Inspired
by the biosynthetic logic of lanthipeptide natural products,
a new methodology was developed to direct the ribosomal synthesis
of macrocyclic peptides constrained by an intramolecular thioether
bond. As a first step, a robust and versatile strategy was implemented
to enable the cyclization of ribosomally derived peptide sequences
via a chemoselective reaction between a genetically encoded cysteine
and a cysteine-reactive unnatural amino acid (O-(2-bromoethyl)-tyrosine).
Combination of this approach with intein-catalyzed protein splicing
furnished an efficient route to achieve the spontaneous, post-translational
formation of structurally diverse macrocyclic peptides in bacterial
cells. The present peptide cyclization strategy was also found to
be amenable to integration with split intein-mediated circular ligation,
resulting in the intracellular synthesis of conformationally constrained
peptides featuring a bicyclic architecture.
Bacterial infections are becoming increasingly difficult to treat due to the development and spread of antibiotic resistance. Therefore, identifying novel antibacterial targets and new antibacterial agents capable of treating infections from drug-resistant bacteria is of vital importance. Structurally simple, yet potent fusaricidin or LI-F class of natural products represents a particularly attractive source of candidates for the development of new antibacterial agents. We have synthesized eighteen fusaricidin/LI-F analogs and investigated the effect of their structure modification on conformation, serum stability, antibacterial activity and human cell toxicity. Our findings show that substitution of an ester bond in depsipeptides with an amide bond may afford equally potent analogs with improved stability and greatly decreased cytotoxicity. Lower overall hydrophobicity/amphiphilicity of amide analogs in comparison to their parent depsipeptides, as indicated by the HPLC retention times, may explain dissociation of antibacterial activity and human cell cytotoxicity. These results indicate that amide analogs may have significant advantages over fusaricidin/LI-F natural products and their depsipeptide analogs as lead structures for the development of new antibacterial agents.
Background: Most reported ADAM17 inhibitors are zinc-binding and not selective. Results: Novel selective ADAM17 inhibitors were discovered and characterized. Conclusion: Novel ADAM17 inhibitors act via a non-zinc-binding mechanism. Significance: Selective non-zinc-binding inhibitors of ADAM proteases can be useful research and therapeutic tools.
In order to provide effective treatment options for infections caused by multidrug-resistant bacteria, innovative antibiotics are necessary, preferably with novel modes of action and/or belonging to novel classes of drugs. Naturally occurring cyclic lipodepsipeptides, which contain one or more ester bonds along with the amide bonds, have emerged as promising candidates for the development of new antibiotics. Some of these natural products are either already marketed or in advanced stages of clinical development. However, despite the progress in the development of new antibacterial agents, it is inevitable that resistant strains of bacteria will emerge in response to the widespread use of a particular antibiotic and limit its lifetime. Therefore, development of new antibiotics remains our most efficient way to counteract bacterial resistance.
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