Andrew S. Misura

Side Chain Sar of Bicyclic Beta-Lactamase Inhibitors (Blis). 1. Discovery of a Class C Bli for Combination with Imipinem.

Bridged monobactam beta-lactamase inhibitors were prepared and evaluated as potential partners for combination with imipenem to overcome class C beta-lactamase mediated resistance. The (S)-azepine analog 2 was found to be effective in both in vitro and in vivo assays and was selected for preclinical development.

Efficacy of Caspofungin against Aspergillus flavus, Aspergillus terreus, and Aspergillus nidulans

ABSTRACT The echinocandin caspofungin is a potent inhibitor of the activity of 1,3-β-d-glucan synthase from Aspergillus flavus, Aspergillus terreus, and Aspergillus nidulans. In murine models of disseminated infection, caspofungin prolonged survival and reduced the kidney fungal burden. Caspofungin was at least as effective as amphotericin B against these filamentous fungi in vivo.

In Vivo Efficacy of a Novel Oxazolidinone Compound in Two Mouse Models of Infection

ABSTRACT A novel oxazolidinone, AM 7359, was evaluated in two mouse models of Staphylococcus aureus infection. AM 7359 and linezolid were equally efficacious in a methicillin-susceptible S. aureus organ burden model and a methicillin-resistant S. aureus localized infection model. However, AM 7359 was eightfold more efficacious than linezolid against a linezolid- and methicillin-resistant S. aureus strain in this localized (thigh) infection model.

Efficacy of Caspofungin in a Juvenile Mouse Model of Central Nervous System Candidiasis

ABSTRACT Neonatal candidiasis is an increasingly common occurrence causing significant morbidity and mortality and a higher risk of dissemination to the central nervous system (CNS) than that seen with older patients. The current understanding of optimal antifungal therapy in this setting is limited. We have developed a model of disseminated candidiasis with CNS involvement in juvenile mice to assess the efficacy of the echinocandin caspofungin relative to amphotericin B (AmB). Juvenile mice were inoculated intravenously with 5.64 × 104 CFU of Candida albicans MY1055. Treatment with caspofungin at 1, 2, 4, and 8 mg/kg of body weight/day, AmB at 1 mg/kg/day, or a vehicle control (VC) was initiated 30 h after infection and continued for 7 days. Pharmacokinetic parameters for caspofungin were also determined. Culture and histology showed evidence of disseminated candidiasis with multifocal encephalitis at the start of antifungal therapy. Survival was 100% in all treated groups, while mortality was 100% in the VC by day 11 after infection. By day 5, all mice in the caspofungin treatment (four doses) groups showed reductions in kidney and brain burden relative to the VC, while AmB treatment reduced kidney burden but gave no reduction of brain fungal burden. Systemic levels of caspofungin were similar in infected and uninfected mice, while brain levels were higher in infected animals. In this juvenile mouse model, caspofungin demonstrated dose-dependent activity, equivalent to or better than that of AmB at 1 mg/kg, against disseminated candidiasis with CNS involvement.

N-alkyl-4-piperidinyl-2,3-diarylpyrrole derivatives with heterocyclic substitutions as potent and broad spectrum anticoccidial agents.

Diaryl-(4-piperidinyl)-pyrrole derivatives bearing cyclic amine substituents have been synthesized and evaluated as anticoccidial agents. Improvements in potency of Et-PKG inhibition, such as azetidine derivative 3a, and broad spectrum anticoccidial activities in feed, such as morpholine derivative 8c, have been achieved.

Novel orally active inhibitors of β-1,3-glucan synthesis derived from enfumafungin.

The clinical success of the echinocandins, which can only be administered parentally, has validated β-1,3-glucan synthase (GS) as an antifungal target. Semi-synthetic modification of enfumafungin, a triterpene glycoside natural product, was performed with the aim of producing a new class of orally active GS inhibitors. Replacement of the C2 acetoxy moiety with various heterocycles did not improve GS or antifungal potency. However, replacement of the C3 glycoside with an aminoether moiety dramatically improved oral pharmacokinetic (PK) properties while maintaining GS and antifungal potency. Installing an aminotetrazole at C2 in conjunction with an N-alkylated aminoether at C3 produced derivatives with significantly improved GS and antifungal potency that exhibited robust oral efficacy in a murine model of disseminated candidiasis.

Experimental model of reversible myelosuppression caused by short-term, high-dose oxazolidinone administration

Aims: To develop a murine model of oxazolidinone-induced myelosuppression observed in man for identification of potentially less myelosuppressive compounds within this chemical therapeutic class. Methods: Female C3H mice were treated orally, once-daily, with linezolid for between 2 and 7 days. A total of 24 h after the last dose, mice were euthanized, blood was collected by cardiac puncture and analyzed for hematologic parameters against vehicle control animals. Results: Results from three independent experiments demonstrated that oral treatment with linezolid at 50 mg/kg produces mild, reversible anemia characterized by reticulocytopenia in greater than 4 days in mice. Conclusions: Use of this model to screen potential chemotherapeutic agents will facilitate discovery and guide structure–activity relationship chemistry for less myelosuppressive compounds.