Abstracts


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Small molecule approaches toward the non-microbicidal modulation of bacterial biofilm growth and maintenance
Richards J.J., Melander C.

Bacterial biofilms are defined as a surface attached community of microorganisms that are protected by an extracellular matrix of biomolecules. Within a biofilm state, bacteria are more resistant to antibiotics and are inherently insensitive to antiseptics and basic host immune responses. The NIH has estimated that 65-80% of all microbial infections are biofilm-based. Biofilm infections of indwelling medical devices are also of major concern, as once the device is colonized, infection is virtually impossible to eradicate. Bacterial biofilms underlie the persistent colonization of hospital facilities, which perpetuates nosocomial infections. Hospital-acquired infections place a $10 billion burden on the U.S. healthcare system annually. Given the prominence of biofilms in infectious diseases, there has been an increasing effort toward the development of small molecules that will modulate bacterial biofilm development and maintenance. This, coupled with the spread of multi-drug antibiotic resistance across many of these bacteria, has put a tremendous burden on the scientific and medical community to alleviate biofilm-related problems. In this review, we will highlight the development of small molecules that inhibit and/or disperse bacterial biofilms through non-microbicidal mechanisms. The review will be segmented into providing a general overview of how bacteria develop into biofilm communities, why they are important, and the difficulties associated with their control. This will be followed by a discussion of the numerous approaches that have been applied to the discovery of lead small molecules that mediate biofilm development. These approaches are grouped into: 1) discovery/synthesis of molecules based upon naturally occurring bacterial signaling molecules, 2) chemical library screening, and 3) discovery/synthesis of natural product and natural product analogues. Â^© 2009 Bentham Science Publishers Ltd.


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From vancomycin to oritavancin: The discovery and development of a novel lipoglycopeptide antibiotic
Allen N.E.

The introduction of penicillin in the 1940s, erythromycin in the 1950s and methicillin in the 1960s was quickly followed in each case by appearance of resistance to these antibiotics. By comparison, glycopeptide resistance required nearly thirty years to appear following clinical introduction of vancomycin. The reason for the delay is likely related to the clever mechanism of action of glycopeptide antibiotics. These antibiotics interfere with biosynthesis of the bacterial cell wall by binding to a critical cell wall intermediate. High level resistance required a collection of genes to reorder cell wall biosynthesis enabling bacteria to bypass the critical steps susceptible to inhibition by vancomycin and other glycopeptide antibiotics. There have been various efforts, with mixed success, to identify novel glycopeptide structures able to circumvent high level glycopeptide resistance. This review focuses on the discovery and development of oritavancin, a lipoglycopeptide antibiotic having exquisite activity against staphylococci and other gram-positive bacteria including MRSA and those resistant to high concentrations of vancomycin. The oritavancin story includes a combination of natural products screening, medicinal chemistry-directed modification, and extensive microbiological, biochemical, pharmacological, and clinical evaluation. The story behind this agent also reveals the pharmaceutical business and regulatory challenges that can have a major impact on development of new antibiotics and obtaining regulatory approval for clinical useage. Â^© 2010 Bentham Science Publishers Ltd.


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Antiprotozoal agents: An overview
Graebin C.S., Uchoa F.D., Bernardes L.S.C., Campo V.L., Carvalho I., Eifler-Lima V.L.

The therapy of parasitic diseases has relied, until recently, on the use of a very limited number of drugs, most of them of low efficacy, leading to side effects and in certain cases with high toxicity. This review focuses on the chemotherapy to treat diseases caused by Trypanosoma cruzi (Chagas' disease), Trypanosoma b. gambiense and Trypanosoma b. rhodesiense (sleeping sickness), Plasmodium (malaria) and Leishmania (leishmaniasis). Therefore, we will summarize drugs currently available and future specific chemotherapy against these neglected diseases under clinical evaluation. The most advanced antichagasic candidates are represented by posaconazole, TAK-187 and albaconazole, which have completed their pre-clinical development as anti-T. cruzi agents, while new quinines concerning to ferroquine, tafenoquine and AQ-13 are in phase I or II of clinical trials as promising candidates for the treatment of malaria. Although parafuramidine has been under phase III clinical trials to treat Human African Trypanosomiasis (HAT), its development was discontinued due to liver problems. Finally, new approaches for the treatment of leishmaniasis were achieved by using miltefosine and, more recently, the aminoglycoside paromomycin, which was approved after clinical trials and, owing to its milder adverse effects and low cost, is being considered as a potential first-choice treatment for the disease. Thus, this review aims to highlight the available drugs to treat four endemic parasitic diseases, as well as promising therapeutic approaches and their corresponding targets under development, but it is not intended to be an exhaustive survey on the subject. Â^© 2009 Bentham Science Publishers Ltd.


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Current understanding of polymyxin B applications in bacteraemia/sepsis therapy prevention: Clinical, pharmaceutical, structural and mechanistic aspects
Garidel P., Brandenburg K.

Polymyxin B (PMB) belongs to a class of antibiotics discovered more than six decades ago. PMB was used for various bacterial infection threatening, in particular to sepsis. Its use, however, was abandoned because of the observation of severe side effects. In the last years this view changed due to the appearance of multi-drug resistant Gram-negative pathogens, which were resistant to most available antibiotics, leading to a re-evaluation of the polymyxin antibiotics (PMB and PME). Although there is a large market potential for the development of drugs to fight sepsis, the available successful clinical strategies are very limited. The cause for this lies in the clinical failures of a number of drug candidates, which were tested in the last years. This was attributed to some extent to our elementary understanding of the pathophysiology of sepsis, to not optimally designed clinical trials and a lack of appropriate pre-clinical models to establish the proof of concept (POC). At that time there were just humble knowledge about the structural mechanisms involved in the advantageous aspects of PMB-endotoxin interactions to increase the knowledges outcome in sepsis therapy. Therefore, the current paper describes the clinical aspects of PMB application in bacteraemia and sepsis therapy. However, the focus of the presented paper lies in the structural and mechanistic aspects of PMB-endotoxin (LPS: lipopolysaccharide) recognition and how this knowledge can be applied for the development or improvement of new clinical drug candidates to support sepsis therapies. Due to chemical similarities between PME and PMB, certain aspects of the use of PME as an antimicrobial agent and in sepsis therapy are considered and compared to PMB. Â^© 2009 Bentham Science Publishers Ltd.


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The use of structure-guided design to discover new anti-microbial agents: Focus on antibacterial resistance
Charifson P.S., Grossman T.H., Mueller P.

Serious attempts to address antibiotic resistance, a worldwide public health concern, have recently become more intensive. In hospital settings, resistance to antibacterial agents has been recognized by clinicians for several decades. Resistant strains are now isolated on a daily basis from patients with community-acquired infections further elevating the level of concern among public health officials. The pharmaceutical industry has generally focused its attentions on chronic therapeutic indications in recent years (e.g. cardiovascular and metabolic diseases), but will likely be forced to re-engage in antibacterial discovery efforts as therapeutic options diminish for the treatment of infections caused by multi-drug resistant pathogens. The ability to squeeze additional utility out of known classes of antibacterial agents has become limited and antibacterial discovery scientists will need to focus on new approaches and targets. These new approaches will need to include strategies that explicitly address resistance up front and simultaneously attempt to facilitate the slower development of resistance as new compound classes enter clinical use. One approach that can be a useful component of antibacterial discovery efforts and prospectively address resistance is structure-guided design (SGD). This review will describe several recent examples in which SGD was applied as part of a multidisciplinary effort to address antibacterial resistance. These include dihydrofolate reductase inhibitors, broad-spectrum β-lactamase inhibitors, novel oxazolidinones, aminoglycoside mimetics, peptide deformylase inhibitors, and inhibitors that simultaneously target DNA gyrase and topoisomerase IV. Â^© 2009 Bentham Science Publishers Ltd.


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Mutations associated with anthelmintic drug resistance
Beech R.N., Silvestre A.

A major concern for helminth parasite control in human and animal health is the development of anthelmintic resistance. The mutations that lead to such resistance do so in several ways including, loss of drug binding, modification of response once the drug has bound and loss of the drug target altogether. Benzimidazole resistance is best characterized by amino acid substitutions at three positions of the beta-tubulin protein: F167Y, E198A and F200Y, each of which causes loss of drug binding. Macrocyclic lactone resistance has been linked in the laboratory to mutations in different ligand-gated chloride-channel subunit genes, Hco-glc-5, Hco-lgc-37 and Con-avr-14 with substitutions A159V, K159R and L256F. These alter the channel response to drug binding, reducing its effects, which can also be seen in vivo. Levamisole resistance, including pyrantel and other related compounds, has been more difficult to characterize. More recently, loss of specific acetylcholine gated ion-channels that are targeted by the drug has been demonstrated with functional and molecular evidence. The loss of specific ion-channel targets of both the macrocyclic lactones and the new monepantel also seems to be a more general mechanism of anthelmintic resistance that requires further study. Praziquantel resistance is associated with SNPs in the subunit forming voltage-gated Ca2+ channels. By placing our knowledge of the characteristics of these mutations in a framework of their biochemistry, functional characteristics, population genetics and effects in vivo gives us a more comprehensive understanding of how these mutations behave. This in turn should ultimately help us to minimize their impact. Â^© 2010 Bentham Science Publishers Ltd.


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Activities of ceragenin CSA-13 against established biofilms in an in vitro model of catheter decolonization
Pollard J., Wright J., Feng Y., Geng D., Genberg C., Savage P.B.

Bacterial biofilms on medical devices are a primary source of infection, and efforts have been made to develop means of decontaminating colonized devices including hemodialysis catheter "lock" solutions. Because bacterial biofilms are inherently resistant to many antibiotics and widespread use of antibiotics contributes to resistance development, there is a need for new approaches to biofilm eradication. We have developed a class of compounds, termed ceragenins, that mimic the antimicrobial activities of antimicrobial peptides. The ceragenins are active against established biofilms. We tested solutions of a lead ceragenin, CSA-13, with and without EGTA against biofilms comprised of Gram-negative and positive organisms. Similar solutions containing ciprofloxacin were used as comparators. The ceragenin solutions eradicated biofilms at concentrations comparable to those required for eradication by ciprofloxacin. However, against a methicillin-resistant strain of Staphylococcus aureus, CSA-13 proved to be far superior to ciprofloxacin. Â^© 2009 Bentham Science Publishers Ltd.


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Antiviral sesqui-, Di- and sesterterpenes
Rezanka T., Siristova L., Sigler K.

Terpenoids, biosynthetically related ubiquitous compounds found in virtually all living organisms from marine invertebrates to blooming plants, are derived from the same precursor but their structures and biological and/or pharmacological activities are widely different. Our review concerns terpenoid compounds with antiviral activities, from the simplest sesquiterpenes to diterpenes and sesterterpenes. They include commercially produced therapeutics, compounds with documented antiviral effects and potential future medical use, as well as substances in different stages of clinical research and testing. All of them are based on natural compounds, with only partial man-made changes in the basic structure or mere substituent modifications. Â^© 2009 Bentham Science Publishers Ltd.


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Membrane drug transport in helminthes
Kerboeuf D., Riou M., Neveu C., Issouf M.

Helminths are responsible for numerous health problems in both animals and human around the world. In animals, they cause heavy losses in meat, milk and wool production. The only available mean for controlling the resulting diseases are currently treatments with anthelmintics. Unfortunately, many cases of drug resistance have emerged affecting most of the antiparasitic compounds. While attempts are made for finding new groups of drugs, efforts are also made for understanding the underlying mechanisms of drug resistance or reduced efficacy of anthelmintics. Among the mechanisms, the identification of alterations in drug transport, specifically in active transport due to protein transporters, has been the aim of several recent investigations. Mechanisms very similar to those responsible for failures in cancer therapy have been described. Many progresses in genomic analyses have been made, especially thanks to the model nematode Caenorhabditis elegans. A better knowledge of the role of these transporters in the efficacy of anthelmintics should conduct to the development of new strategies in antiparasitic therapy and the identification of effective and non-toxic inhibitors of the efflux pumps of helminths. Â^© 2010 Bentham Science Publishers Ltd.