Polyene Macrolides Biosynthetic Engineering

Dominic Leonardo^*
*Correspondence: Dominic Leonardo, Department of Medical Chemistry, University of Huddersfield Queensgate Campus, Queensgate, Huddersfield, UK, Email:

Editorial

Strong antifungal compounds known as polyene macrolides are also effective against parasites, enveloped viruses, and prion disorders. As antifungal antibiotics, they are crucial to medicine, but their therapeutic usage is constrained by substantial side effects. The genetic investigation and manipulation of the streptomycetes that make nystatin, amphotericin B, candicidin, pimaricin, and rimocidin/CE-108-related polyenes have made significant strides in recent years. Typically, polyketide chain construction and cyclization are followed by oxidative changes and glycosylation of the macrolactone ring to produce polyenes. Engineering polyene biosynthetic pathways at both the early and late stages has led to the creation of new compounds. These substances have made it possible to investigate structureactivity correlations in greater depth, and some of them may improve treatment indices. Polyene antibiotic toxicity can be decreased chemically or through liposomal formulation. Although new lipid formulations with significantly lower toxicity and a better pharmacokinetic profile have been made available for clinical usage, these formulations are still prohibitively expensive for routine medical care. Although the manufacture of some semi-synthetic derivatives is not commercially viable, they have very low toxicity [1].

In order to lessen the toxicity of polyene antibiotics, chemists have been chemically altering them for the past 40 years, with AmB receiving the most of their attention. According to these research, a positive charge on the mycosamine amino group is crucial for its antifungal activity, but a suppressed charge on the exocyclic carboxyl group lessens toxicity. While the toxicity of the AmB analogues N-methyl-N-D-fructosyl amphotericin B methyl ester (MFAME) and MS8209 has significantly improved, their production costs are prohibitive. Engineered biosynthesis makes it possible to obtain chemicals as primary fermentation products and can produce analogues that are impossible to produce chemically. In order to replace a gene through homologous recombination with the chromosome, engineering biosynthesis often entails manipulating cloned polyene biosynthetic genes and introducing the modified DNA into the producing organism. Although development has been slowed down by how time-consuming these procedures are, they have been effectively used by polyene producers. A genetically altered streptomycete is a viable source of a novel chemical, though, once it has been obtained. For better exploitation of polyene biosynthesis, heterologous expression and "recombineering" techniques have been extensively used on smaller biosynthetic gene clusters [2,3].

The majority of polyenes go through a special late alteration that involves oxidising a methyl branch into a carboxyl group. Amphotericins missing exocyclic carboxyl groups were projected to be similar to AmB methyl ester, a less toxic semi-synthetic counterpart, which led to the targeting of the amphN gene. The amphN gene was inactivated in a number of early attempts without success. A mutant that produced both the tetraene 8-deoxy-16-descarboxyl- 16-methyl amphotericin A and the heptaene 16-descarboxyl-16-methyl amphotericin B was created after the amphNM region of the S. nodosus chromosome was deleted. Due to the fact that the methyl branch connected to C-16 was not oxidised to a carboxyl group, glycosylation with mycosamine appeared to occur smoothly in this case, suggesting that the AmphDI glycosyl transferase has some flexibility towards its aglycone substrate. The deletion of two modules from the AmphC protein led to the first successful modification of the amphotericin PKS and a mutant that produced a pentaene in a good yield. The later pentaene demonstrated no antifungal properties while being water soluble. Recent ES-MS findings show that although the pentaene has an exocyclic carboxyl group, it has neither been glycosylated nor C-8 hydroxylated. Using haemolytic assays, the toxicity of amphotericin analogues was evaluated. While 23 and 24 still showed antifungal action, the 16-methyl- 16-descarboxyl analogues 23, 24, and 25 had less hemolytic activity than AmB. Therefore, it seems that these novel compounds' characteristics are similar to those of AmB methyl ester [4,5].

The creation of new pimaricin derivatives has been impeded by the absence of an effective gene delivery mechanism for the pimaricin-producing strain S. natalensis. The recent creation of an intergeneric conjugationbased gene transfer system from E. coli will make it easier to manipulate the genes in charge of pimaricin production and may be useful for creating novel designer polyene macrolides with improved antifungal activity and pharmacological features. The rimocidin/CE-108 cluster was sequenced, and the results showed a modular PKS that appears to catalyse the synthesis of both tetraenes. Both acetyl CoA and butyryl CoA appear to be acceptible beginning units for the Rim A loading module. When an acetyl starter is used, CE-108 is produced, whereas rimocidin is produced when a butyryl beginning is used. It is still unclear how the beginning units for rimocidin and/or CE-108 biosynthesis are chosen. S. diastaticus var. 108 simultaneously produces both chemicals, and their relative proportions appear to be greatly influenced by the fermentation conditions. Since the creation of CE-108, the rimJ gene, which encodes a suspected crotonyl-CoA reductase, has been crucial in producing butyryl units [2, 5].

Conclusion

Over twenty novel polyene compounds have been produced by engineered biosynthesis in the previous four years. Some of these substances seem to be less harmful while yet having antifungal and antiparasitic properties. Production of libraries of novel compounds and thorough analysis of structure-activity connections will be made possible by further manipulation of PKS and polyene modifying enzymes. This work should move more quickly thanks to recent advancements in streptomycete genetic manipulation. For testing as possible therapeutic candidates, the most promising novel polyenes will be needed in huge quantities. The understanding of the regulation of polyene production has advanced significantly. For increasing the yields of novel polyenes, this information will be of great value.

Acknowledgement

None.

Conflict of Interest

The author reported no potential conflict of interest.

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