Recent Patents on Anti-Infective Drug Discovery - Volume 13, Issue 3, 2018

Background: Heavily treated HIV-1 infected patients may have limited therapeutic alternatives. In order to ensure sustained HIV-RNA suppression in these patients and to improve current antiretroviral treatment regimens in the fight against multi-drug resistant strains, new drugs are needed. Recently, two new drugs among the new generation of entry inhibitors showed promises for both their characteristics and mechanism of action. Objective: To outline ibalizumab (Patent: US20120121597A1) and fostemsavir (Patent: US8871771) future applications in people living with multi-drug resistant HIV with few remaining treatment options. Methods: We analysed the available literature and data from ongoing clinical trials about ibalizumab and fostemsavir. Results: Ibalizumab is a new humanized monoclonal antibody. It acts as post-attachment inhibitor by binding CD4 2nd domain of T lymphocyte and preventing HIV connection to CCR5 or CXCR4 and has been recently approved by Food and Drug Administration in the United States of America as a new intravenous antiretroviral agent for heavily treated HIV adults with multi -drug resistant infection. Fostemsavir (formerly BMS-663068), the oral prodrug of temsavir, is another attachment inhibitor. It acts by preventing the viral connection to CD4 by binding gp120. This drug showed encouraging results in heavily treated patients as add-on agent to current antiretroviral regimens, in particular for subtype B virus. It is currently being investigated in a phase 3, two-cohort (randomized and non-randomized), trial. Conclusion: The history of ibalizumab and fostemsavir will be written in next years. Continuing the research will be crucial to obtain evidence based guidelines for the management of heavily treated HIV-1 infected patients with limited therapeutic options.

The global spread of carbapenemase-encoding genes among Gram-negative nosocomial pathogens has led to the revival of polymyxins. Colistin and polymyxin B, despite their serious adverse effects, have become last resort treatment options for multi- or even extensively-drug-resistant bacterial infections due to Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. Their use, however, has been followed by an increase in polymyxin resistance rates and the spread of transferable resistance genes limiting further the treatment options and contributing to the emergence of pan-drug-resistance. In the present review, the to-date known polymyxin resistance mechanisms, as well as patents related to polymyxin resistance, are discussed.

Background: Carvacrol is the major constituent of essential oils derived from plants. It exhibits antimicrobial, antioxidant, anticancer, anti-inflammatory, and anticholinesterase activity. The analogues of carvacrol can be prepared via selected synthetic routes, resulting in potent compounds. Objective: Modifying carvacrol by the introduction of selected functionalities has the potential to enhance the biological activity of carvacrol. The functionalities on carvacrol such as the hydroxyl group, benzene ring and alkyl groups can be modified or used for hybridization with important pharmaceutical scaffolds. Results: In one of the patents cited, EP1053744B1, the modification of the hydroxyl group and the introduction of allyl groups into the benzene ring resulted in carvacrol analogues with antibacterial activity. Modifying the hydroxyl group influenced the hydrophobicity of the analogues and the size of the ring substituent. The hydrophobicity and the size of the ring substituent influence the analogues interactions with bacterial cells. The analogues of carvacrol with anticancer activity were influenced by the position of the substituted groups on the benzene ring. Substituent introduced at the ortho and para- positions resulted in better antitumor activity when compared to the ones with substituents on the meta-position. Conclusion: Based on several reports on cavarcrol analogues, more research on the development of carvacrol analogues will result in potent compounds that can overcome drug resistance which is currently a challenge in the treatment of diseases, such as bacterial infections, cancer, fungal infections etc. However, more biological evaluation is required in order to fully understand the mode of action of these analogues on selected pathogens.

Background and Aims: AIDS (acquired immune deficient syndrome), a deadly human infectious disease is caused by HIV (human immunodeficiency viruses) infection. Patient’s mortality was eventually reduced to one-fourth by combined chemotherapy (usually 3 chemical drugs simultaneously) than earlier HIV/AIDS treatments (single drug or vaccine) in the clinic. Results: Combined treatments against HIV/AIDS are still incurable for all patients despite a high rate of patient’s survival. Basic viral pathological study and advancing drug development systems for curable medications are indispensable nowadays and in the future. Conclusion: Up to date, therapeutic trinity (combined therapy) against HIV/AIDS is generally among chemical drugs. In this article, several forms of other therapeutic attempts for effectively curing efforts against HIV/AIDS are proposed-including the development of next generation therapeutic HIV vaccines and schedules, new categories of bio-therapy, different pathways of immune-modulation, herbal medicines in general (allopathic, Ayurveda and traditional Chinese medicines), high quality of physical exercises, and especially therapeutic combinations guided by latest medical discovery and principles (new forms of therapeutic trinity against HIV-induced pathogenesis and human mortality).

Background: In Asia, an estimated one million deaths are caused by communityacquired pneumonia (CAP) each year. Despite the high mortality in elderly people, a large number of CAP patients have been treated and survived with optimal life expectancy. A few studies have been done on adult CAP therapeutic approaches in Asia. Moreover, differences have been noted between these studies and European data. We aimed to investigate the efficacy of oral Levofloxacin (TAVANEX), 750 mg, once daily for five days versus parenteral Ceftriaxone 1gr BD, plus oral Azithromycin (250 mg, once daily) for seven to ten days (standard regimen) in CAP treatment. Materials and Methods: We conducted a prospective randomized trial among 150 patients with CAP in Qaem Hospital of Alborz city from December 2016 to June 2017. A group of CAP patients were randomized in two treatment groups. One group was treated with oral Levofloxacin (TAVANEX), 750 mg, once daily for five days and the other group with parenteral Ceftriaxone 1gr BD plus oral Azithromycin (250 mg, once daily) for seven to ten days (standard regimen). The efficacy and side effects of the assigned drugs were compared between two groups. The probability level for statistical significance was set at P ≤ 0.05. Results: The body temperature (P value=0.09), WBC count (P value=0.15), respiratory sounds (P value=0.18) and admission duration (P value=0.15) showed no significant differences after treatment between two groups. There was no report of hospital mortality, clinical deterioration and antibiotic escalation during hospital admission in both groups of study. In standard regimen group, only two (2.7%) patients had skin rash while in Levofloxacin group one case (1.3%) had skin rash, two patients (2.7%) had gastrointestinal problems and three (4%) patients showed central nervous system (CNS) complications. In both groups, the reticulonodular pattern was more frequently observed in Chest X-ray. Although standard regimen group (n=27, 36%) showed more consolidation than patients in Levofloxacin group (n=22, 29.3%), and the ground glass pattern was observed more in Levofloxacin group. Conclusion: We concluded that monotherapy with oral Levofloxacin was as effective as treatment with Ceftriaxone plus Azithromycin combination in patients with CAP who required hospitalization.

Background: Mycobacterium tuberculosis as an intracellular pathogen causes Tuberculosis (TB). Due to the long time required for treatment, hepatotoxicity of drugs and also emergence of Multidrug-Resistant (MDR) and Extremely Drug Resistant (XDR) strains, TB is currently a major public health problem. Some medicinal plants possess remarkable activity against Mycobacterium. Among them, Lamiaceae family are of pharmaceutical interest because of their potential antimicrobial properties. The aim of the study was to evaluate the in vitro activities of Satureja rechingeri, Satureja khuzestanica and Zataria multiflora against MDR M. tuberculosis and two Non-Tuberculous Mycobacteria (NTM). Methods: The essential oils were prepared by the standard method. The confirmed strains were obtained from the microbial collection of Tehran University of Medical Sciences. Minimum Inhibitory Concentrations (MICs) of essential oils of plants against mycobacterial strains were determined using standard broth microdilution method. Results: MDR M. tuberculosis was completely inhibited by Z. multiflora at 78μg/ml concentration. S. rechingeri and S. khuzestanica also showed same anti-mycobacterial activity against MDR M. tuberculosis with MICs of 156 μg/ml. The MICs of the essential oils against M. tuberculosis H37Rv, M. kansasii and M. fortuitum were in the range from 39 to 156 μg/ml. Conclusion: The studied medicinal plants showed notable effects against mycobacterial strains. Our results indicated that utilization of Lamiaceae family can be helpful for treatment of mycobacterial infections.

Aim and Background: Azoles as antifungal drugs have been used to treat leishmaniasis for many years. Several evidences suggesting that the primary target of azoles is the heme protein, which co-catalyzes cytochrome P-450-dependent 14α-demethylation of lanosterol. Little is known about the structural changes caused by azoles with atomic force microscopy (AFM) or scanning electron microscopy (SEM). In the current work, several patented antileishmanial agents reviewed (US8809555) (US 0269803 A1) (TW201802093 A). The present study aimed to determine ultrastructural damage in Leishmania major (L.major) induced by the newly synthesized azole. Methods: In this study, we investigated the morphological alterations of the parasite treated with our new synthesized azole namely trans-2-(4-chlorophenyl)-2,3-dihydro-3-(1Himidazol- 1-yl)-4H-1-benzopyran-4-one (IF-2) against L.major promastigotes stage using two high-resolution microscopic techniques: atomic force microscopy and scanning electron microscopy. Results: The results showed remarkable topographical and morphological alterations in the cell membrane at promastigote stage of L. major treated with the potent investigated azole (IF-2) ( IC50 values ≤8.9 μg/mL). Both techniques revealed membrane damage and also losing the flagellum in the observed cells. Conclusion: Our results strongly confirm the Leishmania cell wall as a potent target for the new synthesized azole (IF-2). Accordingly, focus on membrane integrity and glycoconjugates of Leishmania parasite to design new therapeutic agents is recommended.

Background and Objective: Today, resistance to multiple classes of antibiotics, and notably to the β-lactam and aminoglycosides in A. baumannii is becoming a great problem and it necessitates to make a new approach to combat with multidrug-resistant (MDR), extensive drug-resistance (XDR) or Pandrug-resistant (PDR) isolates. In this case, a new strategy and ways should be designed and introduced against such infections. Therefore the aim of the present study was the evaluation of antibacterial activity of nanoconjugate gentamicin and amikacin with gold against clinical isolates of A. baumannii that were collected from burn wound infection. There are some patents of gold nanoparticles that are conjugated with antibiotics (WO2017161296A1, US20090181101A1). Methods: Eighteen A. baumannii were collected from burn wound infections. For confirmation and detection of aminoglycoside-resistant genes, PCR was carried out. Gold nanoparticles and nanoconjugates were prepared according to the protocol. For the evaluation of the nanoconjugate, Dynamic light cattering, Transmission electron microscopy and FTIR Analysis were carried out. Then, the antibacterial activity of nanoconjugates was conducted by using micro broth dilution method. Result: Prevalence of aminoglycoside-resistant genes was aacC1, aphA6, aadA1, aadB genes 55.5%, 22.2%, 38.8% and 22.2% respectively. Synthesis of bare nanoconjugates resulted in nanoparticle in a size of 10 nm. Amikacin bound to Gnps showed excellent antibacterial activity (94.5%) and just one isolate showed intermediate resistance. Also, gentamicin bound to Gnps had a good antimicrobial effect (50%) in contrast to gentamicin alone. Conclusion: Our study showed that a combination of amikacin and gentamicin with Gnps has a significant antibacterial efficiency against clinical isolates of A. baumannii. Gnps can be used as extraordinary molecular carriers for targeting, and delivery of the antibiotic molecules to the specific infection.