Recent Patents on Anti-Infective Drug Discovery - Volume 4, Issue 2, 2009

Phototorhabdus is an insect pathogenic enterobacterium which maintains a mutualistic interaction with heterorhabditid nematodes. While the bacteria live in the nematode gut, the nematodes live in the soil and infect insect larvae, releasing their symbiotic bacteria into the insect blood. Here the bacteria reproduce and kill the insect by septicaemia. The nematodes then feed on the bacterial biomass and undergo several rounds of reproduction before emerging from the cadaver carrying their bacterial symbionts. Photorhabdus secretes a versatile armory of antimicrobial molecules into the insect corpse. These biocides exert a range of antimicrobial killing activities and serve a dual function. They minimize competition from non-symbiotic bacteria and prevent microbial putrefaction of the nematode-infected insect cadaver. The goal of this review is to describe current knowledge of the molecular mechanisms involved in the production of bacteriocins by Photorhabdus. Recent important advances in identifying novel potent antibiotic compounds from Photorhabdus and elucidating their complex mode of action in relation to pathogenicity and symbiosis associations are also discussed. The last part of this review focuses on the potential role Photorhabdus antibiotics may play in contributing to the discovery of novel pharmaceutical and agrochemical products. The present article is a short review of recent patents on Photohabdus.

The scarcity of new molecules that can act on bacteria is a major problem. New strategies for developing such molecules might be based on recent concepts in microbiology. Hyperstructures are large assemblies of molecules and macromolecules that perform functions such as DNA replication, RNA degradation and chemotaxis and the interactions between hyperstructures have been proposed to constitute an intermediate level of organisation in cells. Functioningdependent hyperstructures form in the presence of their substrate and dissociate in its absence. An entirely new therapy for bacterial diseases might therefore be devised based on the manipulation of hyperstructures. One way to do this would be to supply cells with hybrid metabolites or hybolites made by a pairwise, covalently linked combination of the thousands of small molecules involved in metabolism. Some of these hybolites would be substrates for two, very different, hyperstructures and might do much more than simply inhibit key enzymes and processes within the hyperstructures: they might provoke the assembly of two hyperstructures in the same space or lead to hyperstructures emitting misleading signals. It is conceivable that hybolites might even convert a pathogenic Mr Hyde into an inoffensive Dr Jekyll. The article also discusses the major patent applications of hyperstructures in bacteria.

Legionella are aerobic, gram-negative, motile, rod-shaped bacteria, which form a distinct taxonomic unit within the γ - 2 subdivision of the Proteobacteria. The reservoirs of Legionella are natural or man-made water systems where the bacteria survive and disseminate as obligate intracellular parasites of free living protozoa. In the human lung, the bacteria invade alveolar macrophages inducing the potentially lethal pneumonia commonly known as Legionnaires' disease. Although all Legionella species are considered potentially pathogenic for humans, Legionella pneumophila is the aetiological agent responsible for most reported cases of community- and nosocomially-acquired legionellosis. The Opolysaccharide in the lipopolysaccharide of L. pneumophila is composed of a repeating homopolymer of α-(2→4)-linked 5,7-diamino-3,5,7,9-tetradeoxy-D-glycero-D-galacto-non-2-ulosonic acid (legionaminic acid). The outer region of the core enriched with 6-deoxy sugars and N- and O- acetylated sugars as well as the highly N- and O-acylated O-chain contribute to a high hydrophobicity of the bacterial surface, which enables these bacteria to spread. Lipids A from Legionella contain a backbone with 2,3-diamino-2,3-dideoxy-D-glucose and unusual fatty acids. The present article indicates some patents useful in the diagnostics of Legionnaires' disease.

Extracellular adenosine 5'-triphosphate (eATP) is an important mediator of cell-to-cell interactions in the nervous, vascular and immune system. Its low release by different cells, as mast cells, platelets, red blood cells, T cells and also by nerve terminals, requires different mechanisms and especially occurs in physiologic conditions. However, in pathologic conditions, as inflammation, eATP can highly increase, following its release by damaged cells. Elevated levels of eATP provoke the activation of some purinergic receptors, mainly the P2XR, which are located on mononuclear phagocytes, T cells and endothelial cells. The activation by eATP of inflammatory/immune cells leads to their release of some inflammatory mediators, such as the cytokines IL-1β and TNFα. These cytokines are able to further activate other cells, as endothelial cells, favouring their increased expression of adhesion molecules; such process enhances circulating cell recruitment to the inflamed tissue. The blockade of the purinergic-mediated activation of the inflammatory/immune cells might represent a useful tool to reduce the spreading of the inflammatory/immune response. This review will summarize the beneficial effects of the use of periodate oxidized ATP (oATP), an inhibitor of P2XR, in the treatment of some experimental models of inflammatory/immune diseases. The article is a short review of recent patents related to the anti-inflammatory/analgesic/antiangiogenic effects of oATP and to its role in the autoimmune diseases.

Current TB drug development is beset with many problems. There is a perceived lack of commercial return on investment, as the vast majority of TB patients come from impoverished areas of the world. Clinical trials for new TB drugs are complex, protracted and very expensive. Therefore, the development of new anti-tuberculosis drugs requires simultaneous forward planning of the design of the trials that will be required for licensing purposes. In this article we briefly review the current state of new TB drug development and discuss issues related to intellectual property (IP), with a special emphasis on how IP can facilitate rather than hinder the development of better TB drugs. We also list and discuss the major patent applications that underpin TB drugs that have entered prominent clinical trials and additional applications that were filed over the last five years for drugs resulting from basic upstream research.

Staphylococcus pasteuri is a coagulase-negative, Gram positive organism which is emerging as an agent of nosocomial infections and a blood derivatives contaminant, though its role in causing human disease mostly remains controversial. Despite the paucity of isolates recovered, this bacterium has recently appeared to express resistance against several classes of antibiotic compounds, such as methicillin/oxacillin, macrolides, lincosamides, streptogramins, tetracyclines, chloramphenicol, streptomycin, fosfomycin, as well as quaternary ammonium compounds. Also, authors will discuss some essential patents related to the topic reviewed.

Orthodox medicine has been very active in the field of topical anti-infective agents and current chemotherapy has procured valid antibiotics, antivirals, vaccines, antibodies, and antiparasitic drugs to be parenterally and/or topically used. However, these drugs may cause side effects and sometimes provide unsatisfactory results because pathogens become drug-resistant. Another drawback is represented by their cost, which compromise their use or their availability in poor Countries. Therefore, there is a critical need for new strategies to treat dermatological affections. The old intuition for using ozone in the treatment of necrotic wounds, especially if due to anaerobic bacteria, is now justified by the studies about reactive oxygen species generation by granulocytes and macrophages as the first line of defense during an infection. As a consequence, the disinfectant value of ozone has been increasingly appreciated during the last fifteen years. This review summarizes the patents filed and issued, with particular emphasis to the more recent patents, about the antiinfective topical use of ozone: i) in the gaseous form; ii) after gaseous ozone saturation of aqueous, not-oily pharmaceutical vehicles and solvents; iii) where gaseous ozone chemically reacts with unsaturated substrates leading to therapeutically active ozonated derivatives. We hope that recent advances and a better understanding of the ozone chemistry and biology will be able to create the mental attitude to prove the validity of large-scale therapeutic use of both ozone and ozone derivatives as topical anti-infective agents by performing multicenter, randomized clinical studies, as aptly requested by orthodox medicine.

Descending Necrotizing Mediastinitis is a rare complication that can be secondary to dental infections or surgical procedures involving the oral region. Despite a prompt pharmacological therapy and surgical intervention, a delayed diagnosis is still responsible for a too high mortality rate (about 40%). We present a review of the current literature on Descending Necrotizing Mediastinitis, focusing on the evolution of its management from Pearse to today. In particular, recent patents focused on novel compositions and methods to prevent and treat oral infections.

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