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Contents

Editorial Pp. 1

Unique Applications of Novel Antifungal Drug Combinations Pp. 3-15
Chiatogu Onyewu and Joseph Heitman
[Abstract] [Full text article]

Recent Synthesis of Marine Natural Products with Antibacterial Activities Pp. 17-48
Ines Mancini, Andrea Defant and Graziano Guella
[Abstract] [Full text article]

Activities of Quinolones Against Obligately Anaerobic Bacteria Pp. 49-56
R. Schaumann and A.C. Rodloff
[Abstract] [Full text article]

Mechanism of Action and Potential for Use of Tea Catechin as an Anti-infective Agent Pp. 57-62
Tadakatsu Shimamura, Wei-Hua Zhao and Zhi-Qing Hu
[Abstract] [Full text article]

The First Years of Linezolid Experience in Clinical Practice: A Balance and Future Implications Pp. 63-70
Roberto Manfredi and Leonardo Calza
[Abstract] [Full text article]

Extended-Spectrum Cephalosporinases in Enterobacteriaceae Pp. 71-82
Hedi Mammeri and Patrice Nordmann
[Abstract] [Full text article]

Abstracts

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Editorial

We first would like to thank our new Advisory Board Members for their efforts in supporting the review of manuscripts. This aspect is much appreciated.

The field of research on anti-infective agents and new targets has shown strong progress on many fronts targeted towards antibacterial, antifungal and antiviral agents. Most notably are the advances in the discovery and clinical development of inhibitors of hepatitis C virus. NS5B polymerase inhibitors in the nucleoside and non-nucleoside classes, such as NM283, R1626 and HCV-796 have continued to advance to Phase II clinical trials. The HCV NS3-4A serine protease as an attractive target led to inhibitors such as VX-950 and SCH-503034 for clinical development. Immunomodulators such as Albuferon, Locteron, CPG10101 and ANA-975 are the likely a components of the combination region, with the latter two being Toll-like receptor (TLR) agonists.

An interesting trend for the discovery of new antibacterial agents continues to be based on genomics and bioinformatics approaches. A relatively large number of novel essential targets have been proposed. Genomic approaches, coupled with biochemical studies, are also useful in understanding modes of action of antibacterial agents.

Invasive fungal infections, particularly in immunocompromised patients, are limiting our arsenal of antifungal agents and remains a problem of unmet medical need. New agents are clearly needed to compliment current strategies and advances in this area.

Dr. Mark L. Nelson served as a Guest Editor on “Chemical Evolution of Natural Products Antibiotics,” Vol. 5, Number 3. This journal issue covered three invited reviews that addressed the growing area of antibiotics evolution. We express our thanks to all contributions in this issue.

Twenty-six excellent review articles were published in four issues of Volume 5. These reviews span all three major areas of anti-infectives research: antivirals, antibacterials and antifungals. The emphasis of the journal is on the medicinal chemistry aspect of anti-infectives and promising agents. We encourage submission of reviews on comparative structure activity relationship analyses, technologies in inhibiting certain targets, mechanistic studies, synthesis and biological properties of new agents and validation of new targets of potential therapeutic intervention, as well as pharmacokinetic/pharmacodynamic relationships.

Contributors to Volume 5, Number 1: I.E.J.A. Francois, B.P.A. Cammue, M. Borgers, J. Ausma, G.D. Dispersyn, K. Thevissen, J. Fotie, D.S. Bohle, A.M. Carmona-Ribeiro, D.B. Vieira, N. Lincopan, J.N. Ablin, P. Cravo, R. Culleton, A. Afonso, I.D. Ferreira, V.E. do Rosario, Sk. Md. F. Akbar, H. Murakami, N. Horiike, M. Onji, R. Dolcetti, D. Di Luca, A.R. de Lera, A.A. Joshi and C.L. Viswanathan.

Volume 5, Number 2: S.M. Jachak, R. Jain, S. Batra, Z. Tusi , S. Madapa, A.J. Kesel, P.M.M. Guedes, J.L.R. Fietto, M. Lana, M.T. Bahia, T. Rezanka, M. Sobotka, J. Spizek and K. Sigler.

Volume 5, Number 3: J. Grunewald, C. Mahlert, F. Kopp, M.A. Marahiel, S.T.D. Hsu, E. Breukink, R. Kaptein, J. Li, C.W.T. Chang, A. Igoudjil, K. Begriche, D. Pessayre, B. Fromenty, A.S. Galabov, A. Angelova, F.M.E. Wagenlehner and K.G. Naber.

Volume 5, Number 4: J. Liu, H.P. Ren, L.M. Schang, J. Fotie, J. Yuan, T. Lim, Z. Liu, D. Qiu, B. Wong, H. Luo, X.S.B. McManus, D. Yang, C.S. Coffin, S.S. Lee, D. Kerboeuf, M. Riou, J.S. Hamdan and R.C. Hahn.

The list to credit for all these achievements is long. We thank the referees for their time and effort in reviewing the articles. The hard working and enthusiastic team of the journal, particularly Ms. Afshan Siddiq, is greatly acknowledged. We also thank Ms. Michele Markey of Wyeth Research for her support.

Tarek S. Mansour and Phaik-Eng Sum
Co-Editors in Chief
Anti-Infective Agents in Medicinal Chemistry

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Unique Applications of Novel Antifungal Drug Combinations
Chiatogu Onyewu and Joseph Heitman

[Full text article]

Candida albicans is a commensal fungal organism that can over-proliferate and cause disease in the appropriate host setting. C. albicans can cause irritating superficial skin and mucocutaneous infections such as diaper rash and vaginal yeast infections, respectively. In immunocompromised hosts, these infections can progress to disseminated disease in which the organism enters the blood and colonizes multiple organs. Consequently, Candida infections result in a considerable amount of morbidity and mortality every year. Most modern-day antifungal drugs block ergosterol biosynthesis. Several of these agents are fungistatic and do not kill the fungal cell, thus facilitating the emergence of drug-resistant species, which further complicate therapy. Alternatively, some of the most effective antifungal drugs are too toxic for continuous use or can only be administered intravenously. The ideal antifungal drug would be non-toxic, fungicidal, and amenable to self-administration. Previous studies have demonstrated that specific commercially available drugs from two unrelated drug classes (calcineurin inhibitors and ergosterol biosynthesis inhibitors) act synergistically to kill Candida by targeting distinct molecular pathways in the organism. Calcineurin inhibitors are immunosuppressive agents, so systemic administration of these drugs would be counter-intuitive for treatment of already immunocompromised individuals. However, this drug combination can be applied to topical antifungal therapies for a variety of cutaneous and mucocutaneous fungal infections that afflict a diverse population, including immunocompromised patients.

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Recent Synthesis of Marine Natural Products with Antibacterial Activities
Ines Mancini, Andrea Defant and Graziano Guella

[Full text article]

The emergence of multiple-drug-resistant strains of bacteria, the indiscriminate use of antibiotics and the increasing susceptibility of individuals with acquired immunodeficiency syndrome (AIDS) to infection from Mycobacterium induce an urgent need for development of new strategies to treat bacterial infections. Many natural products from marine sources are endowed with promising antibacterial activities, thus representing invaluable leads in the plans for antibiotic drug discovery. In this context, organic synthesis plays a decisive role in confirming (or revising) the chemical structures of the natural compounds allowing also access to suitable amounts of the target (and its analogs) for structure-activity relationship (SAR) investigations. In this overview, we focus on the total and partial synthesis of antibacterial marine metabolites and their related compounds published since 2000, discussing the retrosynthetic analysis of the strategies adopted. It includes the total synthesis of pestalone, squalamine, abyssomicin C and litosterol, the revised structure by total synthesis for the antituberculosis pseudopteroxazole and agelasine C, the preparation of the core-structure of zamamistatin and access to momeric and dimeric congeners of active peptide halocidin. Review with 132 references.

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Activities of Quinolones Against Obligately Anaerobic Bacteria
R. Schaumann and A.C. Rodloff

[Full text article]

Quinolones are of clinical and scientific interest since their discovery based on the nalidixic acid in the early 1960s. They are based on two types of ring structures, the quinolone nucleus and the naphthyridone nucleus. Nalidixic acid as the first discovered agent is a naphthyridone and has only a moderate activity against Gram-negative rods. The modification of the quinolone and naphthyridone structures resulted in increasing activities of the quinolones against Gram-negative, Gram-positive, atypical and obligately anaerobic bacteria and mycobacteria. The quinolones are now divided into four groups due to their different spectrum of activity. The first and second group of quinolones i.e. norfloxacin, ciprofloxacin or ofloxacin have no or only little activity against obligately anaerobic bacteria. In contrast, the newer quinolones like sitafloxacin, clinafloxacin, trovafloxacin, moxifloxacin, gatifloxacin, garenoxacin and others like i.e. WCK 771 and ATB-492 have significant improved activities against anaerobes. Thus, these quinolones have been considered for the treatment of anaerobe and mixed infections. The present review provides an overview of the activities of quinolones against obligately anaerobic bacteria as described by in vitro as well as in vivo studies.

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Mechanism of Action and Potential for Use of Tea Catechin as an Anti-infective Agent
Tadakatsu Shimamura, Wei-Hua Zhao and Zhi-Qing Hu

[Full text article]

“Drinking several cups of green tea a day keeps the doctor away” is clearly an overstatement. However, extensive research has revealed that the predominant catechin from tea (Camellia sinensis), epigallocatechin gallate (EGCg), has significant medicinal and health-promoting properties. This review summarizes what is presently known about the antimicrobial properties of EGCg, with a particular focus on the synergistic relationship between EGCg and β-lactams in the inhibition of methicillin-resistant Staphylococcus aureus (MRSA). The mechanisms of action and prospects for use of tea catechins such as EGCg as an anti-infective agent are discussed.

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The First Years of Linezolid Experience in Clinical Practice: A Balance and Future Implications
Roberto Manfredi and Leonardo Calza

[Full text article]

Multi-antibiotic resistant Gram-positive cocci, which include Staphylococcus aureus, the coagulase-negative staphylococcal group, Enterococcus faecalis and Enterococcus faecium, and other streptococci, represent emerging pathogens especially in the setting of the immunocompromised, hospitalized patients, in particular when surgery, invasive procedures, or prosthetic implants are of concern, patients are admitted in intensive care units, or underlying chronic disorders and immunodeficiency are to be considered, and broad-spectrum antibiotics or immunosuppressive drugs are needed for prolonged administration. During the recent years, the phenomenon of multi-resistant Gram-positive cocci is spreading from the Hospital into the community, where the retrieval of such microorganism is progressively increasing. The spectrum of available antimicrobial compounds for an effective management of these relevant infections is significantly impaired in selection and clinical efficacy by the emerging and spread of methicillin-resistant and more recently glycopep-tide-resistant Gram-positive microbial strains. The first oxazolidinone derivative linezolid, together with the recently licensed quinupristin-dalfopristin, daptomycin and tigecycline, followed by a number of glycopeptides, fluoroquinolones, and other experimental compounds on the pipeline or approaching the market in the year 2006, represent an effective response to the great majority of these concerns. Because of their innovative mechanisms of action, their maintained or enhanced activity against multiresistant pathogens, their effective pharmacokinetic-pharmacodynamic properties, their frequent possibility of synergistic activity with other compounds effective against Gram-positive pathogens, and a diffuse potential for a safe and easy administration, also when compromised patients are of concern. The main problems related to the epidemiological and clinical features of multiresistant Gram-positive infection, the potential clinical indications of all recently available compounds compared with the standard of care of treatment of resistant Gram-positive infections, and updated data on efficacy and tolerability of linezolid as the golden standard compound for vancomycin-resistant Gram-positive cocci in multiple clinical situations, are outlined and updated on the ground of an extensive review of all the available. Recent evidences are commented from the international literature.

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Extended-Spectrum Cephalosporinases in Enterobacteriaceae
Hedi Mammeri and Patrice Nordmann

[Full text article]

Extended-spectrum AmpC β-lactamases are derived from chromosomal cephalosporinases by amino acid deletion, insertion and replacement. These structural changes are responsible for an increased catalytic efficiency against extended-spectrum cephalosporins, such as ceftazidime, cefotaxime, cefepime, and cefpirome. An overview of the molecular and biochemical characterization of these identified β-lactamases in Enterobacteriaceae is provided. The structural modifications that account for the broadening substrate specificity and the phenotypes of resistance of the clinical isolates are detailed.