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New aminocoumarin antibiotics from genetic engineering
Tedesco
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The dramatic increase in the number of antibiotic-resistant pathogenic bacteria in the past decade has focused the attention on the need for new anti-infective drugs. The shuffling of biosynthetic genes from different pathways and even organisms via genetic engineering represents a promising alternative approach to create new compounds and overcome bacterial resistance to existing drugs. Recent advances in the chemical DNA synthesis allow expanding the possible genes to be used in this approach and therefore the variety of new bioactive compounds. Aminocoumarins are potent inhibitors of DNA gyrase, but one reason for their restricted clinical application is the low activity against Gram-negative pathogens. One powerful approach could be a Trojan-horse strategy using the iron transport abilities of catechol siderophores in order to carry drugs with catechol motifs into Gram-negative cells. In this work, a catechol moiety was introduced into the chemical structure of an aminocoumarin antibiotic, mimicking the siderophore structure and promoting its active transport inside the cell by siderophopre transporters.
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