Tuberculosis (TB) remains one of the worlds most important infectious diseases. The causative agent, Mycobacterium tuberculosis, is the leading cause of death of any infectious agent. Each year, approximately 8 million people develop active pulmonary TB and 2 million die from this disease. The World Health Organization has declared TB a global health emergency, the first disease so designated. Moreover, multi-drug resistant strains of M. tuberculosis have been classified by the Centers for Disease Control and Prevention as potential weapons of bioterrorism.In the United States, the incidence of TB has been falling over the past half-century, but remains high in HIV-infected persons, the elderly, homeless and under-served populations, and immigrants from endemic areas. Moreover, the emergence of multidrug-resistant strains complicates TB control efforts and posts a health threat to the general public, especially immunocompromised individuals. In HIV patients, an infection strain that has developed resistance to available drugs results in a 50% death rate within 60 days.The current TB vaccine, M. bovis BCG, is a live attenuated form of the bovine TB pathogen developed in the 1900s. The vaccine is of modest efficacy but has been used in combination with drug therapy as a means to control the disease. (more...)

Influenza viruses commonly cause upper respiratory tract infections that can be aggressive and potentially lethal in high risk groups, such as infants, the elderly, pregnant women, and those with compromised immunity. Translation of viral mRNAs by the host ribosome requires recognition of the mRNA N-7-methyl-GMP "cap". Influenza viruses don't synthesize their own cap, but instead snatch the host cell's cap. Cap snatching is initiated by endonuclease activity in the PA subunit of viral RNA-dependent RNA polymerase. The PA-subunit is a two-divalent-cation-dependent endonuclease. PA-subunit specific siRNA down regulates viral mRNA production and blocks viral production in cell culture, indicating that the PA-subunit may be a good drug target. (more...)

Pseudomonas elastase (LasB) plays a critical role in pseudomonal infections. Clinical isolates of P. aeruginosa secrete elastase B (LasB), an elastolytic metalloproteinase that is encoded by the lasB gene. LasB exerts a proteolytic action that extends from broad tissue destruction to delicate action on the host immune machinery. The enzyme also acts inside the bacterial cell to activate the intracellular pathway that initiates growth as a bacterial biofilm and increases its virulence. Due to this property, LasB is recognized as a potential target for developing new antibiotics. While potent inhibitors are commercially available, most of these are peptide based. Though effective in their ability to block the virulence process, these inhibitors suffer from poor in-vivo stability and pharmacodynamic properties. This hinders their potential therapeutic use. (more...)

 AIDS, the disease caused by the virus HIV, represents a devastating global pandemic. According to a United Nations report in 2010, HIV has killed nearly 30 million people worldwide, with over 2.5 million additional infections each year. Detecting HIV particles is critical not only to patient diagnosis, but also for basic and clinical research, the source of future therapies. Unfortunately, current methods are severely lacking. Phenotypic testing can take over a month to complete and only reports a single time point. Another system widely used for research employs cell lines that express CD4 and co-receptors at abnormally high levels, rendering results of questionable physiological relevance. Patients, physicians, and researchers alike would benefit greatly from a new method of detecting and characterizing HIV; one that is rapid, sensitive, adaptable, and most importantly, physiologically accurate.      (more...)

The crystal toxin from Bacillus thuringiensis (Bt) is commonly used as a biological pesticide against larval caterpillars of various moths, butterflies, flies, mosquitoes and beetles, and nematodes such as roundworms. Improving the efficacy of the Bt crystal toxins may potentially increase the protection of crops against pests. (more...)

Herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital herpes, a sexually transmitted disease estimated to affect more than 500 million people worldwide. About one in six people in the United States aged between 14 and 49 years has genital herpes caused by HSV-2. In addition to causing painful recurring genital sores and emotional stress in those infected, the disease can be particularly severe in immunosuppressed patients and can cause death or brain damage in babies born to infected mothers. Antiviral drugs are being used widely to treat HSV-2, but they are ineffective at eradicating the disease. There is therefore an urgent need for a safe and effective HSV-2 vaccine. (more...)

T cells are adaptive immune cells essential for durable responses against infection and cancer. They are equipped to respond to these challenges with bursts of proliferation, cytokine production, and cytotoxicity. These responses allow direction of complementary innate immune responses, while the T cells directly attack virally-infected host cells and cancer cells alike. However, the consequences of dysregulated T cell function are dire: poor T cell responses (i.e. exhaustion and tolerance) in the cases of chronic viral infection and cancer enable viral persistence and tumor outgrowth, while unchecked responses result in immunopathology in response to certain viral infections or autoimmunity such as multiple sclerosis. Therefore, the capacity to therapeutically modulate T cell responses - augmenting or blunting where appropriate, would be of pivotal clinical relevance in treatments for cancer, chronic viral infection, and autoimmunity. (more...)

Several classes of antiviral drugs that inhibit the reverse transcriptase, the protease or the fusion protein, respectively, have been developed for HIV treatment. Since single- or multi-drug resistance ranges from 10% to 70% in different patient age groups, there is unmet need in developing new drug candidate for novel viral protein targets. (more...)

Kawasaki disease (KD) is a childhood disease prevalent in Asian populations, especially Japan. Disease incidence is approximately 1/1000 for Asians, and 2/10,000 in Caucasian populations. One quarter of disease patients are susceptible to life-threatening coronary artery aneurysms. (more...)

This invention uses multi-functional magnetic imaging probes to image high risk atherosclerosis and nonatherosclerotic sites such as areas of cancer, infection, immunological conditions and inflammation. The invention incorporates the use of micelles containing the manganese to which are attached to oxidation specific antibodies. This multi-functional particle is injected intravenously and will enter an area of atherosclerotic plaque in the vessel wall or other site of inflammation (primary or metastatic cancer, liver disease, arthritis, Alzheimer's, macular degeneration, etc.) and the antibody will direct the micelle with the manganese to an oxidation specific epitope. Once it binds, the micelle will be taken up into a macrophage. Lysosomal enzymes in the macrophage will then cleave the manganese off the micelle which greatly enhances its relaxivity, which is a key part of the invention, that then allows the manganese to be detected by molecular bio-magnetic resonance imaging (MRI).The unique aspect of this invention is the fact that manganese is normally not easily visible by MRI when it is complexed to another carrier. However, manganese is visible to MRI when it is in a free state. Because free manganese cannot be injected for specific localization, it must be complexed to a carrier that will do two things: 1) deliver the manganese to a specific targeting area, which in this case is via the oxidation specific antibody and 2), have a mechanism by which the manganese is released to be seen with MRI techniques. This invention has these two novel aspects of using a targeting agent to deliver the manganese and through the natural pathophysiology of atherosclerosis allowing the manganese micelle to be taken out by macrophages and subsequently released in the macrophage. This results in a macrophage specific imaging. Since macrophages are associated with unstable atherosclerotic lesions and all areas of inflammation, this technique may allow a novel approach to image macrophage activity and therefore lesions that would predict higher cardiovascular risk. (more...)

HBV infection can lead to chronic infections that result in 0.6 million deaths per year worldwide by causing liver failure and cancer. Clearance of HBV infection is age dependent, with the majority of adult-acquired infections leading to spontaneous clearance, whereas infection in young children often leads to chronic infections. To study these early events of infection and immune activation that lead to HBV clearance or persistence, in vivo models are needed to screen and validate lead drug candidates. HBV cannot infect mice, however, researchers at UCSF have generated transgenic mouse models that mimic critical features of primary HBV infection observed in humans. (more...)

Influenza has been the cause of yearly epidemics and global pandemics throughout history. Due to the high degree of sequence conservation between disease genes in humans and flies, Drosophila has been enlisted to serve as a powerful multicellular host model to identify novel interactions between viral proteins and host machinery. Among influenza's eleven viral genes, NS1 (nonstructural protein 1) is known to be indispensable for virulence. There are very few effective drugs to treat influenza infection and these drugs (e.g., Tamiflu) act on highly mutable extracellular proteins that function in the late phase of viral escape from the cell. Also, viral surface proteins which are the main targets for vaccines mutate rapidly to evade suppression. Knowledge of new host signaling responses to viral infection could lead to therapies targeted to these interactions. These treatments may be effective at suppressing the pathogenesis of many different strains of flu unlike vaccines which typically target only a few strains and require constant reformulation since the virus can evade host antibodies. (more...)

HCV is a chronic viral disease with increasing rates of morbidity and mortality worldwide. Current therapy (interferon and ribavarin) often has poor compliance over time due to side effects, frequently requiring additional treatment and increasing costs for patients. More importantly, neither directly targets the virus so only symptoms can be ameliorated. New HCV therapies mirror the approach taken in drug discovery against HIV, often targeting viral proteases but suffering the same limited success caused by rapid genetic variation of the virus. (more...)

HCV infection has a worldwide prevalence of 3% and is the main indication for liver transplantation to treat cirrhosis in developed countries. In the United States, HCV is the most common chronic blood borne infection, afflicting 1.8% of the population and is the major etiological factor responsible for the recent doubling of hepatocellular carcinoma. Currently, no vaccination for HCV exists. In addition, significant proportions of patients (greater than 33%) are nonresponsive or relapse to the current treatment for HCV that includes pegylated interferon alfa-2a (PEGASYS®) and ribavarin. Adverse events are also commonly reported with HCV therapies and many patients are excluded from interferon therapy due to neutropenia or risk of side effects. Several HCV drugs in late-stage development target viral replication proteins, suggesting such approaches may effectively complement or substitute for protease inhibition or immune modulation therapies, which both increase adverse events in patients. Thus, novel approaches to target components of viral replication represent a promising avenue to improve disease outcomes and build on the repertoire of HCV therapeutics to reduce iatrogenic complications. (more...)

Group A streptococcus (GAS) is a ubiquitous human pathogen behind a spectrum of diseases. Worldwide, invasive S. pyogenes infections result in excess of half a million deaths each year. To date, there has been no effective GAS vaccine developed in part because there are more than 150 serotypes. A diagnostic for GAS has been developed utilizing the carbohydrate structure of the GAS called Group A carbohydrate (GAC) consisting of a rhamnose backbone and an immunodominant N-acetylglucosamine (GlcNAc) side chain. Initially, utilizing this same structure as a potential vaccine produced good outcomes in animals but safety concerns were raised since antibodies generated against the GlcNAc side chain could precipitate other conditions (e.g. rheumatic carditis and Sydenham's chorea). (more...)

The market for new therapeutic products that will combat resistant strains of infectious pathogens commands $26 billion annually.  The U.S. market share for new generation antibiotics alone is expected to reach $10 billion this year.  To overcome the growing problem of microbial resistance, drug development companies have adopted a number of strategies based on the production of beta-lactamases, including developing new beta-lactamase inhibitors that can be co-administered with beta-lactam antibiotics.  This particular strategy has yielded three beta-lactamase inhibitors are all active against most class A enzymes, such as TEM-1, but not against class C enzymes, like AmpC.  Also, these inhibitors afford no protection to cephalsoporins clinically and have never been combined, for example, with the 3rd generation cephalosporins, leaving these widely used drugs susceptible to the evolution of the extended spectrun beta-lactamases (ESBLs).  Thus there is pressing need for new inhibitors that can be combined with a primary beta-lactam, especially a cephalosporin, rescuing these first-line antibiotics for continued clinical utility. (more...)

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Tuberculosis (TB) remains one of the world's most important infectious diseases. The causative agent, Mycobacterium tuberculosis, is the leading cause of death of any infectious agent. Each year, approximately 8 million people develop active pulmonary TB and two million die from this disease. The World Health Organization (WHO) has declared TB a global health emergency, the first disease so designated. Compounding the problem, strains of M. tuberculosis resistant to the major antibiotics used to treat tuberculosis are rapidly emerging worldwide. This has given new urgency to the need to develop an effective prophylaxis for TB. Vaccination is particularly important for developing nations and at-risk populations.Four billion people in the world have been vaccinated with the currently used vaccine, bacille Calmette-Guerin or BCG, and approximately 100 million additional individuals are vaccinated with BCG each year. Since BCG provides only partial immunity to tuberculosis, these people could benefit from a booster vaccine that enhances their level of protection against tuberculosis.  (more...)

The rise of community- and hospital-acquired methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. More than 90,000 Americans acquire potentially deadly MRSA infections each year, which annually are estimated to kill more people than AIDS in the United States. Proteins displayed on the surface of S. aureus play key roles in the infection process as they promote bacterial adhesion to host cells and tissue, acquire essential nutrients and circumvent the immune response. Most surface proteins in S. aureus are attached to the cell wall by the Sortase A (SrtA) enzyme. Thus, sortase enzymes are a universal target for therapeutic agents against Gram-positive bacteria. (more...)

Apicomplexan parasites cause a wide array of diseases of medical and veterinary importance including malaria (Plasmodium spp.), toxoplasmosis (Toxoplasma gondii), coccidiosis (Eimeria spp.) and neosporosis (Neospora caninum). While the biology of the human pathogens is better understood, little is known of how the veterinary pathogens infect their specific hosts and cause disease. Neospora caninum is an important veterinary pathogen that causes abortion in cattle and neuromuscular disease in dogs. Neospora has also generated substantial interest because it is an extremely close relative of the human pathogen Toxoplasma gondii. While for Toxoplasma there are a wide array of molecular tools and reagents available for experimental investigation, relatively few reagents exist forNeospora. (more...)

Methicillin-resistant S. aureus (MRSA), a bacterial strain that is highly resistant to some antibiotics, is a major problem at healthcare delivery sites such as hospitals and health clinics. According to the U.S. Centers for Disease Control and Prevention, in 2005 there were an estimated 478,000 hospitalizations with a diagnosis of S. aureus infection in U.S. hospitals. Of these, approximately 278,000 hospitalizations were related to MRSA. The estimated number of people developing a serious MRSA infection (i.e., invasive) in 2005 was greater than 94,000. Approximately 19,000 persons died during a hospital stay related to these serious MRSA infections.Serious MRSA disease is still predominantly related to exposures to healthcare delivery. About 85 percent of all invasive MRSA infections were associated with healthcare, and of those, about two-thirds occurred outside of the hospital, while about one third occurred during hospitalization. (more...)

A system using nanotechnology to synthetically replicate the body's immune function for uses in body fluid filtration, stimulation of immune system, therapeutics and diagnostics. (more...)

Immunostimulatory nucleic acid molecules (ISS) are DNA sequences, originally found in bacteria, that enhance an immune response by activation of specific cells and proteins, including cytotoxic T cells (CTLs). These activated CTLs recognize and destroy cells in the body that have been altered, e.g. by infection with a virus or by transformation into cancer cells. However, individuals who are deficient in helper T cells may not derive the benefit of ISS stimulation. (more...)

Scripps Institution of Oceanography (SIO) at UC San Diego is one of the oldest, largest, and most important centers for global science research and education in the world. With the oceans covering 70 percent of the earth's surface, it is no surprise that approximately two-thirds of the world's animal phyla are found in marine environments and many are exclusively marine. SIO scientists were among the first to explore the natural product chemistry of marine organisms and this research helped to develop the field of marine natural products chemistry and the realization that the oceans harbor myriad new organic molecules with utility for the development of pharmaceuticals and other products. This research led to the discovery of hundreds of new compositions of matter for new products—some of which are already well progressed into commercial development. Two compounds are now entering phase II clinical trials. One of these, Salinosporamide A, is a potent proteasome inhibitor. The second compound, which is derived from the fungal metabolite halimide, acts as a vascular disrupting agent. (more...)

Overview: This technology bundle includes the following cases. SD2004-100: Methods for Using Pharmacologically Active Agents Containing Esterified Phosphonates SD2005-175: Substituted Phosphate Esters of Nucleoside Phosphonates SD2004-259: New Drug Derivatives for Promoting Oral Delivery to the Lung SD2010-158: Phosphonates with Reduced Toxicity for Treatment of Viral Infections SD2008-145: MicroRNAs for Inhibiting Viral Replication SD2006-145: RNA ‘Friendly’ Ligands with Anti-Viral Activity for the Treatment of Hepatitis C Background:Approximately 4 million people in the United States and probably more than 100 million people worldwide are infected with hepatitis C virus (HCV). The virus has the unique ability to cause persistent infection in susceptible hosts after parenteral or percutaneous transmission. Nearly 70 to 80 percent of infected persons become chronic carriers, and chronic and progressive HCV infection carries significant morbidity and mortality (e.g., major cause of cirrhosis, end-stage liver disease, and liver cancer). Phosphonate Derivatives with Increased Efficacy and/or Oral BioavailabilityNucleoside therapy has long been regarded as the gold standard in small molecule approaches to treating viral diseases, but the toxicity, side effects, and need for intravenous administration have limited their adoption. Below is a related group of technologies for the treatment of viral diseases and cancer from the laboratory of Dr. Karl Hostetler, a well-known leader in the area of nucleoside chemistry. Dr. Hostetler’s research comprises multiple approaches to making nucleoside compounds more efficacious by increasing their biovailability in order to simplify both dosing and the ease of administration. A brief summary of the various types of derivatives that are available from Dr. Hostetler’s laboratory is listed here with links to issued patents, patent applications, or publications, as applicable. SD2004-100: Methods for Using Pharmacologically Active Agents Containing Esterified Phosphonates—Phosphonate compounds have long been known to have antiviral, antiproliferative, and other therapeutic benefits. Compositions of alkyl esters of phosphonates are identified for the treatment, prevention, or amelioration of a variety of medical disorders associated with viral infections, cell proliferation, and bone metabolism. Detailed description available (see U.S. issued patent number 7,652,001). SD2005-175: Substituted Phosphate Esters of Nucleoside Phosphonates—Novel alkoxyalkyl phosphate derivatives of nucleoside phosphonates (nucleoside phosphonates linked via their phosphonate residue to the phosphate of alkoxyalkyl-phosphate, alkylglycerol-phosphate, or alkyl-phosphate) have been designed and synthesized that have broad-spectrum antiviral activity when tested in cell culture assays against a variety of viruses, including herpes simplex virus-1 and -2, vaccinia virus, human cytomegalovirus, and cowpox virus. The level of antiviral activity demonstrated is greatly increased compared with that of the unmodified nucleoside phosphonates. These compounds and compositions have utility in the treatment, prevention, or amelioration of some symptoms associated with cell proliferation. Detailed description available (see U.S. patent publication number US2009-0156545). SD2004-259: New Drug Derivatives for Promoting Oral Delivery to the Lung—Methods and compositions are provided for treating lung diseases, including but not limited to infections and small cell and non-small-cell lung cancer, by conjugating a drug of interest to glycerol ethers or glycerol phosphate ethers. These compounds were designed specifically to provide enhanced bioavailability to the tissues of the lung while providing the ease of oral administration. By using a special lipid linker attached to the phosphonate moiety, oral uptake and lung delivery of the conjugate is enhanced, while drug accumulation in the kidney is reduced. Detailed description available (see U.S. patent publication number US2008-0221061). SD2010-158: Phosphonates with Reduced Toxicity for Treatment of Viral Infections—This invention describes novel phosphonate compounds that are less toxic and have excellent activity and selectivity compared with previous derivatives, such as ODE–(S)-HPMA, against both RNA and DNA retroviruses, such as hepatitis C virus and HIV. Detailed description available. SD2008-145: MicroRNAs for Inhibiting Viral Replication—The laboratory of Dr. Michael David has discovered a group of cellular miRNAs that are regulated by interferon. Within this group, several have predicted targets with HCV genomic RNA. It has also been found that alpha-interferon potently inhibits the expression of the liver specific miRNA-122, which is indispensable for HCV replication. Interferon induction has been verified for multiple miRNAs using real time PCR. These findings not only provide a new approach for the attenuation of HCV infection, but also may provide a new fundamental concept for the basis of the antiviral role of interferon. This is believed to be the first demonstration of a ligand-induced miRNA in a mammalian system. This technology provides compositions and methods for combating viral infection through RNA interference through the use of cellular microRNA mimics to treat virus-infected cells. Detailed description available (see international patent application 2009029681). Interferon Modulated miRNAs Localization in the HCV Genome miR-A Core, E2, NS3, NS4B, NS5B miR-B CORE, NS3, NS5B miR-C CORE, NS2, NS3, NS4B, NS5B miR-D E NS3, NS5G 2 miR-E E2, NS4A NS5B mi-R-F CORE, NS2, NS3, NS5A, NS5B miR-G E2, NS3, NS4B, NS5B miR-H E1, 32, NS3, NS5A Advantages: Potential aid to better design of siRNAs for antiviral applications. New approach to diagnostic assays as prognostic markers of efficacy of HCV treatment. May provide a method to improve clinical efficacy of interferon treatments. Related Materials: Pedersen IM, Cheng G, Wieland S, Volinia S, Croce CM, Chisari FV, David M. Interferon Modulation of Cellular MicroRNAs as an Antiviral Mechanism. Nature. 2007 Oct 18;449(7164):919-22. PubMed PMID: 17943132; PubMed Central PMCID: PMC2748825. (See also: Beard MR, Helbig KJ. Control of HCV Replication: When Size Does Not Matter. Hepatology. 2008 Mar;47(3):1092-4. PubMed PMID: 18302297.) SD2006-145: RNA ‘Friendly’ Ligands with Anti-Viral Activity for the Treatment of Hepatitis C—Dr. Thomas Hermann and Maia Carnevalli have developed a novel class of chemical compounds that inhibit HCV protein synthesis by targeting one of several highly conserved cis-acting RNA elements unique to the HCV genome. This research project includes the investigation of other such elements and the design, synthesis, and testing of additional new compounds. Detailed description available (see U.S. published patent application number WO2009099897). Advantages: Novel class of compounds not previously described in the literature.  Inhibitors of hepatitis C virus protein synthesis. Targets sequence is unique to the HCV genome and critical to initiation of viral protein synthesis. Binding to the target has been demonstrated. Inhibitory activity of a test compound has been demonstrated.  None or minimal cytotoxicity at concentrations sufficient to inhibit viral replication. Five model compounds have been synthesized and tested; synthesis and testing of additional compounds continues. (more...)

Hepatitis C virus (HCV) afflicts about 170 million people worldwide and yet the mechanisms responsible for the entry and trafficking of HCV into cells are poorly understood. HCV induces an acute illness and often leads to chronic hepatitis and in some cases may lead to hepatocellular carcinoma and/or cirrhosis. There currently is no treatment that the majority of patients with HCV respond to, and those that are given interferon plus ribaviron often display serious adverse side effects. (more...)

Defensins are cysteine-rich, cationic antimicrobial peptides expressed by leukocytes and epithelial cells of mammals and birds. These peptides, which can be considered endogenous antibiotics, play an important role in innate host defense against pathogens due to their antibacterial, antifungal and antiviral activities. Three defensin subfamilies exist in vertebrates: alpha-defensins, beta-defensins, and theta (circular) minidefensins. All of these have largely beta-sheet structures that are stabilized by three intramolecular cystine disulfide bonds, and derive from a common ancestral gene. Theta defensins are much smaller (18 amino acid residues) than alpha or beta defensins (29-45 residues), and their antiviral properties are considerably more robust than their antibacterial and antifungal effects. (more...)

The host immune system is crucial to final resolution of viral infection. Unfortunately, many viruses, such as HIV-1 and hepatitis C virus (HCV), can evade the immune system. There is no pharmaceutical treatment that can eradicate these viruses from infected individuals. The fate of these infected individuals hinges on the findings of new therapeutic approaches, which has been a long-standing goal of HIV/AIDS research. (more...)

Protective immunity mediated by CD8 T cells are believed to play an important role in the outcome of human immunodeficiency type I (HIV) disease. (more...)

Aging is accompanied by a dramatic decline in immune functions involving both B and T cells. Clinical findings of increased morbidity and mortality following infections, higher incidences of cancer, and diminished antibody responses to specific vaccines are examples of immunologically-based medical problems of the elderly. However, despite a large body of research on the nature of these immunological deficits, there is no known mechanism that explains the progressive decline of immune competence with age. Nor is there a reliable biomarker to identify which subset of chronologically old individuals are at risk immunologically. (more...)

Mycobacterium tuberculosis is a disease that infects millions of people each year; in addition, the related bacterium, Mycobacterium bovis, infects domesticated animals, resulting in substantial economic losses. Currently, humans are administered Bacille Calmette-Guerin (BCG) vaccine to prevent tuberculosis. However, BCG vaccines have variable efficacy - on average about 50%. Recombinant BCG vaccines have been developed that express a key antigen of M. tuberculosis and are more potent than BCG. However, these recombinant BCG vaccines contain antibiotic resistance markers; regulatory authorities want vaccines to be free of such antibiotic resistance markers to diminish their dissemination to other pathogens in the environment. Unmarked vaccine vectors (i.e. those lacking an antibiotic resistance marker) have been produced by various means, but these methods have resulted in low levels of expression of recombinant proteins. Preferably, unmarked strains would not only express large amounts of the recombinant proteins, but express them from genes integrated into the chromosome because such constructs tend to be more stable than when the genes are expressed from a plasmid. Due to safety, potency, regulatory, and stability issues, there is a need for a better vaccine that can prevent and treat tuberculosis in humans and animals. (more...)

Conventional antibiotics are often used in the treatment of skin infections and inflammation. Topical and oral antibiotics are common in the treatment of acne, which is aimed at killing the Propionibacterium acnes, the bacteria linked to the pathogenesis of acne vulgaris. Erythromycin and tetracycline are frequently prescribed for reducing P. acnes, though the efficacy of antibiotics has been declining as the prevalence of this microbe has become widespread. Excessive utilization of antibiotics due to improper use and inaccurate diagnosis is contributing to microbes gaining resistance to conventional therapeutics. Due to random genetic mutations that occur from natural selection and evolution, microbes develop resistance genes that make it impervious to antibiotics, exposing many current compounds to obsolescence. The new generation of antimicrobial compounds must therefore eradicate microbes independent of its survival machinery, such as cell wall or RNA synthesis. Novel strategies for killing pathogenic cells can also yield alternative uses for treating other skin diseases. (more...)

UCSF investigators have identified a novel endogenous agent that activates the Aryl Hydrocarbon Receptor. (more...)

Several novel alkaloids that act as inhibitors of the enzyme mycothiol S-conjugate amidase (MCA), a cellular detoxicant in Mycobacterium smegmatis, have been identified and isolated. Since MCA is also found in such pathogenic strains of actinomycetes as M. tuberculosis, M. avium complex and M. leprae, but is absent in eukaryotes, it represents a potential target for new antimycobacterials. A recent crystal structure of MCA reveals that it represents a novel enzyme fold within the general class of zinc metalloproteases. This novel class of inhibitors may therefore provide lead compounds for the development of antimycobacterial drugs. These new drugs may prove useful by acting in combination with existing drugs to increase their effectiveness against, for example, tuberculosis. The novel alkaloids may also function as lead compounds for the development of broad-spectrum antibiotics against Gram-positive organisms such as Staphylocccus and Streptococcus. With the growing increase in drug resistant organisms, the need to find new antimicrobials is becoming increasingly urgent. The isolated amidase inhibitors could be valuable lead compounds for the development of antibiotics effective against antibiotic-resistant strains, such as methycillin- and vancomycin-resistant Staphylococcus and Streptococcus. (more...)

A series of novel derivatives of phosphonate compounds has been synthesized. These novel compounds have demonstrated enhanced activity against poxviruses and herpes viruses in tissue culture cells when compared with the unmodified parent molecules. When evaluated against existing alkoxyalkyl analogs of phosphonates, the new compounds are easier and faster to synthesize while retaining the increased bioavailability demonstrated by the alkoxyalkyl phosphonate analogs. (more...)

While successful vaccines have been developed against acute infections, persistent infections have remained refractory to both natural immunity and vaccination protocols. The standard strategy of selecting immunogens on their ability to generate a strong T-cell response has proven ineffective. In reality, one observes immunogens that generate a surfeit of T-cells but are completely ineffective as vaccines. On the other hand, one can immunize with DNA and get protection using a gene against which no immunity is generated during natural infection. Therefore, to vaccinate against persistent infections, a vaccine may have to be better than natural immunity. An effective approach may be evolved by learning from and targeting the "Achilles heel" of natural immunity. (more...)

Erythropoietin (EPO) is a naturally occurring hormone that stimulates the production of red blood cells. Recombinant EPO, marketed as Epogen® or Procrit®, have been used as a treatment for anemia and neutropenia, especially in those patients suffering from the effects of cancer chemotherapy, chronic renal failure, or treatment for HIV. Recombinant EPO is administered intravenously, with patients traveling to a clinic or hospital periodically to receive it. (more...)

The detection of retrovirus is potentially of great importance both for diagnosis of numerous serious diseases and for monitoring retroviral-based gene therapy. However, since it is difficult to ascertain whether or not a given retrovirus may be present in a patient, the identification of diseases with possible retroviral etiology has not been straight forward and application of retroviral gene therapy techniques has been inhibited. In the case of rheumatoid arthritis, for example, the disease has been intensively investigated, yet its origins remain unresolved. Many researchers hypothesize that rheumatoid arthritis is caused by several viruses, including retroviruses. There have been reported links to retroviruses to other diseases but such links have usually been difficult to confirm These difficulties are due to the uncertainty of reliably detecting reverse transcriptase activity (by PERT for example) over background for cellular enzymes (such as telomerase). Assays such as electron microscopy visualizations and immunofluorescent probing methods are also not useful due to their low sensitivity. (more...)

Sepsis is a morbid condition induced by a toxin, the introduction or accumulation of which is most commonly caused by infection or trauma. Sepsis-inducing toxins have been found associated with pathogenic bacteria, viruses, plants and venoms. Among the well described bacterial toxins are the endotoxins or lipopolysaccharides (LPS) of the gram-negative bacteria. Upon introduction of LPS into the blood it binds to lipopolysaccharide binding protein (LBP). LBP recognizes the lipid A region of LPS and forms high affinity complexes with both rough and smooth form LPS. During the acute phase, LBP is synthesized by hepatocytes, and reaches very high concentrations in serum. The macrophage/polymorphonuclear leukocyte differentiation antigen, CD14, binds LPS in the presence of LBP when present as LPS-LBP complexes, and this binding event activates cellular responses. Therefore, there continues to be a need for reagents that interfere with LPS:CD14-mediated cell activation. (more...)

UCSD researchers have developed an invention useful for: augmenting immunity (both cellular and antibodies) against cancer and infectious diseasesExpanding immune cells (B cells, dendritic cells, macrophages and T cells) in vitro for reinfusion of them or their productsImmunological testing of immune function. In one embodiment, the invention is a soluble recombinant fusion protein containing multiple CD40 ligands ("CD40L"). This protein affects macrophages and B cells in the same manner as membrane CD40L. The same technology can be applied to produce other members of the TNF family, such as TNF-alpha, FasL, TRAIL, RANKL, 4-1BBL, and others. (more...)

Comparative genomics has, historically been limited to the study of changes that occurred over millions of years. Evolution, however, is a dynamic and recurring reality, which can be responsible for such vexing realities as the emergence of new pathogens and the acquisition of drug-resistance. From a more proactive stance, the ability to design, manipulate and evaluate the consequences of specific stressors could dramatically improve the ability to design beneficial mutations for industrial processes that use bacteria for anything from food and chemical production to the clean-up of oil spills. (more...)

The number of deaths from hepatitis C (HCV) is expected to surpass that resulting from HIV in the near future. There is no vaccine or drug available that acts directly on the virus. Current therapy typically consists of combined interferon and ribavirin, both of which have significant side effects that are often severe enough to necessitate additional treatment, thus increasing the overall cost and affecting patient compliance with the treatment regimen. Viral proteins are the targets of many research projects to find new drugs to treat HCV. These targets are often analogous to those of many HIV programs. One of the challenges to developing a monotherapy targeting viral proteins is the high genetic variability of HCV. (more...)

Propionibacterium acnes (P. acnes) bacteria is involved in many human polymicrobial diseases. It is the causative agent in acne vulgaris, a human polymicrobial disease. Acne vulgaris is the most common skin disease, affecting more than 85 percent of people at some time during their lives and currently affects more than fifty million people in the U.S. Current antibiotic therapy for acne lesions provides a non-specific treatment that kills the majority of skin bacteria and impacts the homeostasis of skin- and intestinal-resident flora. Acne vulgaris can result in severe inflammatory lesions that are highly associated with P. acnes infection. There are no appropriate therapeutic modalities that are long-lasting and systemically effective and that specifically suppress P. acnes-induced pathogenesis and inflammation. In addition, these bacteria have the ability to trigger inflammatory responses. Many antibiotics have been used for acne treatment, but these antibiotics in general are non-specific, short lasting, and normally are applied when acne lesions have already occurred (such as in late stages of acne). Available topical treatments for acne lesions, including drugs, are palliative and effective only while treatment is maintained. When treatment is discontinued, increased acne gain inevitably results. (more...)

Actinomycetes are well known soil bacteria that were once believed to occur in the ocean only when washed in from land. Today, it is clear that unique populations of marine actinomycetes reside in ocean sediments and that these bacteria are fundamentally different from those on land. Although terrestrial actinomycetes have been the source of many of today's more than 120 drugs, marine actinomycetes have only recently been incorporated into the discovery process. These bacteria are now proving to be a particularly rich source of unique natural products, many of which display potent biological activities. (more...)

Parasitic diseases, such as malaria, African sleeping sickness, Chagas disease and trichomoniasis, are major worldwide health problems for which new chemotherapy is desperately needed. For example, an estimated five million cases of the sexually transmitted disease trichomoniasis occur each year in the United States alone. Malaria kills over a million people a year worldwide and is second only to tuberculosis in its impact on world health. Current treatments for these diseases have varying degrees of effectiveness and serious problems with toxicity, drug-resistant strains, and lack of selectivity. Therefore, there is a need for the development of new therapeutics for the treatment of these diseases.Researchers at the University of California, San Francisco have discovered that a novel series of small molecules, in a class that has previously been evaluated for antiviral and anticancer therapy, is effective in killing a variety of parasites, including those that cause malaria, trichomoniasis, Chagas disease and African sleeping sickness. By screening a library of these novel small molecule compounds, the researchers found several promising lead compounds that killed a range of parasites in cell culture assays and had no toxicity in mouse studies. These compounds therefore represent a potentially powerful new therapeutic avenue for parasitic diseases. (more...)

Researchers at UCSF have developed new C. albicans strains that use different auxotrophic markers that do not affect the virulence of C. albicans in a mouse model. Furthermore, these researchers have cloned complementing markers to be used in selection of knockout mutants from Candida strains other than C. albicans, thereby greatly reducing misintegration of DNA gene disruption fragments into the Candida auxotrophic marker site instead of the knockout target site. Combining these strains and markers with a fusion PCR technique allows for quick and efficient disruption of both alleles of the target gene in C. albicans. Generating homozygous knockouts is improved from 2% to 70% efficiency for knocking out the more difficult second allele. (more...)

UCSF investigators have developed a novel targeted pro-drug technology that can selectively deliver a chemotherapeutic payload to cells in areas of high concentrations of endogenous free ferrous iron. The pro-drug can be conjugated to a variety of existing and novel pharmacologically active compounds to increase their therapeutic window and lower systemic toxicity by increasing the selectivity of their delivery. Applications include therapies for cancer and malaria and as imaging agents.  (more...)