Micacocidin, a drug against Mycoplasma pneumoniae – From biosynthetic knowledge to SAR studies and target fishing

Abstract

The cell wall-lacking bacterium Mycoplasma pneumoniae is one of the leading causes of community-acquired pneumonia and other respiratory disorders in children. Recent reports of resistance emerging under antibiotic treatment have caused great concern and underline the importance to develop new effective drugs against this pathogen [1]. Using a genome mining strategy, we previously identified the gene cluster for the biosynthesis of micacocidin, a thiazoline-containing natural product with pronounced activity against M. pneumoniae [2]. Although the organization of the micacocidin assembly line reflects the close relationship to the siderophore yersiniabactin, the molecular basis for the subtle, yet pharmacologically significant structural differences between the two compounds were not clear. We dissected the early steps in micacocidin biosynthesis through a combination of stable isotope feeding experiments, gene inactivation, as well as in vivo and in vitro reconstitution of enzymatic key reactions. This approach led to the identification of a highly unusual iterative acting type I polyketide synthase [3]. Exploiting the promiscuity of this enzyme, new micacocidin analogs were engineered for structure-activity relationship studies [4]. Furthermore, clickable groups could be introduced into micacocidin, setting the stage for target fishing studies.