Current Drug Targets - Infectious Disorders, Volume 4, No. 4, 2004
Contents
New Aminoacyl-tRNA Synthetase Inhibitors as
Antibacterial Agents Pp.261-272
The Escalating Challenge of Vancomycin
Resistance in Staphylococcus aureus Pp.273-294
R.F. Pfeltz and B.J.
Wilkinson
Molecular Mechanisms of Fluoroquinolone
Resistance in Klebsiella Pp.
295-302
Yun-Liang Yang
Tsai-Ling Lauderdale and Hsiu-Jung Lo
Advances in Adjuvant Therapy Against Acute
Bacterial Meningitis Pp.
303-309
Virginia Pomar,
Sergi Martinez, Roger Paredes and Pere Domingo
IPC Synthase as a Useful Target for
Antifungal Drugs Pp. 311-322
Yuichi Sugimoto,
Hiroki Sakoh and Koji Yamada
New Acridone Inhibitors of Human Herpes Virus
Replication Pp. 323-330
K.F. Bastow
Recent Advances in Rhinovirus Therapeutics Pp. 331-337
Catherine H.
Charles, Michele Yelmene and Guang X. Luo
New Advances in HIV Entry Inhibitors
Development Pp. 339-355
Stefano Rusconi,
Andrea Scozzafava, Antonio Mastrolorenzo and Claudiu T. Supuran
Abstracts
[Back to top] New Aminoacyl-tRNA Synthetase Inhibitors as
Antibacterial Agents
J. Pohlmann and H.
Brotz-Oesterhelt
Increasing rates of bacterial resistance to known classes of antibiotics present a severe global challenge. As a consequence, the search for new chemical entities that address novel bacterial targets remains ongoing. Aminoacyl-tRNA synthetases (aa-RS) are essential enzymes for protein biosynthesis and emerged as an interesting target class in antibacterial research. These enzymes are present in all living organisms, and they are indispensable for the highly specific translation of the messenger-RNA (mRNA) template into protein via specific transfer-RNAs (tRNAs) as adapter molecules. When one aa-RS is inhibited, the corresponding tRNA is not charged and is therefore unavailable for translation. This leads to protein synthesis inhibition, which, in turn, causes cell growth arrest. Consequently, each compound that inhibits any of the aa-RS is a potential antibacterial agent. The clinical utility of this principle is proven by the natural product Ile-RS inhibitor pseudomonic acid, which is currently marketed as an antibacterial agent for topical application. Various chemical structures that inhibit aa-RS have been identified. These inhibitors have either been isolated from natural sources or have been generated synthetically. The synthetic inhibitors are modifications of natural inhibitors, derivatives of the natural synthetase substrates and reaction intermediates, or have been identified by screening of compound libraries. The recent progress achieved with these different classes of aa-RS inhibitors and their antibacterial potential in vitro and in vivo is discussed in this review.
[Back to top] The Escalating Challenge of Vancomycin
Resistance in Staphylococcus aureus
R.F. Pfeltz and B.J. Wilkinson
The glycopeptide antibiotic vancomycin is considered indispensable for the treatment of multidrug-resistant Staphylococcus aureus infections, and so the acquisition by these organisms of transmissible glycopeptide resistance elements from enterococci had been anticipated with apprehension. It was therefore a considerable surprise when vancomycin-intermediate S. aureus (VISA) clinical isolates were reported in 1997, with a novel, borderline-resistance phenotype acquired without genetic exchange. Clinical vancomycin-resistant S. aureus (VRSA) were not reported until 2002, expressing high level, transmissible resistance by virtue of vanA resistance determinants within enterococcal transposable elements residing on staphylococcal plasmids. This review will provide an update on the frustratingly variable characteristics of the VISA phenotype, focus on the progress made in understanding the molecular basis of the VISA resistance mechanism from the viewpoint of genetic regulation and cell wall stress response, and summarize the information currently available on VRSA. Finally, alternatives to vancomycin that are already available or nearing approval will be briefly reviewed, with attention to their limitations and potential for resistance development.
[Back to top] Molecular Mechanisms of Fluoroquinolone
Resistance in Klebsiella
Yun-Liang Yang
Tsai-Ling Lauderdale and Hsiu-Jung Lo
Klebsiella are well-recognized community and nosocomial pathogens responsible for septicemias, urinary tract infections, pneumonia, and soft tissue infections. The emergence of multi-drug resistant Klebsiella is becoming a global concern. Since fluoroquinolones are excellent antibiotics for clinical therapy of complicated infections, their consumptions have increased rapidly. Coincidental with the increased usage of fluoroquinolones, the incidences of drug resistance have increased, which highlights the need for understanding the molecular mechanisms of fluoroquinolone resistance. Alterations in targets and reduction of intracellular drug accumulation are two major mechanisms involved in fluoroquinolone resistance. This review focuses on the mechanisms of action of fluoroquinolones and molecular mechanisms of drug resistance, including known and proposed ones, and the discussion on clinical impact of multi-drug resistance in Klebsiella.
[Back to top] Advances in Adjuvant Therapy Against Acute
Bacterial Meningitis
Virginia Pomar, Sergi Martinez, Roger
Paredes and Pere Domingo
Death and co-morbidity derived from acute bacterial meningitis remain unacceptably high and are mainly related to immune-mediated cerebral dysfunction. Cerebral edema, hydrocephalus and ischaemic cerebrovascular events are severe complications that eventually occur following the activation of a complex network of cytokines, chemokines, proteases and oxidants released after cerebrospinal fluid infection. The caspase pathway appears to play a central role in the induction and amplification of the host inflammatory response. Such overactive immune reactions induce brain cell damage but, importantly, they may potentially be blocked. Several agents have been developed aiming to counteract the deleterious effects of such immune imbalance. These drugs are candidates to become adjuvant therapy against acute bacterial meningitis in the future, in addition to dexametasone. We review the current state-of-art of bacterial meningitis adjuvant therapy, including caspase inhibitors, antioxidants, poly (ADP-ribose) polymerase inhibitors, inhibitors of lipid peroxidation and metalloproteinase inhibitors.
[Back to
top]
IPC Synthase as a Useful Target for Antifungal Drugs
Yuichi Sugimoto, Hiroki Sakoh and Koji
Yamada
Inositol phosphorylceramide (IPC) synthase is a common and essential enzyme in fungi and plants, which catalyzes the transfer of phosphoinositol to the C-1 hydroxy of ceramide to produce IPC. This reaction is a key step in fungal sphingolipid biosynthesis, therefore the enzyme is a potential target for the development of nontoxic therapeutic antifungal agents. Natural products with a desired biological activity, aureobasidin A (AbA), khafrefungin, and galbonolide A, have been reported. AbA, a cyclic depsipeptide containing 8 amino acids and a hydroxyl acid, is a broad spectrum antifungal with strong activity against many pathogenic fungi such as Candida spp., Cryptococcus neoformans, and some Aspergillus spp. Khafrefungin, an aldonic acid ester with a C22 long alkyl chain, has antifungal activity against C. albicans, Cr. Neoformans, and Saccharomyces cerevisiae. Galbonolide A is a 14-membered macrolide with fungicidal activity against clinically important strains, and is especially potent against Cr. neoformans. These classes of natural products are potent and specific antifungal agents. We review current progress in the development of IPC synthase inhibitors with antifungal activities, and present structure-activity relationships (SAR), physicochemical and structural properties, and synthetic methodology for chemical modification.
[Back to top] New Acridone Inhibitors of Human Herpes
Virus Replication
K.F. Bastow
Modern biomedicinal research with acridones began with plant secondary metabolites but the successful development of these alkaloids into drugs has yet to be realized. However, there are synthetic acridones unrelated to the natural products now emerging as promising bioactive compounds. The purpose of this mini-review is to highlight the renewed interest in acridones for antiviral drug research, with the emphasis placed on several derivatives in early stage development for treating herpes virus infection.
Novel anti-herpes acridones developed using a ligand-based approach have much simpler structure and generally have higher selectivity than the corresponding alkaloids. Three sub-types are currently classified on the basis of activity against Herpes Simplex Virus (HSV) and, or Human Cytomegalovirus (HCMV) and all of them inhibit viral replication postadsorption. In terms of mode/mechanism of action, this "second wave" of early generation lead molecules appears unique in comparison to the natural products and to drugs derived from more traditional templates. Inhibition of HSV replication by these agents is best understood and it occurs after viral DNA synthesis. The mechanism for one prototype inhibitor (5- chloro-1,3-dihydroxy acridone), involves a blockade of viral DNA maturation (cleavage/packaging) and viral capsids accumulate abnormally. Interestingly, the 7-Chloro regioisomer blocks a later stage of viral assembly. At this time it is unclear whether atypical target-interaction or unusual polypharmacology is responsible for the antiviral activities observed and this key issue will hamper future drug development until it is resolved.
[Back to top] Recent Advances in Rhinovirus Therapeutics
Catherine H.
Charles, Michele Yelmene and Guang X. Luo
Human rhinoviruses are the major causative agents of the common cold. Because there are greater than 100 viral serotypes, little immunological protection is afforded to humans by prior rhinovirus exposure, which accounts for the high incidence of infection. In most cases, rhinovirus leads to a short self-limiting illness. However, for asthmatics, the elderly and immunocompromised patients, rhinovirus infection can lead to life-threatening complications. This has spurred a consistent effort over recent decades to identify effective treatments and preventions for rhinovirus infection. While some work has focused on alleviating the symptoms induced as a result of inflammatory pathways stimulated by rhinoviruses, the majority of the research has been focused on limiting or preventing viral infection altogether. Various approaches have been taken to halt rhinovirus infection. Prevention of virus-cell interaction has been the aim of research on viral capsid binders and cell receptor blockers. Interference with correct viral protein processing is the goal of the design and testing of protease inhibitors. Current work is attempting to interfere with viral RNA replication by testing silencing RNA molecules. In this review, we will discuss recent advances in the development and testing of human rhinovirus therapeutics.
[Back to top] New Advances in HIV Entry Inhibitors
Development
Stefano Rusconi, Andrea Scozzafava, Antonio Mastrolorenzo and Claudiu T. Supuran
Considerable advances have been made in the last years in the design of derivatives acting as inhibitors of HIV entry and fusion. The discovery of chemokines focused the attention on cellular coreceptors used by the virus for entering within cells, and consequently the various steps of such processes have been characterized in detail. Intense research led to a wide range of effective compounds that are able to inhibit the initial steps of HIV life cycle. All steps in the process of HIV entry into the cell may be targeted by specific compounds that may be developed as novel types of antiretrovirals. Thus, several inhibitors of the gp120 – CD4 interaction have been detected so far (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine receptor antagonists acting as HIV entry inhibitors also were described in the last period, which interact both with the CXCR4 coreceptor (such as AMD3100; AMD3465; ALX40-4C; T22, T134 and T140), or which are antagonist of the CCR5 coreceptor (TAK-100%, TAK-220, SCH-C, SCH-D, E913, AK-602, UK- 427857 and NSC 651016 in clinical trials), together with new types of fusion inhibitors possessing the same mechanism of action as enfuvirtide (such as T1249). Recently, a third family of antivirals started to be used clinically (in addition to the reverse transcriptase and protease inhibitors), with the advent of enfuvirtide (T20), the first fusion inhibitor to be approved as an anti-HIV agent. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, offering thus the rationale for their combination in therapies for HIV-infected individuals. Many HIV entry and fusion inhibitors are currently being investigated in controlled clinical trials, and a number of them is bioavailable as oral formulations. This is an essential feature for an extended use of these compounds with the purpose of ameliorating adherence of patients to these medications and preventing the development of drug resistance.