Exploring the potential of caelestamide A, a novel antibiotic with activity against Enterobacter cloacae

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1.27 million deaths were directly attributed to antimicrobial resistance in 2019. There is, therefore, an urgent need to discover and develop novel antibiotics that can overcome resistance to current treatments. The overwhelming majority of antibiotics in current clinical use are natural products isolated from bacteria and fungi, or semi-synthetic derivatives.Caelestamide A, a novel antibiotic recently identified as the product of a cryptic biosynthetic gene cluster in Streptomyces caelestis, is structurally related to salinamide A, an RNA polymerase inhibitor with promising activity against the WHO "critical priority" pathogen Enterobacter cloacae. Preliminary experiments have shown that caelestamide A is also active against Enterobacter cloacae and its structural relatedness to salinamide A suggests it has a similar mechanism of action. This is significant because RNA polymerase is a well validated but underexploited target. This project aims to further investigate the antibacterial activity of caelestamide A, confirm that it targets RNA polymerase and develop methods for producing analogues to illuminate its structure-activity relationship.This project also aims to investigate a proposed novel mechanism of self-resistance in the caelestamide producer, S. caelestis, and establish whether a similar self-resistance mechanism is employed by Actinobacteria that produce a structurally unrelated class of antibiotics that targets translation. These studies will establish a general new mechanism for self-resistance in antibiotic-producing bacteria that could be exploited to discover novel antibiotics in the future. The student will be trained in the following during the studentship: natural product isolation and structure elucidation; antibiotic susceptibility testing; biosynthetic engineering; bacterial molecular genetics; bioinformatics; long-read sequencing; protein X-ray crystallography and docking simulations.