Comparative analysis of a cryptic thienamycin-like gene cluster identified in Streptomyces flavogriseus by genome mining
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S H O R T CO M MU N I C A T I O N
Comparative analysis of a cryptic thienamycin-like gene cluster identiWed in Streptomyces Xavogriseus by genome mining Gloria Blanco
Received: 4 October 2011 / Revised: 28 November 2011 / Accepted: 9 December 2011 © Springer-Verlag 2011
Abstract In silico database searches allowed the identiWcation in the S. Xavogriseus ATCC 33331 genome of a carbapenem gene cluster highly related to the S. cattleya thienamycin one. This is the second cluster found for a complex highly substituted carbapenem. Comparative analysis revealed that both gene clusters display a high degree of synteny in gene organization and in protein conservation. Although the cluster appears to be silent under our laboratory conditions, the putative metabolic product was predicted from bioinformatics analyses using sequence comparison tools. These data, together with previous reports concerning epithienamycins production by S. Xavogriseus strains, suggest that the cluster metabolic product might be a thienamycin-like carbapenem, possibly the epimeric epithienamycin. This Wnding might help in understanding the biosynthetic pathway to thienamycin and other highly substituted carbapenems. It also provides another example of genome mining in Streptomyces sequenced genomes as a powerful approach for novel antibiotic discovery. Keywords Carbapenem · -Lactam · Epithienamycin · Antibiotic · Streptomyces cattleya
Introduction Carbapenems constitute an unconventional class of -lactam antibiotics considered among the most therapeutically potent Communicated by Jean-Luc Pernodet. G. Blanco (&) Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, 33006 Oviedo, Spain e-mail: [email protected]
antibiotics currently available (Nicolau 2008). They show a broad spectrum of activity being relatively resistant to most of the clinically encountered bacterial -lactamases. Thienamycin (Fig. 1), the Wrst carbapenem described (Kahan et al. 1979), is the most potent, most broad spectrum of all natural antibiotics known so far (Demain 2009). It is active against aerobic and anaerobic bacteria, both Gram-positive and Gram-negative, playing an important clinical role in the treatment of nosocomial infectious diseases (RodloV et al. 2006). Streptomyces is a bacterial genus that produces the majority of antibiotics and other molecules of medical and industrial signiWcance. Two diVerent species, Streptomyces cattleya NRRL 8057 and S. penemifaciens ATCC 31599, are known to be thienamycin producers. It has also been reported that diVerent strains of S. Xavogriseus produce carbapenem antibiotics structurally very closely related to thienamycin: epithienamycins (Stapley et al. 1981; Cassidy et al. 1981) and PS-6 and PS-7 (Shibamoto et al. 1980). However, although carbapenems are natural products, the clinically used antibiotics are thienamycin derivatives produced by chemical synthesis, since no fermentation procedures in the producer strains have been developed yet. This is mai
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