William J. Watkins

Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa

Conformational restriction of the ornithine residue of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595, 2) furnished bioisosteric proline derivatives that were less toxic in vivo and as active as the lead in potentiating the activity of the fluoroquinolone levofloxacin via the inhibition of efflux pumps in Pseudomonas aeruginosa.

Chapter 14. Progress with antifungal agents and approaches to combat fungal resistance

Publisher Summary This chapter reviews the progress with antifungal agents and approaches to combat fungal resistance. The rising incidence of serious fungal infections attests to the need for more effective therapies. All current agents have some serious liabilities: inadequate spectrum, limited dosage forms, narrow therapeutic window, and rapid emergence of resistance. The search for new agents, particularly those with a novel mode of action, continues unabated. Several new azoles are poised to have an impact on the treatment of mycoses, and the echinocandins continue to show promise as a novel class of antifungal agents, particularly for parenteral use. Other classes continue to be explored, as the demand for alternative therapies remains high. The chapter reviews publications since 1998 pertaining to new agents under development for the treatment of systemic fungal infections, and detail those mechanisms of resistance to established agents that have been demonstrated to be of clinical relevance, together with approaches to combat them. New agents under development are discussed, including azoles, chinocandins/pneumocandin, aureobasidins, pradimicins and benanomycins, polyoxins and nikkomycins, and sordarins. Clinically-important mechanisms of antifungal resistance are elaborated.

Molecular Basis for Fungal Selectivity of Novel Antimitotic Compounds

ABSTRACT Compounds that selectively disrupt fungal mitosis have proven to be effective in controlling agricultural pests, but no specific mitotic inhibitor is available for the treatment of systemic mycoses in mammalian hosts. In an effort to identify novel mitotic inhibitors, we used a cell-based screening strategy that exploited the hypersensitivity of a yeast α-tubulin mutant strain to growth inhibition by antimitotic agents. The compounds identified inhibited yeast nuclear division and included one structural class of compounds shown to be fungus specific. MC-305,904 and structural analogs inhibited fungal cell mitosis and inhibited the in vitro polymerization of fungal tubulin but did not block mammalian cell microtubule function or mammalian tubulin polymerization. Extensive analysis of yeast mutations that specifically alter sensitivity to MC-305,904 structural analogs suggested that compounds in the series bind to a site on fungal β-tubulin near amino acid 198. Features of the proposed binding site explain the observed fungal tubulin specificity of the series and are consistent with structure-activity relationships among a library of related compounds.