CE-108, a New Macrolide Tetraene Antibiotic

SUMMARY From a genetic standpoint, Streptomyces rimosus is arguably the best-characterized industrial streptomycete as the producer of oxytetracycline and other tetracycline antibiotics. Although resistance to these antibiotics has reduced their clinical use in recent years, tetracyclines have an increasing role in the treatment of emerging infections and noninfective diseases. Procedures for in vivo and in vitro genetic manipulations in S. rimosus have been developed since the 1950s and applied to study the genetic instability of S. rimosus strains and for the molecular cloning and characterization of genes involved in oxytetracycline biosynthesis. Recent advances in the methodology of genome sequencing bring the realistic prospect of obtaining the genome sequence of S. rimosus in the near term.

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“…Recently, rimocidin production by Streptomyces diastaticus var. 108 was reported; this strain also produces OTC (174).…”

Section: Gene Disruptions In the Rimocidin Biosynthetic Gene Clustermentioning

confidence: 99%

Genetics ofStreptomyces rimosus, the Oxytetracycline Producer

Petković

Cullum

Hranueli

et al. 2006

Microbiol Mol Biol Rev

101

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“…We used the RimA PKS loading module for rimocidin ( Fig. 1) from S. diastaticus variant 108; RimA PKS is capable of loading the extender module with either acetate or butyrate (21,26) (Fig. 2).…”

mentioning

confidence: 99%

Initiation of Polyene Macrolide Biosynthesis: Interplay between Polyketide Synthase Domains and Modules as Revealed via Domain Swapping, Mutagenesis, and Heterologous Complementation

Heia

Borgos

Sletta

et al. 2011

Appl Environ Microbiol

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Polyene macrolides are important antibiotics used to treat fungal infections in humans. In this work, acyltransferase (AT) domain swaps, mutagenesis, and cross-complementation with heterologous polyketide synthase domain (PKS) loading modules were performed in order to facilitate production of new analogues of the polyene macrolide nystatin. Replacement of AT 0 in the nystatin PKS loading module NysA with the propionate-specific AT 1 from the nystatin PKS NysB, construction of hybrids between NysA and the loading module of rimocidin PKS RimA, and stepwise exchange of specific amino acids in the AT 0 domain by site-directed mutagenesis were accomplished. However, none of the NysA mutants constructed was able to initiate production of new nystatin analogues. Nevertheless, many NysA mutants and hybrids were functional, providing for different levels of nystatin biosynthesis. An interplay between certain residues in AT 0 and an active site residue in the ketosynthase (KS)-like domain of NysA in initiation of nystatin biosynthesis was revealed. Some hybrids between the NysA and RimA loading modules carrying the NysA AT 0 domain were able to prime rimocidin PKS with both acetate and butyrate units upon complementation of a rimA-deficient mutant of the rimocidin/CE-108 producer Streptomyces diastaticus. Expression of the PimS0 loading module from the pimaricin producer in the same host, however, resulted in production of CE-108 only. Taken together, these data indicate relaxed substrate specificity of NysA AT 0 domain, which is counteracted by a strict specificity of the first extender module KS domain in the nystatin PKS of Streptomyces noursei.

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“…The different toxicity of these compounds against the two cell lines might be explained by the intake of higher amounts of drug by macrophage cells (phagocytic and fully differentiated) compared with that of fibroblasts (non-phagocytic and undifferentiated cells). The high trypanocidal activity of CE-108 and CE-108C is remarkable, strongly contrasting with their very low antifungal activities [22,24]; interestingly, these polyenes showed the lowest cytotoxicity amongst the polyenes tested (based on the murine macrophage results in this work), in good agreement with their low haemolytic activity [24,25]. Despite this, it is noteworthy that the three polyene amides tested (AB-400, CE-108B and rimocidin B) had increased trypanocidal activities compared with their parental carboxyl polyenes; a similar effect was observed with their antifungal activity.…”

Section: Discussionmentioning

confidence: 83%

“…108 grown in SYM2 medium, as described previously [22]. The tetraene amides, rimocidin B and CE-108B, were purified from S. diastaticus var.…”

Section: Purification Of Polyenesmentioning

confidence: 99%