This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products. The current knowledge regarding the biosynthesis of the >20 distinct compound classes is also reviewed, and commonalities are discussed.
Enantiomerically pure chiral amines are valuable synthetic intermediates, particularly for the preparation of pharmaceutical compounds. Traditionally, chiral amines have been obtained by resolution-based procedures, for example, by kinetic resolution of a racemate using an enzyme [1,2] or crystallization of a diastereomer using a chiral acid to form a salt. [3] Increasingly, there is a desire to develop asymmetric approaches, or their equivalents, which can in principal deliver the product in 100 % yield and 100 % ee. For example, transaminases have been utilized for the conversion of COMMUNICATIONS
Enantiomerically pure chiral amines are of increasing value in organic synthesis, especially as resolving agents, [1] chiral auxiliaries/chiral bases, [2] and catalysts for asymmetric synthesis. [3] In addition, chiral amines often possess pronounced biological activity in their own right and hence are in demand as intermediates for agrochemicals and pharmaceuticals. [4] Current methods for the preparation of enantiomerically pure chiral amines are largely based upon the resolution of racemates, either by recrystallization of diastereomeric salts [5] or by enzyme-catalyzed kinetic resolution of racemic substrates using lipases and acylases.[6] To develop more efficient methods, attention is turning towards asymmetric approaches or their equivalent, for example, the asymmetric hydrogenation of imines [7] or the conversion of ketones into amines by using transaminases.[8] Attempts to develop dynamic kinetic resolutions, which employ enzymes in combination with transition-metal catalysts, have unfortunately been hampered by the harsh conditions required to racemize amines.[9]Recently we reported a novel catalytic method for the preparation of optically active chiral amines by deracemization of the corresponding racemic mixture (Figure 1).[10] The deracemization approach relies upon coupling an enantioselective amine oxidase with a nonselective reducing agent to effect stereoinversion of the S to R enantiomer via the intermediate achiral imine.The S enantiomer selective amine oxidase used for the deracemization of (R/S)-a-methylbenzyl amine was identified from a library of variants of the wild-type enzyme, from Aspergillus niger, by using a high-throughput colorimetric screen to guide selection.[10] The library of variants was generated by randomly mutating the plasmid harboring the amine oxidase gene by using the E. coli XL1-Red mutator strain. Using (S)-a-methylbenzylamine as the target substrate we were able to identify a variant (Asn336Ser) that possessed significantly improved catalytic activity (47 fold) and enantioselectivity (sixfold) towards this particular substrate compared to the wild type enzyme. To explore the opportunities for using this variant amine oxidase to deracemize other racemic chiral amines we decided to undertake a more detailed study of its substrate specificity. Herein we show that the Asn336Ser variant possesses broad substrate specificity and high enantioselectivity towards a wide range of chiral amines.Prior to carrying out further studies with the Asn336Ser amine oxidase, an additional mutation was introduced into the sequence (Met348Lys) that resulted in a variant enzyme (hereafter referred to as Asn336Ser) with higher specific activity and expression levels although its substrate specificity appeared unchanged (data not shown). Incorporation of an N-terminal histidine tag into the amine oxidase allowed facile purification of both the wild-type and Asn336Ser variant in one step, by a nickel-affinity column, to yield protein of > 90 % purity as evidenced by gel electrophoresis (Figure ...
SummaryMersacidin is a tetracyclic lantibiotic with antibacterial activity against Gram-positive pathogens. To probe the specificity of the biosynthetic pathway of mersacidin and obtain analogs with improved antibacterial activity, an efficient system for generating variants of this lantibiotic was developed. A saturation mutagenesis library of the residues of mersacidin not involved in cycle formation was constructed and used to validate this system. Mersacidin analogs were obtained in good yield in approximately 35% of the cases, producing a collection of 82 new compounds. This system was also used for the production of deletion and insertion mutants of mersacidin. The outcome of these studies suggests that this system can be extended to produce mersacidin variants with multiple changes that will allow a full investigation of the potential use of modified mersacidins as therapeutic agents.
Over the last decade, there has been a resurgence of interest in polymyxins owing to the rapid rise in multi-drug resistant Gram-negative bacteria against which polymyxins offer a last-resort treatment. Although having excellent antibacterial activity, the clinical utility of polymyxins is limited by toxicity, especially renal toxicity. There is much interest therefore in developing polymyxin analogues with an improved therapeutic index. This review describes recent work aimed at improving the activity and/or reducing the toxicity of polymyxins. Consideration to providing activity against emerging strains with reduced susceptibility to polymyxins is also made.
Polymyxins are an important class
of antibiotics for the treatment
of bacterial infections due to multidrug resistant Gram-negative pathogens.
However, their clinical utility is limited by nephrotoxicity. Here,
we report a series of promising next generation polymyxin nonapeptides
identified on the basis of our understanding of the relationship of
structure with activity, cytotoxicity, and kidney compartment accumulation.
We demonstrate that nonapeptides with an amine-containing N-terminal
moiety of specific regio- and stereochemistry possess superior in vitro activity, together with lower cytotoxicity compared
to polymyxin B. We further demonstrate that compounds with a β-branched
aminobutyrate N-terminus with an aryl substituent offer a promising
combination of low cytotoxicity and kidney exposure, leading to low
toxicity in the mouse. From this series, SPR206 has been selected
as a development candidate.
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