Special Series: Natural products at the core of drug discovery

No abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77447/1/21497_ftp.pd

Bishydrazone-Based Antifungal Agents

Hydrazone compounds and pharmaceutical compositions including same are disclosed as having antifungal activity. Such compounds are useful for treating or preventing fungal conditions in a subject in need thereof by administering same

Eis Inhibitors

Compounds and compositions are disclosed, which are useful as inhibitors of acetyltransferase Eis, a mediator of kanamycin resistance in Mycobacterium tuberculosis

A Thorough Analysis and Categorization of Bacterial Interrupted Adenylation Domains, Including Previously Unidentified Families

Interrupted adenylation (A) domains are key to the immense structural diversity seen in the nonribosomal peptide (NRP) class of natural products (NPs). Interrupted A domains are A domains that contain within them the catalytic portion of another domain, most commonly a methylation (M) domain. It has been well documented that methylation events occur with extreme specificity on either the backbone (N-) or side chain (O- or S-) of the amino acid (or amino acid-like) building blocks of NRPs. Here, through taxonomic and phylogenetic analyses as well as multiple sequence alignments, we evaluated the similarities and differences between interrupted A domains. We probed their taxonomic distribution amongst bacterial organisms, their evolutionary relatedness, and described conserved motifs of each type of M domain found to be embedded in interrupted A domains. Additionally, we categorized interrupted A domains and the M domains within them into a total of seven distinct families and six different types, respectively. The families of interrupted A domains include two new families, 6 and 7, that possess new architectures. Rather than being interrupted between the previously described a2–a3 or a8–a9 of the ten conserved A domain sequence motifs (a1–a10), family 6 contains an M domain between a6–a7, a previously unknown interruption site. Family 7 demonstrates that di-interrupted A domains exist in Nature, containing an M domain between a2–a3 as well as one between a6–a7, displaying a novel arrangement. These in-depth investigations of amino acid sequences deposited in the NCBI database highlighted the prevalence of interrupted A domains in bacterial organisms, with each family of interrupted A domains having a different taxonomic distribution. They also emphasized the importance of utilizing a broad range of bacteria for NP discovery. Categorization of the families of interrupted A domains and types of M domains allowed for a better understanding of the trends of naturally occurring interrupted A domains, which illuminated patterns and insights on how to harness them for future engineering studies

Eis Inhibitors

Provided herein are novel small-molecules that have use in the inhibition of Eis, which mediates kanamycin resistance in Mycobacterium tuberculosis. The presently-disclosed subject matter further includes a pharmaceutical composition including a small molecule inhibitor, as described herein, and a suitable pharmaceutical carrier. Methods of treating tuberculosis comprising administering to an individual an effective amount of the disclosed small molecule inhibitors to mediate kanamycin A resistance and treat tuberculosis are also provided

Identification of Ebsulfur Analogues with Broad-Spectrum Antifungal Activity

The invention relates to novel ebsulfur analogues and novel pharmaceutical compositions comprising ebsulfur analogues. The invention also relates to novel methods of treating infections caused by fungal species comprising administration of ebselen, ebsulfur, and ebsulfur analogues

Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors

A series of 22 donepezil analogues were synthesized through alkylation/benzylation and compared to donepezil and its 6-O-desmethyl adduct. All the compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two enzymes responsible for the hydrolysis of the neurotransmitter acetylcholine in Alzheimer’s disease patient brains. Many of them displayed lower inhibitory concentrations of EeAChE (IC50 = 0.016 ± 0.001 µM to 0.23 ± 0.03 µM) and EfBChE (IC50 = 0.11 ± 0.01 µM to 1.3 ± 0.2 µM) than donepezil. One of the better compounds was tested against HsAChE and was found to be even more active than donepezil and inhibited HsAChE better than EeAChE. The analogues with the aromatic substituents were generally more potent than the ones with aliphatic substituents. Five of the analogues also inhibited the action of β-secretase (BACE1) enzyme

Amyloid-β Probes: Review of Structure-Activity and Brain-Kinetics Relationships

The number of people suffering from Alzheimer\u27s disease (AD) is expected to increase dramatically in the coming years, placing a huge burden on society. Current treatments for AD leave much to be desired, and numerous research efforts around the globe are focused on developing improved therapeutics. In addition, current diagnostic tools for AD rely largely on subjective cognitive assessment rather than on identification of pathophysiological changes associated with disease onset and progression. These facts have led to numerous efforts to develop chemical probes to detect pathophysiological hallmarks of AD, such as amyloid-β plaques, for diagnosis and monitoring of therapeutic efficacy. This review provides a survey of chemical probes developed to date for AD with emphasis on synthetic methodologies and structure-activity relationships with regards to affinity for target and brain kinetics. Several probes discussed herein show particularly promising results and will be of immense value moving forward in the fight against AD

A Combination Approach to Treating Fungal Infections

Azoles are antifungal drugs used to treat fungal infections such as candidiasis in humans. Their extensive use has led to the emergence of drug resistance, complicating antifungal therapy for yeast infections in critically ill patients. Combination therapy has become popular in clinical practice as a potential strategy to fight resistant fungal isolates. Recently, amphiphilic tobramycin analogues, C12 and C14, were shown to display antifungal activities. Herein, the antifungal synergy of C12 and C14 with four azoles, fluconazole (FLC), itraconazole (ITC), posaconazole (POS), and voriconazole (VOR), was examined against seven Candida albicans strains. All tested strains were synergistically inhibited by C12 when combined with azoles, with the exception of C. albicans 64124 and MYA-2876 by FLC and VOR. Likewise, when combined with POS and ITC, C14 exhibited synergistic growth inhibition of all C. albicans strains, except C. albicans MYA-2876 by ITC. The combinations of FLC-C14 and VOR-C14 showed synergistic antifungal effect against three C. albicans and four C. albicans strains, respectively. Finally, synergism between C12/C14 and POS were confirmed by time-kill and disk diffusion assays. These results suggest the possibility of combining C12 or C14 with azoles to treat invasive fungal infections at lower administration doses or with a higher efficiency

A Random Sequential Mechanism of Aminoglycoside Acetylation by \u3cem\u3eMycobacterium tuberculosis\u3c/em\u3e Eis Protein

An important cause of bacterial resistance to aminoglycoside antibiotics is the enzymatic acetylation of their amino groups by acetyltransferases, which abolishes their binding to and inhibition of the bacterial ribosome. Enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (Mt) is one of such acetyltransferases, whose upregulation was recently established as a cause of resistance to aminoglycosides in clinical cases of drug-resistant tuberculosis. The mechanism of aminoglycoside acetylation by MtEis is not completely understood. A systematic analysis of steady-state kinetics of acetylation of kanamycin A and neomycin B by Eis as a function of concentrations of these aminoglycosides and the acetyl donor, acetyl coenzyme A, reveals that MtEis employs a random-sequential bisubstrate mechanism of acetylation and yields the values of the kinetic parameters of this mechanism. The implications of these mechanistic properties for the design of inhibitors of Eis and other aminoglycoside acetyltransferases are discussed