Antibiotics constitute one of the most effective classes of therapeutic agents developed over the last century;however, the sustained use of these compounds has led to widespread bacterial resistance, such as in methicillin-resistant Staphylococcus aureus (MRSA), necessitating the development of novel antibacterial compounds. Berninamycin A, from the thiazolyl peptide family, has shown activity against Gram-positive bacteria, including MRSA. Currently, the sequence of events comprising the biosynthesis of berninamycin is unknown as are the structural requirements for its formation in the producing organism. We will therefore: 1) reconstitute berninamycin in vitro from the pre-berninamycin peptide, utilizing the appropriate enzymes from the Streptomyces bernensis gene cluster and 2) investigate the substrate structural requirements for berninamycin synthesis in vivo, through genetic manipulation of S. bernensis. The information garnered from this study will increase our knowledge of how Nature constructs these architecturally unique heterocyclic molecules and may lead to the development of more potent medicines, especially antibiotics.
Antibiotics are one of the most successful classes of drugs developed over the last century and are vital to preserving human health and preventing the spread of disease;the continual use of these compounds, however, has led to widespread bacterial resistance to them, leading to a medical danger and requiring the development of new antibiotics. This project aims to investigate the biological synthesis of a naturally produced antibiotic, berninamycin, a member of a potent yet underexplored class of antibacterial agents known as thiazolyl peptides, along with what features of the molecule are necessary for its production and how it functions as an antibiotic. Our studies may eventually lead to more effective drugs to combat bacterial infection.
|Malcolmson, Steven J; Young, Travis S; Ruby, J Graham et al. (2013) The posttranslational modification cascade to the thiopeptide berninamycin generates linear forms and altered macrocyclic scaffolds. Proc Natl Acad Sci U S A 110:8483-8|