Novel antibiotic classes: The CBA team focusses on discovering novel classes of antibiotic molecules using a number of exciting and successful strategies. The approaches include the testing of unique chemical libraries, the evaluation of the activity of natural products derived from silent biosynthetic gene clusters in rare actinomycetes genus called Dactylosporangium and the reprogramming of bacteria to activate potential prodrugs. The CBA team puts a particular emphasis and value on deciphering the mechanism of action of discovered novel antibiotic molecules and using this information to further developer the molecules into drug-candidates. Thus far, promising advanced programs are running on novel classes of anti-tuberculosis and anti-baumannii molecules, with numerous exploratory programs ongoing to feed the antibiotic pipeline.

Vectorisation of antibiotics: The complex cell wall of bacteria is a formidable xenobiotic penetration barrier and a major hurdle in antibiotic drug development. Vectorisation of potential drugs to improve their bacterial penetration would “open the door” for many novel antibiotic compounds as well as repurposing Gram-positive antibiotics against Gram-negative bacteria. A ERC-COG supported project; AntibioClicks will exploit a newly discovered natural chemical reaction (bioinspired) to vectorise antibiotics so that they are actively transported into the bacteria, for subsequent intracellular release and bacterial killing. This “Trojan horse” strategy opens the door to develop new or repurposed antibiotics to efficiently stealth their way into the most clinically important bacteria.

Antibiotic efflux pump inhibitors. In addition, bacterial penetration, antibiotic efflux pumps are extremely efficient at expelling potential antibiotics out of bacteria, and rendering them inactive. Efflux pumps are a major cause of both innate antibiotic resistance (particularly in Gram-negative bacteria) as well as acquired antibiotic drug resistance. Efflux pump inhibitors (EPIs) would serve as adjuvants to improve antibiotic activity, and fight acquired drug resistance. Through a funded international collaborative program, EFFORT, a novel class of EPIs is being developed that boosts antibiotic activity in a large panel of clinically important Gram-negative bacteria.

Novel mechanisms of antibiotic resistance: Bacteria have co-evolved in competition with bacteria, fungi and eukaryotes, allowing for the development of many effective mechanisms to resist antibiotic selection. Many types of mechanisms of resistance have been described; however these classes of resistance do not explain all resistance phenotypes. The CBA team works on a likely novel mechanism by which bacteria become innately resistant to some antibiotics.