Frontiers in Anti-Infective Drug Discovery

To date, vaccination is an active area of investigation for its application to a great variety of human diseases including infections and cancer. In particular, naked-DNA vaccination has arisen as effective strategy in the preventive medicine field with promising future prospects. The ability of plasmid DNA to activate the humoural and the cellular arms of the immune system against the encoded antigen have resulted in intensive study of new strategies aimed at increasing the DNA vaccine immunogenicity. Nevertheless, plasmid-based vaccines emerged as a safer and advantageous alternative with respect to viral vector vaccines. Recent advances in both the immunological and biotechnological research field made it possible to enhance significantly the DNA vaccine potency. Most of these approaches are based on both the discovery of novel delivery systems and the implementation of plasmid constructs, achieved through genetic engineering. In this review, we will describe some of the most relevant patents issued in the last ten years, supporting the progress made in naked-DNA vaccination against infectious diseases.

Microbial pathogens with resistance to conventional drugs are a problem of global proportions and in response, photodynamic antimicrobial chemotherapy (PACT) has been developed. PACT involves the delivery of a non-toxic photo-sensitiser (PS) to the site of a microbial infection, which is then taken up by the pathogen. Illumination of the PS by light at an appropriate wavelength can lead to inactivation of the pathogen through the production of highly reactive free radical species, which induce oxidative damage to microbial targets such as lipid, proteins and DNA. Here we briefly review light sources for PACT, the desirable electronic and physiochemical properties of PS, and the photochemical and photophysical steps underlying PS antimicrobial action. With reference to recent patents, we then illustrate uses of PACT agents, including: 5-aminolevulinic acid, phenothiazinium based compounds, psoralens and organorhodium complexes.

Infectious diseases have haunted the human population for thousands of years. Although many breakthroughs have been made in the discovery of various treatments and cures for these diseases, multiple complexities enable them to continue to cause illness, disease and death. Evolution, for example, brings about mutations that cause the emergence of new pathogenic species. In addition, resistant species may emerge due to selective pressure of existing powerful antibiotics. The imminent possibility of new pathogenic strains forming and eventually threatening the human population verifies the urgent need for new, innovative strategies in fighting these pathogens. Here we review various important patents that have been licensed for drug development pertaining to protease and kinase inhibitors. Rather than being comprehensive, we have been selective in which patents to include. The goal is to inform the public at large of these new inventions in the pipeline and the status of development of these technologies into drugs to ultimately be used in a clinical setting.

As our aged population increases, the unique spectrum of infections presented by this elderly population, particularly those residing in long term care facilities will challenge our ability to maintain an effective battery of antibiotics. The inability to clear drug from the body due to declining lung, kidney/bladder, gastrointestinal and circulatory efficiency can cause accumulation of standard antibiotic doses in the body. Accordingly, there is a heightened risk of reaching toxic drug levels as well as an increased chance of unfavorable interactions with other medications. On the other hand, we can predict problems that arise in treating elderly patients who may have a history of previous antibiotic treatment and exposure to resistant organisms from multiple hospitalizations. Furthermore, the elderly often acquire infections in tandem with other common disease states such as diabetes and heart disease. Thus, it is essential that optimized dosing strategies be designed specifically for this population using pharmacodynamic (PD) principles that take the unique circumstances of the elderly into account. Rational and effective dosing strategies based on pharmacodynamic breakpoints and detailed understanding of the pharmacokinetics of antibiotics in the elderly further the goal of achieving complete eradication of an infection in a timely manner. Specific PD information on isolates and drug susceptibility profiles as well as patient pharmacokinetic (PK) information along with a history of prior antibiotic treatment is imperative for the rational design of specific treatment for an infection in the elderly. Attention must be paid to the PK/PD of the chosen drug in order to ensure maximum bacterial eradication. In addition, this strategy also seeks to prevent the selection of drug resistant bacteria as well as the minimization of toxic effects in the elderly patient. For elderly patients, antibacterial agents with high tissue penetration, lack of interaction with many drugs commonly prescribed to the elderly and whose clearance is not affected by decline of kidney function, may be a preferred choice for the elderly population.

Severe acute respiratory syndrome (SARS) emerged in late 2002 and was controlled in July 2003 by public health measures. Its causative agent, SARS coronavirus (SARS-CoV) jumped from an animal reservoir to humans and has the potential to re-emerge. Since then, the world has seen another virus that emerged in 2009, the pandemic influenza A (H1N1)v virus. Following the sequencing of the genetic code of SARS-CoV and the deciphering of some of the functions of its proteins, including the cellular receptors and host proteins that participate in the life cycle of the virus, promising lead drugs and new uses of old drugs have been discovered. Engineered monoclonal antibodies have surmounted the hurdle of provoking antibody enhancement as well as providing broad coverage against various SARS-CoV strains and mutants to prevent viral escape. Protease inhibitors are favored small molecule inhibitors because of possible broad spectrum coverage as well as the ability to be formulated for oral use. RNAi-based therapeutics produced impressive in vitro data and is rapid to develop. Interferon and chloroquine are likely to be effective as nonspecific antivirals with a good safety profile. The development of SARS-CoV anti-infectives is ongoing and will undoubtedly strengthen the infrastructure and know-how in the field of antiviral drug discovery.

The microbiota that colonizes the gastrointestinal tract confers health benefits to the host by contributing to dietary digestion, regulating immunity and preventing pathogen colonization and invasion. Lactic acid bacteria (e.g. Lactobacillus) and Bifidobacterium constitute the main groups of probiotics commercialized for human consumption. The prevention and treatment of gastrointestinal infections continues to be complex due to the expansion of antibiotic resistances. The possible uses of probiotics and derived products as therapeutic or preventive drugs against gastrointestinal infections have been intensively investigated, as reflected in a large number of published patents. The possible mechanisms of action of probiotics against gastrointestinal pathogens addressed in diverse patent applications include: (i) modification of the environmental conditions, (ii) competition for nutrients and adhesion sites, (iii) production of antimicrobial compounds, (iv) modulation of the immune and nonimmune defense mechanisms of the host, and (v) regulation of the intestinal neuromuscular function. The molecules responsible for the antimicrobial effects of probiotics include cell-wall fractions, surface proteins, nucleic acids, organic and short-chain fatty acids, antimicrobial proteins and other less-well identified soluble factors. The effectiveness of probiotics is supported by human clinical trials on treatment of acute diarrhea, prevention of antibiotic associated-diarrhea and as adjuvant therapy with antibiotics in eradication of Helicobacter pylori infection. Probiotics and their bioactive compounds constitute attractive alternative or adjuvant drugs as they can reduce the use of antibiotics and improve conventional pharmacological therapies. The advances in the knowledge of novel bioactive molecules and the intricate host-microbe interactions within the intestine and extra-intestinal sites will result in the future development of a new generation probiotic-based products targeting a broader range of pathologies.

Helicobacter pylori infection is a widespread disease causing significant morbidity and mortality, including non-ulcer dyspepsia, peptic ulcer, lymphoma and cancer of the stomach. Moreover, different extra-digestive diseases have been related to such an infection, but only for idiopathic thrombocytopenic purpura and a specific form of iron deficiency anaemia there are reliable data. Several information are available on its pathogenetic mechanisms, as well as on therapeutic approaches. Different regimens have been suggested as first-line treatment, but therapy is still a challenge, no treatment achieving bacterial cure in all cases. New drugs and different treatment schedules have been proposed to cure such an infection. Several new antibiotics have been claimed in the last 5 years, and some of them showed a very powerful antibacterial activity in vitro, even against clarithromycin and metronidazole resistant strains. Among the new compounds, thienylthiazole derivatives, benzamide derivatives and pyloricidins should be regarded as very promising molecules. Novel interesting therapeutic approaches with the highest eradication rate are also described.

Active efflux is a wide-spread mechanism for bacterial resistance to antibiotics, which contributes to poor intrinsic susceptibility, cross-resistance to structurally diverse classes of drugs, or selection of other mechanisms of resistance. Thus, inhibition of efflux pumps appears to be (i) a promising strategy for restoring the activity of existing antibiotics, and (ii) a useful method to detect the presence of efflux determinants in clinical isolates. Structurally dissimilar classes of inhibitors have been patented in the last decade, some are analogues of antibiotic substrates [tetracyclines, quinolones or aminoglycosides] and others are new chemical entities [including substituted indoles, ureas, aromatic amides, piperidinecarboxylic acids, alkylamino- or alkoxyquinolines, peptidomimetics, and pyridopyrimidines]. Their spectrum of activity, in terms of companion antibiotics and bacteria, differ significantly. Narrow spectrum inhibitors are of prime interest as diagnostic tools, while broad spectrum inhibitors are expected for adjuvant therapies. Apart from (i) a peptidomimetic inhibitor of Mex pumps in Pseudomonas aeruginosa (MC-04,124), for which efficacy was evaluated in animal models, and (ii) a piperidinecarboxylic acid inhibitor of fluoroquinolone efflux in Gram-positive (VX-710), which was safely administered to humans, most of these products have only demonstrated their activity in vitro, so further investigations are needed to evaluate their clinical potential.

Tuberculosis (TB) is an important public health problem worldwilde due to AIDS epidemic, the advent of multidrug resistant strains (MDR) and the lack of new drugs in the market. This disease was responsible for almost 1.8 million deaths in 2007, according to WHO (World Health Organization), which declared tuberculosis a global health emergency in 1993. In spite of this problem, there is a lack of development of new TB drug. For example, it has been nearly 40 years since the introduction of a new class of compounds for the treatment of TB. Thus, there is an urgent need for new drugs to fight this disease. Considering that, this review aims to present promising drug candidates in final clinical studies against TB.

This paper reviews the inhibition of various enzymes by neuroleptics, anti-mycotics, antibiotics and other drugs on three species of human pathogenic amoebas, mainly Entamoeba histolytica, Acanthamoeba polyphaga and Naegleria fowleri, and their antiproliferative effects. A recent patent registered by Philip relates to the combination of an antibacterial formulation and antifungal agent for producing a therapeutically effective quantity of an antimicrobial that is suitable for suppressing or treating fungal growth. The rationale behind this patent focused on essential and valid targets with a description of the main pathogenic characteristics of these amoebas. The study of new targets, such as trypanothione and trypanothione reductase, and the drug effects of selected agents were arranged into six main groups: A) Inhibition of disulfide reducing enzymes by neuroleptics, antimycotics and antibiotics; B) Comparative evaluation of the efficacies of several drugs with antiproliferative activities; C) Inhibition of the enzymes for the synthesis of trypanothione, such as ornithine decarboxylase, spermidine synthase and trypanothione synthetase; D) Inhibition of the glycolytic enzyme PPidependent phosphofructokinase (PFK) from Entamoeba and Naegleria by pyrophosphate analogues, different from the host enzyme; E) Inhibition of enzymes secreted by these parasites to invade the human host, for example cysteine proteinases; and F) Inhibition of encystment pathways and cyst-wall assembly proteins.

Chemokines play key roles in inflammatory and immune responses mediated by their respective target cell populations. For instance, release of chemokines from inflammatory cells is a crucial step in the recruitment of cells needed to establish local inflammatory responses (e.g. rheumatoid arthritis). Moreover, recent advances in our understanding of the pathogenesis of human immunodeficiency virus (HIV) infection have revealed that chemokines and chemokine receptors are crucially involved in the molecular mechanism of HIV entry into target cells. Studies have shown that the chemokine receptor CCR5 serves as a critical coreceptor during the viral entry stage of HIV infection, while its ligands macrophage inflammatory protein (MIP)-1α and β and RANTES act as endogenous inhibitors of HIV infection. This makes chemokine/chemokine receptor systems an attractive potential target for the development highly specific drugs with which to improve in the management of HIV. In this review, I will discuss the latest developments in the research on chemokine/chemokine receptor systems, especially MIP-1 and CCR5, with a particular focus on their role in the mechanism of HIV infection and on the development of effective therapies against acquired immunodeficiency syndrome (AIDS).

Ras/Raf/MEK/ERK pathway is a critical downstream signal transduction cascade of most growth factor receptors and is pivotal in oncogenesis, tumor cell malignancy, viral infection, neuronal degeneration, and lymphocyte activation. A number of gain-of-function mutations of Raf genes have been detected in various cancer cells. Moreover, increased MEK/ERK activities were also found in various tumor tissues. Consequently, Raf/MEK/ERK pathway as an anticancer target has been intensively investigated. Numerous small-molecule Raf/MEK/ERK-inhibiting compounds have been reported in the literature and in patent applications. One of Raf inhibitors, the urea derivative Bay 43-9006 (Sorafenib), has recently been approved for treatment of kidney cancer and is under clinical trials for treatment of other cancers. Several Raf inhibitors or mutant B-Raf-selective inhibitors (RAF265 and PLX4032) were also in various stages of clinical trials for cancer treatment. Those inhibitors have also been evaluated preclinically for treatment of viral infection, neuronal degeneration, and inflammatory disease. Thus, small molecule inhibitors of Raf/MEK/ERK pathway may have broad applications in addition to cancer therapy.

Acinetobacter baumannii (AB) is a gram-negative organism that has emerged recently as a major cause of nosocomial infections, because of the extent of its antimicrobial resistance and its persistence in the hospital environment, where intensive care units are the place of greatest risk for acquiring AB.

There is no treatment of choice for AB and it's treatment is based on clinical experience and in vitro susceptibility testing. Also, nowadays Acinetobacter resistance to carbapenems is common and isolates resistant to colistin and polymyxin B have been reported.

Tigecycline, the 9-tert-butyl-glycylamido derivative of minocycline, exhibits a broad-spectrum of activity against numerous pathogens, including AB and several reports place it among the antimicrobials with lower MIC for AB. Tigecycline overcomes the two major mechanisms of resistance to tetracyclines (ribosomal protection and efflux), but tigecycline resistance emerging during therapy has been reported.

Tigecycline efficacy has been demonstrated in clinical studies in skin and skin structure infections and in complicated intra-abdominal infections but, although it seems a good alternative for the treatment of AB infections, there is little evidence about its use in these cases and more clinical experience and adequate trials are needed. The present review shows the recent patents related to treatment by tigecycline in different AB infections.

Cefepime is a semi-synthetic fourth generation cephalosporin with broader Gram-positive and excellent Gram-negative bacterial coverage. Its extended anti-microbial activity and infrequent tendency to develop resistance makes it popular for treatment of infections due to multi-drug resistant organisms. It has good efficacy against β-lactamase and ESBL (extended spectrum β- lactamase)-secreting pathogens, and it has shown great promise in the management of children with severe and nosocomial infections. It possesses superior bactericidal action compared to other cephalosporins and is a cheaper and safe alternative to the carbapenems. It is well-tolerated but needs dose adjustments in newborns, and in children with renal insufficiency. Cefepime is a valuable antibiotic but it should be used judiciously as unnecessary, improper and prolonged use may lead to emergence of cefepime-insensitive bacteria and risk of drop in the efficacy of cefepime. Various recent patents of cefepime have been launched which deal with improvements in its preparation, and with its combinations with β-lactamase inhibitors and newer antibiotics such as linezolid. These developments may further augment the usefulness of cefepime in pediatric infections.

A wide variety of organosulfur compounds that exhibit antibacterial properties are being patented. Functionally, organosulfur groups can act as metal chelators, powerful nucleophiles, or electrophiles depending on the local reaction environment. In this review of patent literature from 1999-2009, the reliance of these compounds on the reaction of the sulfur moiety with its biological target(s) will be discussed with regards to activity, specificity, and antimicrobial spectrum.

Despite alarming data showing the ever increasing number of bacteria becoming resistant to different classes of antibiotics through various mechanisms, the carbapenems remain a unique class of antibiotics that possess the broadest spectrum against Gram-positive, Gram-negative, aerobic and anaerobic organisms. However, bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, carry mechanisms that can inactivate the carbapenems. This article gives a review of the carbapenems that are currently in clinical use as well as discusses the new carbapenems that are in clinical trials. These new carbapenems show promising potential to overcome the resistance against the presently existing carbapenems. The present article shows the recent patents using carbapenems as an effective antibiotic.

Quinones are important naturally occurring pigments widely distributed in nature and are well known to demonstrate various physiological activities as antimicrobial and anticancer compounds. This review will focus on the preparation, therapeutic application, and administration of several benzoquinones, naphthoquinones, and anthraquinones having anti-infective, e.g. antiviral and antibacterial activities, in recent patents.

Chagas disease or American Trypanosomiasis, a parasitic infection typically spread by triatomine bugs, affects millions of people throughout Latin America. Current chemotherapy based on the nitroaromatic compounds, benznidazole and nifurtimox provides unsatisfactory results and suffers from considerable side effects and low efficacy. Therefore, there is an urgent need for new drugs to treat this neglected disease.

Over the last two decades, new advances and understanding in the biology and the biochemistry of Trypanosoma cruzi have allowed the identification of multiple targets for Chagas disease chemotherapy. This chapter summarizes antichagasic agents obtained based on i) target metabolic biochemical pathways or parasite specific enzymes, ii) natural products and its derivatives, iii) design and synthesis of lead compounds. Related patents filed and issued from 2000 to early 2009 are also discussed. Most of them claimed inhibitors on specific parasite targets such as cysteine proteinase, sterol biosynthesis, protein farnesyltransferase, etc. Particularly, those related with cysteine proteinase inhibitors were the most represented. Natural products also displayed many anti-T cruzi lead compounds. In addition, few patents claiming natural or synthetic compounds with antichagasic activity, disclosed no specific target. However, only a small proportion of all these patents displayed specific data of biological trypanocidal activity.

Influenza viruses are etiological agents of deadly flu that continue to pose global health threats, and have caused global pandemics that killed millions of people worldwide. The global crisis involving the avian H5N1 and more recently porcine H1N1 influenza both provide compelling reasons for accelerate fast track development of novel antiviral drugs against the potential pandemic virus. The availability of neuraminidase inhibitors such as oseltamivir (tamiflu) improves our ability to defend against influenza viruses, but the incidences of tamiflu-resistance are on the rapid rise. Nucleic acid-based antiviral drugs are promising classes of experimental antiviral drugs that have been shown in preclinical studies to be effective against seasonal and avian influenza viruses. The potency and versatility of these drugs make them potential candidates to be used in seasonal and pandemic influenza scenarios. Here we review recent patent activity in the development of nucleic acid based drugs directed at influenza. The review will assess the recent patents, research and development of antisense oligonucleotides, immunomodulating RNA and the most rapidly developing area, the exploitation of small interfering RNA for the prevention and treatment of influenza infection.