Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Due to the emergence of antibiotic resistant bacteria (such as methicillin-resistant Staphylococcus aureus, MRSA) there is an urgent need to develop new antibacterial agents. Kibdelomycin is a recently discovered hybrid polyketide/non- ribosomal peptide natural product isolated from Kibdelosporangium sp. MA7385 that has broad spectrum bacteriostatic activity against both Gram negative and Gram positive bacteria (including MRSA). Intriguingly, the molecular structure of this new antibiotic contains many unusual functional groups (e.g. an exocyclic olefin, a dichloropyrrole moiety, etc.) which present opportunities for modification to improve its therapeutic properties. We are undertaking an effort to produce new derivatives of kibdelomycin through semi-synthesis and eventually by precursor directed biosynthesis. In order to realize the goal of precursor directed biosynthesis of kibdelomycin, we will identify the gene cluster of kibdelomycin through analysis of the genome of Kibdelosporangium sp. MA7385. Once we have identified the gene cluster, we will heterologously express the cluster in E. coli and study the key biosynthetic transformations involved in kibdelomycin biosynthesis (for example, we will study the biosynthesis of the dichloropyrrole moiety and also determine whether unnatural pyrrole substrates can be incorporated into the natural product). Through these combined approaches our aim is to produce a small library of kibdelomycin analogs for evaluation as bacteriostatic agents.
By producing new analogs of kibdelomycin, we may be able to develop a new antibiotic that has superior antibacterial properties. Since kibdelomycin acts upon a previously validated bacterial target, it is expected to have high therapeutic potential, and will act as a new tool to combat antibiotic resistant bacteria.
| O'Brien, Robert V; Davis, Ronald W; Khosla, Chaitan et al. (2014) Computational identification and analysis of orphan assembly-line polyketide synthases. J Antibiot (Tokyo) 67:89-97 |
| Lowry, Brian; Robbins, Thomas; Weng, Chih-Hisang et al. (2013) In vitro reconstitution and analysis of the 6-deoxyerythronolide B synthase. J Am Chem Soc 135:16809-12 |
