New Glycosylated Polyene Macrolides: Refining the Ore from Genome Mining

Abstract

Glycosylated polyene macrolides include effective antifungal agents, such as pimaricin, nystatin, candicidin, and amphotericin B. For the treatment of systemic mycoses, amphotericin B has been described as a gold-standard antibiotic because of its potent activity against a broad spectrum of fungal pathogens, which do not readily become resistant. However, amphotericin B has severe toxic side effects, and the development of safer alternatives remains an important objective. One approach towards obtaining such compounds is to discover new related natural products. Advances in next-generation sequencing have delivered a wealth of microbial genome sequences containing polyene biosynthetic gene clusters. These typically encode a modular polyketide synthase that catalyzes the assembly of the aglycone core, a cytochrome P450 that oxidizes a methyl branch to a carboxyl group, and additional enzymes for synthesis and attachment of a single mycosamine sugar residue. In some cases, further P450s catalyze epoxide formation or hydroxylation within the macrolactone. Bioinformatic analyses have identified over 250 of these clusters. Some are predicted to encode potentially valuable new polyenes that have not been uncovered by traditional screening methods. Recent experimental studies have characterized polyenes with new polyketide backbones, previously unknown late oxygenations, and additional sugar residues that increase water-solubility and reduce hemolytic activity. Here we review these studies and assess how this new knowledge can help to prioritize silent polyene clusters for further investigation. This approach should improve the chances of discovering better antifungal antibiotics.

BAC cloning and heterologous expression of a giant biosynthetic gene cluster encoding antifungal neotetrafibricin in streptomyces rubrisoli

“…Various polyene compounds with a sugar motif by glycosyltransferase among several post-PKS modifications have been reported ( Caffrey et al, 2022 ). Interestingly, the sugar moiety of polyene has proved to play an important role in maintaining the antifungal activity, reducing toxicity, or increasing solubility ( Caffrey et al, 2022 ).…”

“…Various polyene compounds with a sugar motif by glycosyltransferase among several post-PKS modifications have been reported ( Caffrey et al, 2022 ). Interestingly, the sugar moiety of polyene has proved to play an important role in maintaining the antifungal activity, reducing toxicity, or increasing solubility ( Caffrey et al, 2022 ). This study evaluated the effect of sugar moiety (rhamnose) in I-NTF by deleting, i-ntf h (glycosyltransferase) in pI-NTF using the BAC modification method ( Nah et al, 2015 ).…”

Polyene Antibiotics Physical Chemistry and Their Effect on Lipid Membranes; Impacting Biological Processes and Medical Applications

“…Unfortunately, and despite its great efficacy, both AmB and Nys have undesirable collateral toxicity [ 45 , 348 ], the most serious being nephrotoxicity and hematotoxicity [ 34 , 49 , 177 ], both of which limit their therapeutic use to a short range of specific clinical cases and that can also result in eventual treatment interruption [ 23 , 24 , 25 , 26 ]. In spite of these unwanted toxic side effects, AmB is still considered the gold standard for serious invasive fungal infections due to its high antifungal activity, the low appearance of resistant strains, and its low cost compared with other treatments.…”

“…Furthermore, a recent review addressed many other forms of polyenes discovered through genome mining. These discoveries could lead to development of better antifungals [ 26 ].…”

Streptomyces BAC Cloning of a Large-Sized Biosynthetic Gene Cluster of NPP B1, a Potential SARS-CoV-2 RdRp Inhibitor

“…NPP B1 was developed by genetic manipulation and is less toxic but more powerful as an antifungal drug with similar efficacy in vivo compared to amphotericin B. Therefore, NPP B1 is a promising candidate for pharmacokinetically improved and less toxic polyene antifungal antibiotics [ 11 , 12 ]. On the other hand, the production level of NPP B1 was very low compared to the strain producing NPP A1 [ 10 ].…”