Current Medicinal Chemistry - Anti-Infective Agents, Vol. 1, No. 1, 2002

Since the discovery of thienamycin (1) in 1976, many studies on the synthesis and structure-activity relationships of parenteral-use drugs have been done and several carbapenems, imipenem (2), panipenem (3), and meropenem (7), have been marketed.

The development of oral carbapenems, however, is a fairly slow process because carbapenems are considered unstable in the stomach and intestine. Recently, several orally active carbapenems without stability problems have been developed as prodrug esters or prodrug peptides, including GV-118819 (12), CS-834 (13), L-084 (14), DZ-2640 (15), and peptidic derivatives of CL 191,121 (16). The active forms (35), (41), (44), (45), (16) of these prodrugs exhibited potent and well balanced antibacterial activities as well as resistance to renal dehydropeptidase-I. The pharmacokinetic parameters of compounds (12), (13), (14), and (15) after oral administration to healthy volunteers were reported. The half-life (t_1/2) of GV-118819 (12) was longer than that of the other compounds, while the Cmax, AUC and urinary excretion rate of L-084 (14) were higher than those of the others.

In this review, the synthesis, chemical and biological properties, and pharmacokinetics of these oral carbapenems are described.

[Back to top] Discovery and Development of Ketolides as a New Generation of Macrolide Antimicrobial Agents

Zhenkun Ma and Peter A. Nemoto

[Full text article]

The rapid development of antibiotic resistance among the major respiratory pathogens has created a serious problem for the effective management of respiratory tract infections. There is a great medical need for new antibiotics which address the problem of antibiotic resistance. Under these circumstances, several novel series of macrolides with a common C-3 ketone group were recently introduced. The information in this area has grown rapidly during the past several years, that has allowed us to deduce some important conclusions regarding structure-activity relationships. The C-3 cladinose sugar attached to the 14-membered ring macrolides is believed to be responsible for the inducibility of macrolide resistance. This moiety also appears to be responsible for efflux resistance. Removing the cladinose and introducing a ketone group at the C-3 position can effectively prevent induction of resistance. This modification can also improve activity against efflux resistance. However, introduction of the C-3 ketone group cannot independently address the resistance problems caused by methylation of ribosome (MLS_B resistance). In order to overcome such resistance, an anchor group must be properly attached to the macrolide skeleton. This anchor group can be introduced at several positions of the macrolide ring. Two successful examples are the 6-O-substituted ketolide ABT-773 and the 11,12-carbamate ketolide telithromycin. Both compounds are currently under clinical development for the treatment of respiratory tract infections.

[Back to top] Modulation of Antibiotic Efflux in Bacteria

Mark L. Nelson

[Full text article]

Bacteria develop resistance to antibiotics by receptor alteration, antibiotic modification and by drug efflux, whereby the antibiotic is removed from intracellular compartments by efflux proteins. This article gives an overview of the chemical and biological properties of the major efflux proteins found within resurgent pathogens, their activity in creating resistance, and the effect of inhibitors of these proteins. The major families of efflux protein inhibitors against bacteria include tetracyclines, indanes, ginsensosides, indoles, reserpine and reserpine analogues, dipeptides, peptidomimetic heterocycles and heterocycles, flavones, and benastatins. Their effect on both Gram-positive and Gram-negative bacteria efflux proteins and bacterial growth is detailed.

[Back to top] Delivery of Anti-Viral Nucleoside Analogues to the Central Nervous System

Tetsuya Hasegawa and Takeo Kawaguchi

[Full text article]

Delivery of anti-viral agents into the central nervous system (CNS) is clinically important. Direct brain infection by viral pathogens including herpes (HSV-I and II, VZV, and CMV) and AIDS virus (HIV-I and II) causes a progressive deterioration in mental function, and even death. Nucleoside analogues are a major source of clinically used anti-viral agents, although their delivery to the brain is severely limited by the presence of the blood-brain barrier and blood-cerebrospinal fluid barrier. Therefore, improvement of the delivery of these nucleoside analogues to the CNS has been investigated under various mechanisms, including metabolizing enzymes, endogenous cellular transport systems, conjugates, chemical delivery systems, and prodrugs.

In this review, we will summarize the following topics: 1) Roles of hydrophobicity, protein binding, and the probenecid-sensitive transport system, in delivery of nucleoside analogues with anti-herpes or anti-HIV activity, to the CNS. 2) Role of brain tissue-localized purine metabolizing enzymes in the delivery of dideoxynucleosides with anti-HIV activity to the brain. 3) Chemical delivery systems for zidovudine (AZT) based on redox trapping within the brain.

[Back to top] Invasive Aspergillosis: Focus on New Approaches and New Therapeutic Agents

Johan Maertens, Koen Theunissen and Marc Boogaerts

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Infections caused by Aspergillus species are an emerging cause of morbidity and mortality in a variety of immunocompromised patients, despite profound environmental protection and the widespread prophylactic use of agents with anti-Aspergillus activity. At the present time, no firm conclusions can be drawn on the use of chemoprophylaxis, mainly due to the lack of reliable, randomized trials. Therefore, universal prophylaxis should be discouraged and prevention should be targeted towards well-defined high-risk patients, although only as part of a properly designed clinical trial. The crude mortality rate of invasive aspergillosis remains unacceptably high and results at least partly from difficulties in obtaining a reliable diagnosis at an early stage of the disease. The concept of empirical antifungal therapy has been introduced in an effort to overcome these diagnostic obstacles, especially since the early implementation of antifungal therapy appears to be the crucial prerequisite to improve the detrimental outcome of established disease. However, the concept has not been sufficiently validated and is not devoid of significant risks and disadvantages. The implementation of sensitive and predictive new diagnostic tools, such as galactomannan detection, high-resolution pulmonary CT-scanning and detection of aspergillar DNA, may allow a more targeted pre-emptive approach, directed towards the high-risk patients and based upon a battery of clinical, radiological and microbiological clues, though without histopathological proof. The high mortality rate results also from shortcomings of the currently available therapeutic arsenal. Amphotericin B, flucytosine and itraconazole are associated with low success rates and are hampered by serious infusion- or drug-related toxicity, by hazardous drug-drug interactions, by pharmacokinetic problems and by the development of resistance. In recent years, several companies have launched new compounds into preclinical and clinical trials. Some of these agents target the fungal cell wall in stead of the cell membrane. They exert their action through inhibition of the synthesis of critical compounds of that fungal cell wall, not present in mammalian cells (e.g. inhibitors of b-(1,3)-D-glucan synthesis). This article will focus on new therapeutic approaches (risk-adapted or targeted strategy) and upcoming antifungal agents with anti-Aspergillus activity, in particular voriconazole and caspofungin acetate.

[Back to top] Current Treatments of Muco-Cutaneous Herpes Simplex Virus Infections

Arjen F. Nikkels and Gérald E. Piérard

[Full text article]

Infection by Herpes Simplex Virus (HSV) types I and II represent a worldwide medical problem. After the primary infection the virus establishes a life-long latency in the dorsal root ganglia and recurrences may occur at unpredictable times and rate. The most frequent clinical presentation of HSV infection is recurrent herpes labialis and herpes genitalis. The clinical expression varies according to the body site, the infected cell type, the relationship between HSV and the host immune status. Viral identification techniques such as immunohistochemistry and in situ hybridization on Tzanck smears and muco-cutanenous biopsies are helpful in the diagnosis of atypical cutaneous lesions.

The treatment modalities of HSV infections include the reduction of viral load using antiviral agents, the non-specific immune stimulation of the host and specific vaccination in order to prevent new acquisition and to mitigate symptoms in already infected individuals.

This review addresses various therapeutic options, their mode of action, and clinical value as well as the indications of the various drugs.

Current Medicinal Chemistry - Anti-Infective Agents, Volume 1, Number 1, 2002

Contents

Abstracts