1,3-Dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Expanding Structural Diversity and the Antibacterial Spectrum.

Antibacterial resistance continues its devastation of available therapies. Novel bacterial topoisomerase inhibitors (NBTIs) offer one solution to this critical issue. Two series of amine NBTIs bearing tricyclic DNA-binding moieties as well as amide NBTIs with a bicyclic DNA-binding moiety were synthesized and evaluated against methicillin-resistant Staphylococcus aureus (MRSA). Additionally, these compounds and a series of bicyclic amine analogues displayed high activity against susceptible and drug-resistant Neisseria gonorrhoeae, expanding the spectrum of these dioxane-linked NBTIs.

Potent LpxC Inhibitors with In Vitro Activity against Multidrug-Resistant Pseudomonas aeruginosa.

New drugs with novel mechanisms of resistance are desperately needed to address both community and nosocomial infections due to Gram-negative bacteria. One such potential target is LpxC, an essential enzyme that catalyzes the first committed step of lipid A biosynthesis. Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against Pseudomonas aeruginosa We report here the in vitro antibacterial activity and pharmacodynamics of ACHN-975, the only molecule from these efforts and the first ever LpxC inhibitor to be evaluated in phase 1 clinical trials. In addition, we describe the profiles of three additional LpxC inhibitors that were identified as potential lead molecules. These efforts did not produce an additional development candidate with a sufficiently large therapeutic window and the program was subsequently terminated.

In vitro potency and fungicidal activity of CD101, a novel echinocandin, against recent clinical isolates of Candida spp.

Candida infections vary in severity and manifestation. Common infections include invasive bloodstream infections among hospitalized/immunocompromised patients and vulvovaginal candidiasis among women. Echinocandins and azoles are commonly utilized to treat Candida infections, although echinocandin use has been restricted to indications amenable to once-daily IV administration. CD101, a novel echinocandin with a long plasma half-life and enhanced stability, is in development for once-weekly IV administration for the treatment of candidemia and invasive candidiasis. In this study, the MIC of CD101 and comparators against 500 recent clinical Candida isolates was determined per Clinical and Laboratory Standards Institute guidelines. For select isolates, the minimum fungicidal concentration (MFC; n=49) and time-kill (n=9) of CD101 and comparators was evaluated. The MIC50/90s (µg/mL; n=100/species) for CD101, anidulafungin, fluconazole, and amphotericin B, respectively, were: C. albicans (0.008/0.03, 0.004/0.008, 0.25/4, 0.25/0.5), C. tropicalis (0.008/0.03, 0.004/0.015, 0.5/2, 0.5/1), C. parapsilosis (1/1, 0.5/2, 0.5/1, 0.5/1), C. glabrata (0.03/0.03, 0.03/0.03, 8/>32, 0.5/0.5), and C. krusei (0.03/0.03, 0.03/0.03, 32/>32, 1/1). CD101 MICs were comparable to anidulafungin and both maintained potency against fluconazole-resistant isolates. Against rare anidulafungin-resistant isolates, the MICs of CD101 and anidulafungin were elevated vs. anidulafungin-susceptible isolates. Similar to anidulafungin, CD101 was fungicidal with an MFC:MIC ratio ≤4 for 95% of evaluable isolates and resulted in 3-log killing by 24-48h for all isolates evaluated by time-kill. The potent fungicidal activity of CD101 highlights the potential clinical utility of CD101 IV for the treatment of invasive candidiasis and candidemia.