Recent Patents on Anti-Infective Drug Discovery (v.7, #3)

Novel Antimicrobial Agents Against Multi-drug-resistant Gram-negative Bacteria: An Overview by George Karras, Venetia Giannakaki, Vasilios Kotsis, Spiros Miyakis (175-181).
No novel antimicrobial agents against multi-drug-resistant Gram-negative bacteria have been available to daily clinical practice during the last 5 years. On the other hand, resistance rates and mechanisms of those pathogens are increasing worldwide. Pan-resistant (against which none of the currently available antibiotics is effective) strains of Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa have been described. Encouraging is the fact that several novel compounds (some of them with mechanisms of action different to those of the antibiotics commercially available) are through the development stages. We summarize the main such compounds that show potential for offering solution to the treatment of Gram-negative multi-resistant bacteria along with the discussion of some patents associated with the topic.

Antimicrobial resistance threatens to compromise the treatment of bacterial infectious diseases. Strains resistant to most (if not all) antibiotics available have emerged. Gram-positive such representatives include strains of Methicillinresistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE) and highly-resistant to penicillin Streptococcus pneumoniae. Although the phenomenon of antimicrobial drug resistance is expanding, limited number of new antibiotics has been successfully developed in the last few decades. Several novel antimicrobial agents, however, are currently in diverse phases of development and undergoing clinical trials. This review will summarize the main candidates for novel antibacterial agents active against Gram-positive multi-resistant pathogens along with the discussion of some patents relevant to the topic.

Microbial natural products have been for decades one of the most successful sources of drugs to treat infectious diseases. The high occurrence of resistances to all major classes of known antibiotics represents today a new challenge and new classes of antibacterial compounds are urgently needed to respond to this unmet clinical need. While natural products discovery programs have been gradually abandoned by big pharma, smaller biotechnology companies and other research organizations are taking the lead in the discovery of novel antibacterials. A survey of recent patents has shown that in spite of the efforts, few novel compounds are being developed that can overcome most of the emerging multi-resistant and pan-resistant pathogens. In order to respond to the current challenges of discovering novel antibiotics, new approaches are required to be developed to further exploit the microbial resources and their biosynthetic potential as an untapped source of novel metabolites. Strategies to mine microbial collections for orphan biosynthetic pathways and novel species thought to be uncultivable, are emerging as a need within antibacterial drug discovery programs, in combination with high throughput screening and chemical dereplication of novel compounds. Different innovative methods that are being developed to respond to the new challenges that are faced today by drug discovery programs will ensure the evolution of these strategies into a completely new framework that will address the renovated interest in the discovery of novel classes of antibiotics.

Methicillin-resistant Staphylococcus aureus (MRSA) plays a significant role in the pandemic of multidrug resistant bacterial infections and is a major cause of hospital-acquired pneumonia. MRSA pneumonia carries a high morbidity and mortality rate especially in elderly diabetics with chronic kidney disease. S. aureus is highly virulent and successful respiratory pathogen. Vancomycin and linezolid are the only two antimicrobial agents FDA-approved to treat MRSA pneumonia. Standard vancomycin dosing is associated with high clinical failure rates and higher dosages are associated with increased nephrotoxicity. Pharmacokinetic and pharmacodynamic limitations are major contributors to poor outcomes with vancomycin. New agents are needed to improve treatment outcomes with MRSA pneumonia. Recently released antimicrobials with in vitro activity are not FDA-approved for treating MRSA pneumonia. Other novel agents are being investigated though none are in late-stage development. Pharmaceutical industry perception of low returns on investment, a Sisyphean regulatory environment, and obstacles to patentability have contributed to declining interest in both the development of novel antibiotics and the improvement of existing generic formulations. Despite decades of investigation into liposomal encapsulation as a drug delivery system that would increase efficacy and decrease toxicity, only liposomal amphotericin B and doxorubicin are commercially available. In this article, the pharmacokinetics and biodistribution of a novel PEGylated liposomal vancomycin formulation along with passive targeting and the enhanced permeability and retention effect of liposomal drug delivery; the pathogenesis of MRSA pneumonia; and recent patents of novel anti-MRSA agents, including inhalational liposomal vancomycin, are reviewed.

Bacterial DNA-dependent RNA polymerase (RNAP) is the central enzyme among the progress of transcription. The ubiquity, structural and functional similarities among different bacterial species make it an attractive target for developing protein-level anti-RNAP bactericidal agents with broad spectrum. However, the practical value of RNAP inhibitors is limited by an extensively observed single mutation in rpoB gene (encoding the β subunit of RNAP), resulting in completely resistant strains. Antisense antibacterials (also called RNA silencers in bacteria) may present an unusual opportunity for developing broad-spectrum sequence-selective nucleic acid based therapeutics. This review will first present a brief state of knowledge on progress and problems in targeting RNAP. Special emphasis will then be given to introduce the advantageous features of RNAP σ70 as a potential target for broad-spectrum antisense inhibition. Characteristics of the antisense antibacterial strategy (including antisense mechanism, basic chemistry involved in nucleic acid analogs, their anti-infection applications in vitro and in vivo) will also be thoroughly described. Notably, our exploration on targeting σ70 gene in gram-negative and gram-positive bacteria respectively for realization of broad-spectrum antisense bactericidal effect will be elaborated on. This firstly demonstrates peptide nucleic acid (PNA)-peptide conjugate as a successful example of broad-spectrum antisense antibacterial. At the end, we will also highlight a few promising targets and delivery strategies that favor the possible development of broad-spectrum antisense antibacterials.

Low-temperature Plasma - a Prospective Microbicidal Tool by Andreas Helmke, Petra Grunig, Ulrich-Markus Fritz, Dirk Wandke, Steffen Emmert, Karin Petersen, Wolfgang Viol (223-230).
The effects of low-temperature plasma treatment on microorganisms typically related to skin diseases are studied qualitatively by the inhibition of growth and viability assays to evaluate the potential for classifying as a prospective antiseptic agent. A variety of microorganisms enveloping gram- negative and gram-positive bacteria as well as one genus of yeast and fungus each were exposed to plasma in vitro. In a comparative approach, two power supplies, both of which produce high voltage pulses yet at different temporal characteristics, are applied for the growth study. While operation with both devices led to growth inhibition of all microbes, the results indicate a superior antimicrobial efficacy for high voltage pulse lengths in the nanosecond scale. Fluorescence assays reveal the efficacy of nanosecond-pulse driven plasma in reducing germ viability. Furthermore, the technical background for patents related to low-temperature plasma technology in the field of plasma medicine is discussed.

Percutaneous Treatment of Hydatid Liver Cysts: An Update by Antonio Giorgio, Giorgio Calisti, Giorgio de Stefano, Nunzia Farella, Umberto Scognamiglio, Valentina Giorgio (231-236).
Liver hydatidosis is the most common clinical presentation of cystic echinococcosis. Although liver cystic hydatidosis is considered a benign disease and many patients do not develop symptoms for years, its complications can be severe and life threatening (usually as a consequence of rupture in the biliary tree, in the peritoneum, in the bronchi, and of anaphylactic shock), thus, treatment is recommended for all viable and active hydatid liver cysts. Among the therapeutical options available for this disease, such as open and laparoscopic surgery and chemotherapy, percutaneous treatments have gained considerable interest over the last two decades, due to their efficacy, safety and high patient acceptability. Percutaneous treatments for liver cystic hydatidosis were once discouraged due to the risk of anaphylaxis following cyst puncture. Following the first uneventful attempts in the mid '80's, these treatments were increasingly used and techniques such as PAIR (Puncture, Aspiration, Injection, Re-aspiration) and its variants were developed and implemented in clinical practice. Although the evidence currently available is not sufficient to support or refuse the superiority of PAIR in terms of efficacy, numerous studies have demonstrated that it carries lower rates of morbidity, mortality, and disease recurrence and is associated with shorter hospital stays compared with surgery. The present review provides a brief history of percutaneous treatments for liver cystic hydatidosis, summarizes the currently available evidence on the subject, gives a brief overview of potential future developments in this field focusing on radiofrequency ablation techniques and presents some new patents on the issue.

The Recent Progress in RSV Vaccine Technology by Andrew Fretzayas, Anna Papadopoulou, Doxa Kotzia, Maria Moustaki (237-241).
The most effective way to control RSV infection would be the development of an expedient and safe vaccine. Subunit vaccines, live attenuated RSV vaccines, plasmid DNA vaccines have been tested either in human or in mouse models without reaching the ultimate goal of efficacy and safety, at least in humans. Viruses such as adenovirus, sendai virus, measles virus were also used as vectors for the generation of RSV vaccines with promising results in animal models. Recent patents describe new techniques for the generation of candidate vaccines. These patents include virus like particles as vaccine platforms, recombinant RSVs or modified RSV F protein as component of the vaccine. Despite the number of the candidate vaccines, the new RSV vaccines should overcome many obstacles before being established as effective vaccines for the control of RSV infections especially for the young infants who are more susceptible to the virus.

Analysis Toward Innovative Herbal Antibacterial & Antifungal Drugs by Sandeep Dhankhar, Seema Dhankhar, Manish Kumar, Sonam Ruhil, Meenakshi Balhara, Anil K. Chhillar (242-248).
The antimicrobial activities of four medicinal plants Argemona mexicana, Achyranthes aspera, Catharanthus roseus, and Syzygium cumini were evaluated against Escherichia coli, Vibrio cholerae, Klebsiella pneumoniae, Proteus vulgaris, Bacillus subtilis, Salmonella typhi and three Aspergillus species. Extracts from Achyranthes aspera and Catharanthus roseus showed the highest antimicrobial potential (MIC 0.375-0.750 mg/ml) while extract from Argemona mexicana and Syzygium cumini, showed less activity. In disc diffusion assay, only eight out of twenty extracts showed antimicrobial activity at a concentration of 25.0 μg/ disc. The GCMS investigation reveals the existence of 2-bornanone; 1, 2-benzenedicarboxylic acid, bis (2-methylpropyl) ester; hexadecanoic acid, methyl ester and hexatriacontane in water extract fraction of C. roseus. The present research article provides a review of some medicinal plants incorporating antimicrobial drugs, together with recent advances in emerging therapeutics in clinical development and related patents for exploitation of herbal medicine.