Development of corramycin as an antibiotic against Gram-negative bacteria
Gram-negative bacteria are naturally insensitive to many antibiotics due to their additional outer membrane. In addition, the bacteria have acquired resistance to clinically used antibiotics in recent decades, resulting in multidrug-resistant bacteria. Novel classes of antibiotics are needed to counteract these existing resistance mechanisms. However, no new antibiotic class against Gram-negative bacteria has been approved in more than 50 years. Corramycin is a natural product from myxobacteria that exhibits selective activity against Gram-negative pathogens. Due to its unique structure and novel mode of action, corramycin displays several promising features, especially a lack of cross-resistance to clinically used antibiotics. In addition, it has been proven to be active in vivo in mouse studies. We are currently working on elucidating the mode of action and improving the production of the compound. Chemical optimisation is expected to ultimately lead to a new pre-clinical candidate.
Corramycin is a structurally unique natural product isolated from the myxobacterium Corallococcus coralloides. The molecule exhibits activity against Gram-negative bacteria from the Enterobacteriaceae family, including multidrug-resistant isolates. The narrow spectrum of activity of corramycin results from the use of specific transporter systems that import corramycin into its target pathogens, reducing the selection pressure on off-target pathogens and causing less harmful effects on the microbiome. Corramycin has a structurally unique scaffold and a novel mode of action, enabling it to overcome existing resistance mechanisms. Corramycin has a rapid bactericidal effect, rendering it effective in a mouse peritonitis model despite its short in vivo half-life. Noteworthy, the natural product shows low frequency of resistance in vivo and an excellent safety profile.
Scientists at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) worked with Sanofi and Evotec on the modification of the corramycin scaffold for several years. By introducing a siderophore moiety, Evotec was able to broaden the antibacterial spectrum of corramycin and significantly increase its activity against Gram-negative bacteria. Based on the pharmaceutical properties of the preclinical candidate, the compound was developed for the treatment of urinary tract infections. However, Evotec ultimately decided to discontinue the project due to the difficulties associated with producing large quantities of the compound required for clinical trials at reasonable cost of goods.
The HIPS scientists are currently working on increasing the production of corramycin. This is being achieved by optimisation of the fermentation process and heterologous expression, and by an improved total synthesis route which also allows the synthesis of derivatives. In addition, further investigations focus on the mode of action and target identification. Ultimately, by means of a multiparameter-optimisation a suitable optimised candidate for further studies shall be identified.
