Nafsika H. Georgopapadakou

Antifungals: mechanism of action and resistance, established and novel drugs.

Serious fungal infections, caused mostly by opportunistic species, are increasingly common in immunocompromised and other vulnerable patients. The use of antifungal drugs, primarily azoles and polyenes, has increased in parallel. Yet, established agents do not satisfy the medical need completely: azoles are fungistatic and vulnerable to resistance, whereas polyenes cause serious host toxicity. Drugs in clinical development include echinocandins, pneumocandins, and improved azoles. Promising novel agents in preclinical development include several inhibitors of fungal protein, lipid and cell wall syntheses. Recent advances in fungal genomics, combinatorial chemistry, and high-throughput screening may accelerate the antifungal discovery process.

Update on antifungals targeted to the cell wall: focus on β-1,3-glucan synthase inhibitors

Currently available antifungal drugs for serious infections are either fungistatic and vulnerable to resistance (azoles) or fungicidal but toxic to the host (polyenes). Cell wall-acting antifungals are inherently selective and fungicidal, features that make them particularly attractive for clinical development. Three classes of such compounds, targeted respectively to chitin synthase (nikkomycins), β-1,3-glucan synthase (echinocandins) and mannoproteins (pradimicins/benanomicins), have entered clinical development. While nikkomycins and pradimicins/benanomicins are no longer in development, echinocandins have emerged as potentially clinically useful and three compounds, caspofungin (MK-991, L-743,872), micafungin (FK-463) and anidulafungin (LY-303366) are in late clinical development (Phase II and III).

Antifungals targeted to sphingolipid synthesis: focus on inositol phosphorylceramide synthase

Currently available antifungal drugs for serious infections have essentially two molecular targets, 14α demethylase (azoles) and ergosterol (polyenes). The former is a fungistatic target, vulnerable to resistance development; the latter, while a fungicidal target, is not sufficiently different from the host to ensure high selectivity. Antifungals in clinical development have a third molecular target, β-1,3-glucan synthase. Drugs aimed at totally new targets are required to increase our chemotherapeutic options and to forestall, alone or in combination chemotherapy, the emergence of drug resistance. Sphingolipids, essential membrane components in eukaryotic cells, but distinct in mammalian and fungal cells, present an attractive new target. Several natural product inhibitors of sphingolipid biosynthesis have been discovered in recent years, some of which act at a step unique to fungi and have potent and selective antifungal activity.

Inhibition of yeast inositol phosphorylceramide synthase by aureobasidin A measured by a fluorometric assay

Inositol phosphorylceramide synthase (IPC synthase) is an essential and unique enzyme in fungal sphingolipid biosynthesis and is the target of the cyclic nonadepsipeptide antibiotic aureobasidin A. As a first step towards understanding the mechanism of aureobasidin A inhibition, we developed a fluorometric HPLC assay for IPC synthase using the Saccharomyces cerevisiae enzyme and the fluorescent substrate analog 6‐[N‐(7‐nitro‐2,1,3‐benzoxadiazol‐4‐yl)amino]‐hexanoyl ceramide (C6‐NBD‐cer). The kinetic parameters for C6‐NBD‐cer were comparable to those for the synthetic substrate N‐acetylsphinganine used previously. Aureobasidin A acted as a tight‐binding, non‐competitive inhibitor with respect to C6‐NBD‐cer and had a K i of 0.55 nM.

Infectious disease 2001: drug resistance, new drugs

The 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held in Chicago on 16-19 December 2001, rescheduled following the tragic events of 11th September. Nonetheless, it attracted thousands of delegates from industry and academia and covered, in over 2200 oral and poster presentations, topics ranging from bioterrorism, microbial pathogenesis and emerging pathogens, to infection control, vaccines, antibiotic resistance and new antimicrobial agents and treatment strategies. Summarized here are highlights on bacterial and fungal drug resistance and on new agents in preclinical and clinical development.

37th interscience conference on antimicrobial agents and chemotherapy (ICAAC) Toronto, Canada, 28 September–1 October 1997

Summary Renewed public awareness of infectious diseases, the commercial success of marketed antimicrobial agents and the well-publicized microbial resistance to them, have greatly stimulated infectious disease research in the pharmaceutical and biotechnology industry and this was reflected in the conference. In the antibacterial field, there were useful updates on newer quinolones, macrolides/ketolides and other agents in development. In the antifungal field, there were updates on newer triazoles, amphotericin B formulations and β-1,3 glucan synthase inhibitors in clinical development. There were also reports on new antifungals with novel mechanisms of action such as protein synthesis inhibitors. In the antiviral field, there were updates on neuraminidase inhibitors for influenza viruses, capsid-directed inhibitors of viral attachment for enteroviruses and combination regimens (for example, protease inhibitors plus non-nucleoside reverse transcriptase inhibitors) for HIV. In the protozoal field, there were insights on sterol synthesis inhibitors. Resistance in all microorganisms was a recurrent theme, fuelling discussions in infection control measures and alternative compounds and targets.