Discovery and Derivatization of Tridecaptin Antibiotics with Altered Host Specificity and Enhanced Bioactivity.

The prevalence of multidrug-resistant (MDR) pathogens combined with a decline in antibiotic discovery presents a major challenge for health care. To refill the discovery pipeline, we need to find new ways to uncover new chemical entities. Here, we report the global genome mining-guided discovery of new lipopeptide antibiotics tridecaptin A and tridecaptin D, which exhibit unusual bioactivities within their class.

Linearization of the Brevicidine and Laterocidine Lipopeptides Yields Analogues That Retain Full Antibacterial Activity.

Brevicidine and laterocidine are macrocyclic lipodepsipeptides with selective activity against Gram-negative bacteria, including colistin-resistant strains. Previously, the macrocyclic core of these peptides was thought essential for antibacterial activity. In this study, we show that C-terminal amidation of linear brevicidine and laterocidine scaffolds, and substitution of the native Thr9, yields linear analogues that retain the potent antibacterial activity and low hemolysis of the parent compounds.

Total Synthesis and Structure Assignment of the Relacidine Lipopeptide Antibiotics and Preparation of Analogues with Enhanced Stability.

The unabated rise of antibiotic resistance has raised the specter of a post-antibiotic era and underscored the importance of developing new classes of antibiotics. The relacidines are a recently discovered group of nonribosomal lipopeptide antibiotics that show promising activity against Gram-negative pathogens and share structural similarities with brevicidine and laterocidine. While the first reports of the relacidines indicated that they possess a C-terminal five-amino acid macrolactone, an N-terminal lipid tail, and an overall positive charge, no stereochemical configuration was assigned, thereby precluding a full structure determination.

Synthesis and structure-activity relationship studies of N-terminal analogues of the lipopeptide antibiotics brevicidine and laterocidine.

The brevicidine and laterocidine family of lipopeptide antibiotics exhibit strong activity against multidrug-resistant Gram-negative bacteria, while showing low propensity to induce resistance. Both peptides feature a branched lipid tail on the N-terminal residue, which for brevicidine is chiral. Here, we report the synthesis and biological evaluation of a library of brevicidine and laterocidine analogues wherein the N-terminal lipid is replaced with linear achiral fatty acids.

Synthetic studies with the brevicidine and laterocidine lipopeptide antibiotics including analogues with enhanced properties and efficacy.

Brevicidine and laterocidine are two recently discovered lipopeptide antibiotics with promising antibacterial activity. Possessing a macrocyclic core, multiple positive charges, and a lipidated N-terminus, these lipopeptides exhibit potent and selective activity against Gram-negative pathogens, including polymyxin-resistant isolates. Given the low amounts of brevicidine and laterocidine accessible by fermentation of the producing microorganisms, synthetic routes to these lipopeptides present an attractive alternative.

Structure-Activity Relationship Studies of α-Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family.

The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca-independent production of -acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive -acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells.

Activity-Based Protein Profiling Identifies α-Ketoamides as Inhibitors for Phospholipase A2 Group XVI.

Phospholipase A2, group XVI (PLA2G16) is a thiol hydrolase from the HRASLS family that regulates lipolysis in adipose tissue and has been identified as a host factor enabling the cellular entry of picornaviruses. Chemical tools are essential to visualize and control PLA2G16 activity, but they have not been reported to date. Here, we show that MB064, which is a fluorescent lipase probe, also labels recombinant and endogenously expressed PLA2G16.

Structure-based design of β1i or β5i specific inhibitors of human immunoproteasomes.

Mammalian genomes encode seven catalytic proteasome subunits, namely, β1c, β2c, β5c (assembled into constitutive 20S proteasome core particles), β1i, β2i, β5i (incorporated into immunoproteasomes), and the thymoproteasome-specific subunit β5t. Extensive research in the past decades has yielded numerous potent proteasome inhibitors including compounds currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. Proteasome inhibitors that selectively target combinations of β1c/β1i, β2c/β2i, or β5c/β5i are available, yet ligands truly selective for a single proteasome activity are scarce.