Recent Patents on Anti-Infective Drug Discovery - Volume 9, Issue 1, 2014

Beta-lactam antibiotics constitute the agents most widely used against bacterial infections worldwide. Hence, the emergence and spread of beta-lactam hydrolyzing enzymes among pathogenic bacteria has proved to be one of the major medical issues especially when these enzymes inactivate carbapenems together with other beta-lactams. The prompt detection of beta-lactamases is important for therapeutic and epidemiological purposes therefore, various appropriate methodologies have been developed throughout the last decades. In the present overview, recent patents related to the detection of beta-lactamases and especially of carbapenemases are discussed.

Background: Vitamin D deficiency and abnormal bone mineral density (BMD) have been reported in HIV patients. We aimed to find out the effects of antiretroviral therapy (ART) on serum vitamin D, parathyroid hormone (PTH) levels, BMD changes and fragility fracture rates in HIV patients. Methods: We collected information about baseline demography, risk factors for fracture, viral load (VL), CD4 count, serum 25-OH vitamin D (n=357), PTH (n=277), phosphate, ionised calcium, creatinine and BMD of spine and hip by DEXA scan (hologic, n=142). Statistical analysis used one-way ANOVA followed by Dunn’s multiple comparison tests. Results Table 1: Total 357 patients, mean age 41.1 (+/- 11.9) years, 249 (66%) black African, 197(52%) females, baseline CD4 count 451 (+/- 184) cells/dl, VL 1.4 log (+/- 1.2) copies/ml, duration of ART 52 (+/- 35) months were included in the analysis. Serum vitamin D was 15.3 (+/- 11.0) ng/ml, PTH (intact) 5.5 (+/- 3.9) pmol/l, corrected calcium 2.13 (+/- 0.9), phosphate 1.0 (+/- 0.2) and creatinine was 73.4 (+/- 21.1) mmol/l. Ninety four (66%) patients had abnormal BMD (T-score of spine or hip or both ≤ 1.0). Vitamin D levels were deficient (< 30 ng/ml) in 297 (78.7%) and PTH was high (>4.1 pmol/l) in 177 (64.8%) patients. Of 91 (30.9%) patients who had vitamin D levels below 10.0 ng/mL, PTH was high in 70 (n=91, 76.9%) and abnormal BMD in 50 (n=61, 75.4%) patients. Thirteen patients (3.2%) had possible fragility fractures. Tenofovir (TDF) users had higher PTH (P=0.002) and lower BMD of spine (0.01) and hip (0.002) and efavirenz (EFV) users had lower vitamin D (0.01) levels. On multivariate analysis including all significant variables, female sex (OR 1.5 CI 1.3-5.9), age over 40 years (OR 1.2 CI 0.9-5.1) and TDF use (OR 1.9 CI 1.6-6.9) were associated with abnormal BMD of hip but not spine. Conclusion: Female patients over 40 years old on tenofovir containing regimens may have increased risk of BMD loss from hip. Whether Vitamin D replacement will prevent further bone loss needs further work.

Toll-like receptors (TLRs) are key players in innate immunity. They are able to sense different microorganisms ranging from protozoa to bacteria, fungi or viruses. Innate immune responses can directly influence adaptive immune responses. Therefore, TLRs are considered as relevant targets for therapeutic applications in immune diseases: such as autoimmune disorders, allergy, sepsis, and cancer. We here review the recent patents based on the modulation of the toll-like receptors to develop anti-infective (prophylactic and/or therapeutic) agents.

Abstract: Affecting more than one third of the world population, tuberculosis remains one of the world’s most dreadful diseases, with no easy cures. Mycobacterial infestation and the evasion of host immune response are significantly responsible for the emergence of pulmonary tuberculosis. Mycobacterium tuberculosis, a weak gram positive, facultative aerobe colonizes in respiratory regions rich in oxygen reserves. Up regulation of CR and MR expression and function due to signaling by LAM results in electing immuno regulatory cytokines IL-4, IL-8 and Th2. Binding of NF-κB complex with mRNA prevention, due to mutation of leucine zipper domain of IK, inhibits the activation of cytokines and receptor molecules. Mechanism of energy generation by conversion of ADP to ATP, initiated by utilizing intermediary and/or end products of carbohydrate, amino acid or fatty acid catabolism is essential in approximating potential drug targets for elimination of the bacterium. A few improved diagnostic techniques have been evaluated over the last few years like Interferon Gamma Relese Assays, Nucleic Acid Amplification tests etc. of which most have certainly proven to facilitate specific detection of TB. Drugs like Rifampicin, Isoniazid etc. have also shown great curing effects on TB patients. Further research is required for better understanding of mechanism of pathogenesis and multiple drug resistance issues for developing the effective therapeutics and diagnostics against TB. The paper focuses on the effective diagnostics and therapeutics applications for tuberculosis prevention and cure based on recent patents and their analysis.

Elvitegravir/cobicistat/emtricitabine/tenofovirDF (EVG/COBI/FTC/TDF) is the new single-tablet, fixed-dose formulation containing an integrase strand transfer inhibitor recently approved as antiretroviral treatment. In this paper we analysed its use and advantages in naïve and experienced HIV-infected patients and we focused on special populations in which EVG/COBI/FTC/TDF could be a suitable option. Furthermore the manuscript reports the recent patent of EVG which may have an influence on the management of HIV-infected patients in the next future.

Anthrax is one of the deadly infectious disease as documented in the CDC website. In spite of the availability of appropriate antimicrobial agents, the mortality related with the anthrax remains high. The pathogenicity of B.anthracis is mainly accredited to the two foremost components: toxins and capsule. Virulence component of B.anthracis includes protective antigen (PA) which plays a vital role in pathogenesis, virulence protein edema factor (EF) and lethal factor (LF). This search for novel therapeutic strategies that attack the proteins involved in the pathogenesis of anthrax and may potentially supplement antimicrobials being investigated. Currently, extensive attempts are in progress to develop novel helpful therapies to all of the virulence components: lethal factor, protective antigen, edema factor and the capsule of B. anthracis. This review discusses the potential anthrax therapeutic, prophylactic measures and diagnostic applications based on recent patents’ prospects.

The Epstein-Barr virus (Human herpesvirus 4) encodes approximately 80 proteins, from which 15 possess at least 90 antigenic epitopes. Many of them stimulate the T cell receptors (TCR), but a few interact with the B cell receptors (BCR). Activation of B-cells and subsequent antibody production has not only been related to at least 3 envelope glycoproteins (mostly gp350) but also to latency associated membrane proteins (LMPs). The majority of EBV epitopes (over 80) inducing either cytotoxic and/or helper T lymphocytes were located on non-structural and/or latency associated polypeptides. The former interaction mediated by CD8plus/T cells is restricted by the HLA I molecules, predominantly of HLA-A subclass. In acute infectious mononucleosis (IM) patients (about 40 %) a considerable proportion of HLA B8 restricted CTL reactivity is directed against a single peptide (RAKFKQLL) of transactivator protein BZLF1/Zta. The EBV vaccines designed so far fall into two categories: those preventing any kind of infection (including prophylaxis of EBVassociated malignancies) and those designed for therapeutic purposes (to be used in subjects already infected). Preventive vaccines protecting against acute disease (such as IM) contain, as a rule, the gp350 polypeptide(s) encoded by the BLLF1 gene. Vaccines destined for tumor prevention rather consist of peptides derived from latency associated nuclear proteins (EBNA 2, 3 and 6) and/or from oncogenic latent membrane proteins (LMP1/LMP2a). Whereas the former generates antibodies preventing virus entry, the latter would potentiate the cell mediated response. In addition to recently described and purified individual recombinant immunogenic EBV polypeptides and/or their mixes, new perspectives were opened by construction of random overlapping strongly immunogenic scrambled polypeptide(s). Further novel approaches are based on carefully selected antigenic peptides (oligopeptides) coming from both, structural as well as non-structural or latencyassociated proteins bound to suitable carriers. Any constructs based on latency-associated proteins might be useful either for immunoprophylactic therapy following bone marrow and/or heart transplantations or for the prevention of EBVrelated tumors such as lymphomas and nasopharyngeal carcinoma. Due to the growing importance of the selected immunogenic epitopes as future vaccine components, at least the half of them has been patented not only as the natural amino acid sequence but also in different variations.