Recent Patents on Anti-Infective Drug Discovery (v.8, #2)

Special Features of Gram-Positive Bacterial Eradication by Photosensitizers by Yeshayahu Nitzan, Marina Nisnevitch (88-99).
Antibiotic resistance of pathogenic bacteria is a major concern and presents a special challenge for developmentof alternative antibacterial modalities. One of these alternative approaches is based on using the photodynamic therapy(PDT) for eradicating bacteria. Photosensitizer-induced PDT exhibits unique properties and demonstrates efficientmicrobe-killing effects. The efficient and irreversible antimicrobial effects of PDT are not dependent on the antibiotic susceptibilityof the pathogenic bacteria to antibiotics. Gram-positive bacteria exhibit efficient binding of the photosensitizerto the bacterial barriers, leading to immediate photoinactivation of the bacteria. Photoinactivation of Gram-positive bacteriaby various photosensitizers has become a high priority, since these bacteria are responsible for life-threatening infectionsin humans, especially in the elderly and in compromised hosts in whom they cause hospital-acquired infections. Thepresent review concentrates on the photoinactivation of Staphylococi, Streptococci, Propionibacterium acnes, Deinococcusradiodurans, aerobic spore-forming Bacilli by various photosensitizers and by various methods described in numerousworks and patents.

Liposome-Encapsulated Photosensitizers Against Bacteria by Chin-Tin Chen, Chueh-Pin Chen, Jen-Chang Yang, Tsuimin Tsai (100-107).
Photodynamic therapy (PDT), utilizing photosensitizers and light, has received considerable interests for its potentialto treat microbial infections. The advantages of antimicrobial PDT include a broad spectrum of action, efficientkilling against wild-type as well as drug-resistant pathogens. Therefore, antimicrobial PDT could be valuable to rapidlyreduce the microbial burden during the management of local infections, especially for the antibiotic resistance. A varietyof photosensitizers have been examined its efficacy against pathogens. To increase the efficacy of photosensitizers, variousdrug delivery systems have been developed. Among these carrier systems, liposomes showed their PDT efficacy andsafety in delivering photosensitizers. This review is focused on the application of liposomes mediated photodynamic inactivationof bacteria along with the discussion of few of recent patents.

Antimicrobial Photodynamic Therapy to Kill Gram-negative Bacteria by Felipe F. Sperandio, Ying-Ying Huang, Michael R. Hamblin (108-120).
Antimicrobial photodynamic therapy (PDT) or photodynamic inactivation (PDI) is a new promising strategy toeradicate pathogenic microorganisms such as Gram-positive and Gram-negative bacteria, yeasts and fungi. The search fornew approaches that can kill bacteria but do not induce the appearance of undesired drug-resistant strains suggests thatPDT may have advantages over traditional antibiotic therapy. PDT is a non-thermal photochemical reaction that involvesthe simultaneous presence of visible light, oxygen and a dye or photosensitizer (PS). Several PS have been studied fortheir ability to bind to bacteria and efficiently generate reactive oxygen species (ROS) upon photo-stimulation. ROS areformed through type I or II mechanisms and may inactivate several classes of microbial cells including Gram-negativebacteria such as Pseudomonas aeruginosa, which are typically characterized by an impermeable outer cell membrane thatcontains endotoxins and blocks antibiotics, dyes, and detergents, protecting the sensitive inner membrane and cell wall.This review covers significant peer-reviewed articles together with US and World patents that were filed within the pastfew years and that relate to the eradication of Gram-negative bacteria via PDI or PDT. It is organized mainly according tothe nature of the PS involved and includes natural or synthetic food dyes; cationic dyes such as methylene blue and toluidineblue; tetrapyrrole derivatives such as phthalocyanines, chlorins, porphyrins, chlorophyll and bacteriochlorophyll derivatives;functionalized fullerenes; nanoparticles combined with different PS; other formulations designed to target PS tobacteria; photoactive materials and surfaces; conjugates between PS and polycationic polymers or antibodies; and permeabilizingagents such as EDTA, PMNP and CaCl2. The present review also covers the different laboratory animal modelsnormally used to treat Gram-negative bacterial infections with antimicrobial PDT.

The technique of photosensitization for eradication of bacterial cells involves the use of molecules called photosesitizers(PSs) which generate reactive oxygen species (ROS) upon illumination with light of a suitable wavelength.ROS can oxidize biological molecules such as proteins, nucleic acids and lipids, which ultimately leads to bacterial celldeath.Use of PS-conjugates and immobilized PS can lead to a reduction in the amount of a compound necessary for bacterialcell eradication. In addition, PS-conjugates for delivering photosensitizer molecules are more effective for clinical applications,since the photosensitizers are targeted directly to bacterial cells.This review reports studies and patents that demonstrate the possibility of increasing bacterial cells eradication by usingspecific and non-specific PS-conjugates such as: PS-antibiotic, PS-polycation (including PS-poly-L-lysine and PSpolyethyleneimine),PS-bacteriophage, PS-IgG and PS-siderophore. Studies and patents describing immobilized PS fordrug delivery are also considered.

Drug combinations (DCs) have been successfully used in different kinds of diseases such as cancer, AIDS,malaria, infectious diseases, asthma, diarrhea, hypertension, neurological disorders, among others. In this context, animportant concept in drug discovery relates to the fixed-dose combinations (FDC), which can be defined as a formulationof two or more biologically active substances, combined in a single drug, and available at certain fixed doses. FDCpresents several advantages, such as reduced risks of emergence of drug resistant strains, improvement of patient compliance,reduced costs of treatment and a simplified drug supply management, shipping and distribution. Due to the importance ofDCs in drug discovery, the purpose of this review is to highlight the importance of this strategy for tuberculosis treatmentand also for studies of new promising drug combinations to be used against this disease, specially focused on resistantbacterial strains. Relevant patents concerning combined treatment of tuberculosis are analyzed.

A Surview of Recent Patents on Anti-Infective Therapy for Clostridium difficile by Germine S. Soliman, Bechoi Saleib, Stephen J. Scholand (139-149).
Clostridium difficile has become the most common infectious cause of healthcare-associated diarrhea, with seriousmorbidity, prolonged hospitalization and even death. Treatment of the disease utilizing today?s therapies does notguarantee a successful outcome. In the past decade, many new ideas and inventions have surfaced exploring differenttreatment strategies of Clostridium difficile associated diarrhea (CDAD). These treatments include antitoxins, novel antimicrobials,immunoglobulins and large inert synthetic compounds. In this paper, we survey of a number of representativepatents issued from 2000 to the present targeting treatment of this difficult and dreaded disease.

Coronaviruses have been thrust into the spotlight by the recurring novel human coronavirus infections followingthe 2003 SARS pandemic. In the years since the initial SARS outbreak, the arsenal to fight this virus family has beensignificantly increased by the rapid growth of coronavirus research. Among the potential viral drug targets, coronavirus3C like proteases (3Cl) have emerged as the most popular drug target. A number of patented inhibitors with promisingclinical potential have been developed via different methods of drug discovery, including virtual screening, natural productisolation and structure assisted rational drug design. This review serves as a summary of the progress in both themethod of drug discovery and the related inhibitors against the coronavirus 3Cl protease.

Patent Selections: (157-160).