Recent Patents on Anti-Infective Drug Discovery - Volume 8, Issue 2, 2013

Antibiotic resistance of pathogenic bacteria is a major concern and presents a special challenge for development of 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 efficient microbe-killing effects. The efficient and irreversible antimicrobial effects of PDT are not dependent on the antibiotic susceptibility of the pathogenic bacteria to antibiotics. Gram-positive bacteria exhibit efficient binding of the photosensitizer to the bacterial barriers, leading to immediate photoinactivation of the bacteria. Photoinactivation of Gram-positive bacteria by various photosensitizers has become a high priority, since these bacteria are responsible for life-threatening infections in humans, especially in the elderly and in compromised hosts in whom they cause hospital-acquired infections. The present review concentrates on the photoinactivation of Staphylococi, Streptococci, Propionibacterium acnes, Deinococcus radiodurans, aerobic spore-forming Bacilli by various photosensitizers and by various methods described in numerous works and patents.

Photodynamic therapy (PDT), utilizing photosensitizers and light, has received considerable interests for its potential to treat microbial infections. The advantages of antimicrobial PDT include a broad spectrum of action, efficient killing against wild-type as well as drug-resistant pathogens. Therefore, antimicrobial PDT could be valuable to rapidly reduce the microbial burden during the management of local infections, especially for the antibiotic resistance. A variety of photosensitizers have been examined its efficacy against pathogens. To increase the efficacy of photosensitizers, various drug delivery systems have been developed. Among these carrier systems, liposomes showed their PDT efficacy and safety in delivering photosensitizers. This review is focused on the application of liposomes mediated photodynamic inactivation of bacteria along with the discussion of few of recent patents.

Antimicrobial photodynamic therapy (PDT) or photodynamic inactivation (PDI) is a new promising strategy to eradicate pathogenic microorganisms such as Gram-positive and Gram-negative bacteria, yeasts and fungi. The search for new approaches that can kill bacteria but do not induce the appearance of undesired drug-resistant strains suggests that PDT may have advantages over traditional antibiotic therapy. PDT is a non-thermal photochemical reaction that involves the simultaneous presence of visible light, oxygen and a dye or photosensitizer (PS). Several PS have been studied for their ability to bind to bacteria and efficiently generate reactive oxygen species (ROS) upon photo-stimulation. ROS are formed through type I or II mechanisms and may inactivate several classes of microbial cells including Gram-negative bacteria such as Pseudomonas aeruginosa, which are typically characterized by an impermeable outer cell membrane that contains 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 past few years and that relate to the eradication of Gram-negative bacteria via PDI or PDT. It is organized mainly according to the nature of the PS involved and includes natural or synthetic food dyes; cationic dyes such as methylene blue and toluidine blue; tetrapyrrole derivatives such as phthalocyanines, chlorins, porphyrins, chlorophyll and bacteriochlorophyll derivatives; functionalized fullerenes; nanoparticles combined with different PS; other formulations designed to target PS to bacteria; photoactive materials and surfaces; conjugates between PS and polycationic polymers or antibodies; and permeabilizing agents such as EDTA, PMNP and CaCl2. The present review also covers the different laboratory animal models normally 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 cell death. Use of PS-conjugates and immobilized PS can lead to a reduction in the amount of a compound necessary for bacterial cell 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 using specific 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 for drug 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, an important concept in drug discovery relates to the fixed-dose combinations (FDC), which can be defined as a formulation of two or more biologically active substances, combined in a single drug, and available at certain fixed doses. FDC presents 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 of DCs in drug discovery, the purpose of this review is to highlight the importance of this strategy for tuberculosis treatment and also for studies of new promising drug combinations to be used against this disease, specially focused on resistant bacterial strains. Relevant patents concerning combined treatment of tuberculosis are analyzed.

Clostridium difficile has become the most common infectious cause of healthcare-associated diarrhea, with serious morbidity, prolonged hospitalization and even death. Treatment of the disease utilizing today’s therapies does not guarantee a successful outcome. In the past decade, many new ideas and inventions have surfaced exploring different treatment 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 representative patents 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 following the 2003 SARS pandemic. In the years since the initial SARS outbreak, the arsenal to fight this virus family has been significantly increased by the rapid growth of coronavirus research. Among the potential viral drug targets, coronavirus 3C like proteases (3Cl) have emerged as the most popular drug target. A number of patented inhibitors with promising clinical potential have been developed via different methods of drug discovery, including virtual screening, natural product isolation and structure assisted rational drug design. This review serves as a summary of the progress in both the method of drug discovery and the related inhibitors against the coronavirus 3Cl protease.