Recent Patents on Anti-Infective Drug Discovery - Volume 7, Issue 1, 2012

Fungal infections are becoming an increasing menace in the hospital care setting. Among them, non-albicans Candida species have gained significant attention. Especially in the ICU setting, therapeutic options are limited in many cases by the side-effects of conventional antifungal therapy. Echinocandins are a relatively new class of antifungal agents that promise good effectiveness against Candida and Aspergillus species. Due to their underlying mechanisms of action, they yield good tolerability and few limitations of usage. In the current manuscript we describe the patents of two recently approved echinocandins, micafungin (US approved 2005) and anidulafungin (2006) and provide an overview of the mechanisms, clinical effectiveness and safety of antifungal therapy with these agents.

Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic complication and a serious cause of vision loss in immunocompromised patients. Even though, a rise in human immunodeficiency virus (HIV) infected individuals seems to be a major factor responsible for the prevalence of CMV retinitis, the introduction of highly active antiretroviral therapy (HAART) significantly reduced the incidence and severity of CMV retinitis. Thorough evaluation of the patient's immune status and an exact classification of the retinal lesions may provide better understanding of the disease etiology, which would be necessary for optimizing the treatment conditions. Current drugs such as ganciclovir, valganciclovir, cidofovir and foscarnet have been highly active against CMV, but prolonged therapy with these approved drugs is associated with dose-limiting toxicities thus limiting their utility. Moreover development of drug-resistant mutants has been observed particularly in patients with acquired immunodeficiency syndrome (AIDS). Continuous efforts by researchers in the industry and academia have led to the development of newer candidates with enhanced antiviral efficacy and apparently minimal side effects. These novel compounds can suppress viral replication and prevent reactivation in the target population. Though some of the novel therapeutics possess potent viral inhibitory activity, these compounds are still in stages of clinical development and yet to be approved. This review provides an overview of disease etiology, existing anti-CMV drugs, advances in emerging therapeutics in clinical development and related recent patents for the treatment of CMV retinitis.

Multidrug resistant gram-negative bacteria are an increasing therapeutic challenge. The beta-lactamases are a group of enzymes that confer resistance to the beta-lactam antibiotics. The carbapenems have been in wide use to treat beta-lactamase producing, multidrug resistant gram-negative bacterial infections. However, the emergence of carbapenemases, enzymes capable of hydrolyzing the carbapenems, has limited our therapeutic options. In the recent years, there has been some development in the discovery of new agents such as boronic acid derivatives, ME1071 and Ca-EDTA that may enhance the activity of existing antibiotics, CTC-96 which reverses antibiotic resistance and polymyxin derivatives with decreased renal toxicity. While global efforts towards new drug development should continue, appropriate use of currently available antibiotics is equally important. In this review, we will discuss the general characteristics of carbapenemases, recent patents with drugs under development and current treatment options.

During the last few years the scientific community has shown a considerable interest in the study of plant materials as sources of new compounds to be processed into antimicrobial agents. In this context, carvacrol, a monoterpenic phenol, has emerged for its wide spectrum activity extended to food spoilage or pathogenic fungi, yeast and bacteria as well as human, animal and plant pathogenic microorganisms including drug-resistant and biofilm forming microorganisms. The antibacterial activity of carvacrol has been attributed to its considerable effects on the structural and functional properties of cytoplasmatic membrane. The data reported in this review provide an overview of the published literature regarding the antimicrobial properties of carvacrol and the recent patents claimed in order to highlight its future applications as a new antimicrobial agent. These could concern either the natural preservation in the cosmetic and food industries or an alternative which supports the conventional antimicrobial protocols. Interestingly, carvacrol alone or associated with one or more synergistic products could be incorporated in different formulations for biomedical and food packaging applications. However, more detailed safety investigations and in vivo studies should be carried out so that this molecule could be used in the future.

Enterococcus is an uncommon but emerging agent of upper and lower airway diseases, including sinuses, trachea, bronchi, lung and pleural infections. In particular, pneumonia and thoracic empyema may jeopardize the clinical outcome of compromised, hospitalized hosts, as well as affect outpatients. Treatment may feel the effects of inherent and acquired resistances such organisms show to commonly used drugs, with the spread of glycopeptide/vancomycin resistant enterococci (GRE/VRE, respectively) being of serious concern. With this work, we want to unearth the impact of members of the genus in the ambit of respiratory infections, and to increase the consciousness of their role as resourceful pathogens for human airways. Also, we are revising patents of interest aiming to timely screen GRE and soon provide clinicians with speciation and glycopeptide resistances.

Rapid emergence of drug resistant Human Immunodeficiency virus (HIV) variants and severe side effects of anti-HIV drugs limit the efficacy of existing anti-HIV therapies. Efforts are being made to develop newer anti-HIV agents. Few newer anti-HIV agents reached the different clinical phases of development and appear promising for future therapy. The present article highlights the current status of available anti-HIV drugs, emerging anti-HIV drug agents and recent anti-HIV drugs patents information.

Diabetes mellitus is the most common endocrine disorder, affecting 16 million individuals in the United States and 200 million worldwide. Despite the use of advanced synthetic drugs for the treatment, use of herbal remedies is gaining higher importance because of synthetic drugs have drawbacks and limitations. The herbal drugs with antidiabetic activity are extensively formulated commercially because of easy availability, affordability and less side effects as compared to the synthetic antidiabetic drugs. Antidiabetic herbal formulations (AHF) are considered to be more effective for the management of diabetes. There are around 600 herbal drug manufacturers in India of which almost all manufacturers are developing AHF in addition to others. Till date, no article is published to give detailed information of the patents on AHF. Thus, this review article undertake the attempt for providing updated information on the type of diabetes and patented AHF which will enhance the existing knowledge of the researchers.

Teas have beneficial effects on human health including cardioprotective, anticarcinogenic, antibacterial, antiviral and antifungal activity. The precise antimicrobial spectrum of tea is difficult to be defined due to variation in the methods of testing that have been used. Antibacterial effects of tea have been demonstrated against a number of microorganisms including Staphylococcus aureus, Vibrio cholerae, Escherichia coli, Shigella spp., Salmonella spp., Bacillus spp., Klebsiella spp. and Pseudomonas aeruginosa. Teas and tea ingredients seem to have both bactericidal and bacteriostatic actions. In addition, tea catechins have been shown to modify the antibiotic sensitivity of bacteria and to alter the expression of factors that determine bacterial virulence. Antiviral effects of green tea have been demonstrated against the influenza virus, as well as against the Herpes simplex virus, tobacco mosaic virus, enterovirus, rotavirus, Epstein Barr virus, HIV virus. Yet, green tea catechins have been shown to have antiviral activities against HIV infection. Antifungal effects of tea have been reported against Candida albicans, Trichophyton mentagrophytes, and Trichophyton rubrum. The present paper describes recent patents on antimicrobial effect of teas and tea ingredients.

The broad use of highly active anti-retroviral therapy (HAART), especially in developing world, has been associated with several problems such as lactic acidosis, lipodistrophy, pancreatitis, hyperlipidemia, insulin resistance and hepatotoxicity. Extensive use of HAART has also resulted in emergence of resistant HIV variants. Thereby, a pressing need for development of novel and cost-effective agents arises from these limitations. Setarud (IMODTM) is a safe, naturally- derived immunomodulator that was introduced for treatment of HIV patients in Iran. It is prepared as a mixture of herbal extracts including Tanacetum vulgare (tansy), Rosa canina and Urtica dioica (nettle) in addition to selenium, flavonoids and carotenes. Tanacetum vulgare may relieve anti-inflammatory symptoms and Rosa canina defers blood glucose and cholesterol elevation. Extracts from Urtica dioica may prevent maturation of myeloid dendritic cells and reduce T cell responses. A significant rise of CD4 count was observed in HIV patients treated by IMODTM in clinical trial phases, which could be explained by its immunomodulatory effects. Anti-oxidative activity of compounds in IMODTM might play a role in the clinical outcomes of patients treated with this drug. Moreover, IMODTM may show improving activity upon lipid profile and liver metabolism. According to studies on IMODTM, it seems that IMODTM has minor side effects. IMODTM with international publication number WO 2007/087825 A1 is an herbal extract which includes Rosa canina, Urtica dioica, Tanacetum vulgare, and selenium comprising a treatment by pulsed electromagnetic field of high frequency and is useful in treatment of HIV infection and AIDS.

Active efflux of antibiotics is one of the major mechanisms of drug resistance in bacteria. The efflux process is mediated by membrane transporters with a large variety of unrelated compounds as their substrates. Though these pumps are responsible for the low intrinsic resistance of a bacterium to a drug, their overexpression, accumulation of mutations in these proteins and their synergy with other drug resistance mechanisms hampers effective antimicrobial treatment. As efflux pumps have been reported to play vital roles in mediating multidrug resistance in clinical isolates from varied geographic locations and varied populations, the inhibition of efflux pumps appears to be an attractive approach to combat the problem of drug resistance. Efflux pump inhibitors can be utilized for increasing the antibiotic concentration inside a pathogenic cell making these drugs more effective, reduce the accumulation of other resistance mechanisms in a cell and for diagnostic purposes to evaluate the presence and contribution of the efflux mechanism in a pathogen. A large number of inhibitors have been discovered and patented in last two decades but the process of discovery, testing and commercialization is rather slow. Some of the important inhibitors include the energy decouplers, phenothiazines, analogs of popular antibiotics, inhibitors of serotonin re-uptake, to name a few, that have been used as adjuvants in the antimicrobial chemotherapy to potentiate the activity of some important antimicrobials in deadly pathogens that have worried the mankind since long. This review describes the role of efflux pumps in governing the resistance phenotype of a pathogen, efflux pumps found in bacteria and the efflux pump inhibitors that have been studied and patented so far.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/targets and therapeutic agents related to antiinfective drug discovery.

I the author (Vincenzo Savini) of the paper entitled "Bacterial Contamination of Platelets and Septic Transfusions: Review of the Literature and Discussion on Recent Patents About Biofilm Treatment" published in ‘Recent Patents on Anti-Infective Drug Discovery’ 2010; 5: 168-176, volume-5, no.2 regretfully confirms that some clerical errors had occurred in spite of my careful attention. I accept all responsibility of corrections of these errors from the paper.