Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 13, Issue 5, 2013

The interest that surrounds the bacterium Helicobacter pylori (H. pylori) is due not only to its causal role in several gastroduodenal diseases, but also to its supposed involvement in the pathogenesis of extra-gastric manifestations. This review provides a literature update on the hypothetic correlation between H. pylori and headache. To identify all publications on this issue, a MEDLINE search of all studies published in English from 1965 to 2013 was conducted. The authors examined three aspects of this potential association: epidemiology, intervention trials and pathogenesis. While in the former, the results are contradictory, in the intervention studies, it has been documented that at 6 and 12 months, bacterial eradication is associated to disappearance of symptoms in 23% and 28% of cases, and to a significant decrease of intensity, frequency and duration of acute attacks in the remaining patients. Under a pathogenetic aspect, if H. pylori has a role, it does not act through oxidative stress. In conclusion, the eradication of H. pylori seems efficient at least in a subgroup of patients suffering from migraine. Further investigations should focalize on particular subgroups of patients and, encouraged from data produced by intervention studies, evaluate the long-term benefit of eradication.

Tuberculosis (TB) remains as one of the most serious public health problems worldwide. It is one of the main causes of death in poor and developing countries, especially in sub-Saharan Africa, where it may be associated with the human immunodeficiency virus (HIV). It has been estimated that one third of the world population is infected by Mycobacterium tuberculosis (Mtb), and there were about 8.7 million new TB cases, and about 1.4 million yearly deaths due to TB in 2011. DOTS is the currently used drug therapy in TB but there is non-compliance which results in emergence of resistance. Bacille Calmette Guérin (BCG), an attenuated vaccine derived from Mycobacterium bovis, is the only licensed TB vaccine, but not recommended in HIV-infected infants. There are 14 vaccine candidates that have entered clinical trials and over 35 candidates in discovery and preclinical development. Mycobacterium indicus pranii [Mw; MIP] and M. vaccae are in phase III clinical trial and the Drug Controller of India licensed MIP for human use in India.

Trichomoniasis is a common sexually transmitted disease (STD) caused by a protozoan parasite called Trichomonas vaginalis. This disease, with roughly 170 million new infected people worldwide per year, is associated with various problems such as pre-term delivery, high infant mortality or low birth weight. In addition, trichomoniasis increases patient susceptibility to HIV infection. The mainstay medication for trichomoniasis is metronidazole, but some resistant strains to this treatment have been identified. Moreover, treatment with metronidazole is associated with numerous side effects. Thus efforts to identify new alternative drugs in order to control trichomoniasis are vital. The use of medicinal herbs has gained widespread acceptance in both developing and non-developing societies because of owing to fewer side effects and better patient tolerance. In our search for alternative drugs in the treatment of trichomoniasis, we reviewed the effect of different plant extracts on Trichomonas vaginalis in vitro.

Leishmaniasis is a parasitic disease caused by Leishmania, transmitted by the bite of some sandfly species. It is endemic in 88 countries throughout the world. Pentavalent antimonials are the standard therapy for leismaniasis. Saffron (crocus sativus) belongs to the iridaceae family. This paper will outline the benefits and challenges of repurposing saffron for treating leishmaniasis.

Anti-retroviral drug resistance evolves as an inevitable consequence of expanded combination Anti-retroviral Therapy (cART). According to each drug class, resistance mutations may occur due to the infidel nature of HIV reverse transcriptase (RT) and inadequate drug pressures. Correspondingly, resistance to Nucleoside Reverse Transcriptase Inhibitors (NRTIs) occurs due to incorporation impairment of the agent or its removal from the elongating viral DNA chain. With regard to Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), resistance mutations may alter residues of the RT hydrophobic pocket and demonstrate high level of cross resistance. However, resistance to Protease Inhibitors requires complex accumulation of primary and secondary mutations that substitute amino acids in proximity to the viral protease active site. Resistance to novel entry inhibitors may also evolve as a result of mutations that affect the interactions between viral glycoprotein and CD4 or the chemokine receptors. According to the current studies, future drug initiative programs should consider agents that possess higher genetic barrier toward resistance for ascertaining adequate drug efficacy among patients who have failed first-line regimens.

The L-amino acid oxidase (LAAO) is a multifunctional enzyme, able to partake in different activities including antibacterial activity. In this study, a novel LAAO (Mb-LAAO) was isolated from the venom of M. bornmuelleri snake using size exclusion chromatography followed by RP-HPLC and partially characterized. However, the molecular weight of the Mb-LAAO determined by ESI-MS and SDS-PAGE was 59 960.4 Da. Once the enzymatic activity test confirming the enzyme’s identity (transformation of L-leucine) was done, the Mb-LAAO was evaluated for its antibacterial activity against Gram-negative bacteria. It showed a remarkable effect against M. morganii and K. pneumoniae. Moreover, no cytotoxic activity was observed for Mb-LAAO against human erythrocytes arguing for an exploration of its pharmaceutical interest.

The design, synthesis, structure and the antimycobacterial activities of a new class of nitrogen heterocycles, namely N1-substituted-diphenyl ether-bis-pyridazine (BP), is presented. An efficient, facile and straight applicable method for preparation of BP derivatives is described. The primary cycle high throughput screening reveals that two BP compounds, 2a and 3b, are potent inhibitors against Mycobacterium tuberculosis (Mtb), with their antitubercular activity being superior to the second-line antitubercular drug Pyrimethamine and being equal to Cycloserine. The data from cycle-2 screening confirm the results from cycle-1. The MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation, indicate the intracellular drug effectiveness against Mtb of these compounds, the lack of toxicity, a significant activity against both replicating and non-replicating Mtb and, a bactericidal mechanism of action (for 2b). SAR correlations have been done. Overall, the BP derivatives and especially compound 2b, appeared as a new leading antitubercular structure, which makes it a promising lead for further drug development.

The discovery and exploitation of new drug targets is a key focus for both the pharmaceutical industry and academic research. To provide an insight into trends in the exploitation of new drug targets, we have analysed different methods during the past six decades and advances made in drug target discovery. A special focus remains on different methods used for drug target discovery on infectious diseases such as Tuberculosis, Gastritis, Malaria, Trypanosomiasis and Leishmaniasis. We herewith provide a paradigm that is can be used for drug target discovery in the near future.