Most natural antibiotics are made by the actinomycetes, a group of Gram-positive, mvcelial bacteria that includes the genera Streptomyces and its relatives.  After the “Golden Age” of antibiotic discovery in the 1960s, very few new antibiotics were discovered, but the need for novel compounds increased, with the rise of such dangerous pathogens as methicillin resistant Staphyloccus aureus (MRSA), vancomycin resistant Enterococcus faecalis (VRE) and multiply drug resistant (MDR) Mycobacterium tuberculosis. In the 1990s, pharmaceutical companies turned to combinatorial chemistry to generate large libraries of compounds, but this approach to antibiotic discovery was unsuccessful because the compounds did not react with biological targets in the way that natural metabolites have been selected to do over millions of years of evolution. More recently, advances in Streptomyces genetics made possible the generation of novel, “hybrid” antibiotics by genetic engineering.  More promising is the discovery from actinomycete genomics that the organisms have the potential to make many more interesting compounds than are revealed by classical screening campaigns. The current challenge is to find ways to wake up the “sleeping” gene clusters so as to make available a whole gamut of novel metabolites for assessment as antibiotics. Examples of promising strategies aimed at this objective will be discussed.

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