electronic properties of geometry-optimized molecules. A new theory called Quantum Chemical Topology (QCT) (based on “Atoms in Molecules”) provides descriptors for QSAR/QSPR. These modern and more realistic descriptors capture electronic effects and replace the Hammett constants. Methods: QCT locates Bond Critical Points (BCPs) in 3D space. Properties such as the electron density or its Laplacian describe the bonds. A molecule is compactly represented in an abstract space of BCP properties^1. Partial Least Squares and various machine learning techniques can map the QCT descriptors to a wide variety of activities of medicinal, ecological (toxicological) interest. Cross-validation and randomisation testing protect against chance correlation. True external validation features in our recent studies. Our method can localise a part in the molecule where the chemical change associated with the observed activity actually happens. Results: In the case of the antitumour activity of phenylbutenones we confirmed^2 the hypothesis that these compounds act via a Michael addition. In the context of mutagenic activity^3 we determined a preferred mechanistic pathway for the initial hydroxylation of dimethyl heteroaromatic triazenes, a hitherto ambiguous issue. We studied^4 seven datasets: (1) pKa of substituted imidazolines and (2) imidazoles, (3) the ability of indole derivatives to displace [^3H] flunitrazepam from binding to bovine cortical membranes, (4) the influenza inhibition constants for benzimidazoles, (5) the interaction constants for amides and the enzyme liver alcohol dehydrogenase, (6) the natriuretic activity of sulfonamide carbonic anhydrase inhibitors and (7) the toxicity of benzyl alcohols. Hepatoxicity^5 and nitroaromatic toxicity^6 were also investigated. Conclusions: Electronic effects can be captured by a novel class of QCT descriptors that come directly from modern ab initio wavefunctions. Active sites in molecules are highlighted and robust predictions made for diverse activities.  [1] P. L. A. Popelier, J.Phys.Chem.A, 1999, 103, 2883. [2] S. E. O'Brien and P. L. A. Popelier, J.Chem.Soc., Perkin Trans. 2, 2002, 478. [3] P. L. A. Popelier, U. A. Chaudry, and P. J. Smith, J.of Comp.-Aided Molec.Design, 2004, 18, 709. [4] P. L. A. Popelier and P. J. Smith, Eur.J.Med.Chem., 2006, 41, 862. [5] K. Roy and P. L. A. Popelier, Bioorg.Med.Chem.Lett., 2008, 18, 2604. [6] K. Roy and P. L. A. Popelier, QSAR & Comb.Sci., 2008, 27, 1006. 
Pharmacokinetic and pharmacodynamic interactions between mepivacaine and antihypertensive drugs POPESCU SM^1, BANICERU M^2, POPESCU F^3, NECHIFOR M^4 ^1,2,3University of Medicine and Pharmacy Craiova, Romania; ^4University of Medicine and Pharmacy “Gr.T.Popa” Iassy, Romania Background: Aims: To analyse 1) the pharmacokinetic interaction between mepivacaine and propranolol and 2) pharmacodynamic interactions between mepivacaine and some antihypertensives drugs. Methods: 1) A randomised, double blind, cross-over pharmacokinetic study included 10 male normotensives. Each subject received 51 mg mepivacaine for dental local anaesthesia (LA) two hours after he ingested 30 mg of propranolol or placebo. Mepivacaine concentration in venous serum was measured after 5, 15, 30, 45, 60 minutes from injection by gas chromatography. 2) A pharmacodynamic study included 62 male patients, divided in 3 groups: normotensives, nontreated hypertensives, treated hypertensives (with enalapril, propranolol, or verapamil). They were tested for dental sensitivity, blood pressure (BP) and cardiac rate before and after a local anaesthesia with mepivacaine 3% for a maxillary tooth. Results: 1) Peak serum concentrations of mepivacaine, Cmax, (1.214 +/- 0.746 μg · mL-1) were significantly increased by propranolol (2.249 +/- 1.559 μg · mL-1, p < 0.05). 2) Pain intensity determined by mepivacaine injection (measured with visual analogue scale) varied in this order: untreated hypertensives  treated hypertensives  normotensives. Latency of pulpal LA was under 5 minutes, and latency of soft tissue LA was under 2 minutes for all groups. Duration of LA varied in the following order: normotensives  enalapril hypertensives  untreated hypertensives  propranolol hypertensives  verapamil hypertensives. In verapamil and also propranolol treated hypertensives groups, duration of LA was significantly longer then for normotensives and untreated hypertensives. BP dropped significantly 90 minutes after anaesthesia in normotensive group and treated hypertensives, while for nontreated hypertensives it slightly changed. Cardiac rate did not varied significantly in all groups. Conclusions: There are pharmacokinetic interactions between mepivacaine and propranolol that could explain the effect of propranolol of increasing mepivacaine toxicity. There are also pharmacodynamic interactions between mepivacaine and antihypertensives, manifested especially for LA parameters, verapamil and propranolol increasing the duration of local anaesthesia.	The Role of the Genotype in the MAGIC BULLET Effect of Psychotropic Drugs POPOVA NK, NAUMENKO VS, TIKHONOVA MA Institute of Cytology and Genetics, Behavioral Neurogenomics Lab., Novosibirsk, Russia Background: Recent progress in neurogenomics has opened up new lines of research in the crucial pharmacologic problem - the mechanisms underlying the difference in individual sensitivity to drugs. The present experiments tested the hypothesis that critical mechanism in the response to psychotropic drugs involves genetically defined serotonin 5-HT receptor expression. Aims: 1) To elucidate the effect of differences in the 5-HT1A receptor gene expression and the density of 5-HT1A receptors on the sensitivity to 5-HT1A agonist 8-OH-DPAT. 2) To compare the effect of chronic imipramine treatment on 5-HT2A receptor mRNA level in genetically predisposed to catalepsy and noncataleptic rats. Methods: The study included 85 Norway rats selectively bred for high level and for the lack of fear-induced aggression, 27 rats selectively bred for predisposition to catalepsy (GC) and 28 Wistar rats. Specific binding of [3H]8-OH-DPAT and 5-HT1A and 5-HT2A receptor mRNA levels were estimated. As functial correlates for 5-HT1A receptors, 8-OH-DPAT-induced (0.5 mg/kg i.p.) hypothermia and lower lip retraction (LLR) were used. Imipramine (15 mg/kg per day) was given to Wistar and GC rats in drinking water for 27 days. Results: 8-OH-DPAT produced a distinct hypothermic reaction in nonaggressive Norway rats and did not affect the body temperature in aggressive rats. Similarly, LLR was expressed much more in nonaggressive than in aggressive animals. Considerable differences between the highly aggressive and the nonaggressive rats were shown in the 5-HT1A receptor gene expression and 5-HT1A receptor density in the brain regions. A significant decrease in Bmax of specific binding of [3H]8-OH-DPAT in the frontal cortex, hypothalamus, and amygdala and a reduction in 5-HT1A receptor mRNA level in the midbrain of aggressive rats compared to nonaggressive were found. In genetically predisposed to catalepsy GC rats, 5-HT2A receptor mRNA level in the frontal cortex was lower than in control Wistar rats. Chronic imipramine treatment attenuated catalepsy and produced two-fold increase in 5-HT2A receptor mRNA level in GC rats without any effect on 5-HT2A receptor expression in Wistar. Conclusions: 1) MAGIC BULLET effect depends on genetically defined state of the target. 2) The 5-HT receptor gene expression is essential for response to psychotropic drugs.
Sperm immobilization factor: potential candidate for fertility control and antibacterial targeting bacterial motility PRABHA V Panjab University, Chandigarh, India Unplanned pregnancies present a great risk to the reproductive health of women. Therefore female-controlled vaginal products directed towards contraception are needed urgently. In the present study efforts have been made to evaluate the contraceptive potential of sperm immobilization factor (SIF) isolated from Staphylocccus aureus isolated from an infertile woman. The results showed that sperm motility was completely inhibited by SIF along with complete loss of viability. The effect on the sperm motility was found to be dose and time dependant. The minimum effective concentration of SIF required for complete immobilization of spermatozoa (40 x 10^6) in vitro within 20 s was found to be 150g. Intravaginal administration of SIF (50g) before mating during proestrous-estrous transition phase caused complete blockage of conception in mouse model. Sub-acute toxicity studies in mice indicated that repetitive intravaginal application of SIF at a dose of 100g for 14 consecutive days induced no abnormality either in length of the estrous cycle or in the morphology of the vaginal tissue. Furthermore, no adverse effect was observed on subsequent reproductive performance, neonate survival and development of pups. In addition, SIF was also found to induce immobilization in various motile bacteria in vitro viz. Escherichia coli, Pseudomonas aeruginosa and Proteus mirabilis which are known uropathogens. 6-8 h old cultures of these bacteria when incubated along with SIF caused 100% immobilization. As motility and adherence represent an integral aspect of bacterial pathogenesis, therefore, targeting bacterial motility can be exploited as a potential antibacterial therapy. Though, antibiotics have been used ever since their discovery. However, the complications involving the emergence of multi-drug resistant strains and causing chronic toxicity pose a challenge for modern medicine. Because of public concern, now the focus has shifted towards the use of safer therapeutic agents. Newer biocompatible agents including the microorganisms and their products are being examined for their potential as antimicrobials. It is suggested that SIF could be developed as a potent vaginal contraceptive as well as antibacterial agent targeting bacterial motility for future use in humans.