Tuberculosis treatment is very lengthy and further exacerbated for prevalent multi-drug resistant strains. To feed the drug development pipeline for the antibiotic treatment of tuberculosis, the CBA team and its collaborative partners in medicinal chemistry (particularly Dr. B. Villemagne and Pr. N. Willand, U1177, https://www.deprezlab.fr/) have discovered and characterised a novel class of anti-tuberculosis molecules named TricyclicSpiroLactams (TriSLas) that are potent inhibitors of the type II NADH dehydrogenase. Inhibition of this enzyme prevents the bacteria from properly respiring and generating the energy it needs to grow (doi:10.1021/acs.jmedchem.2c01493). Current collaborative research efforts are focused on the final optimisation of TriSLas antibiotics towards clinical development

The complex cell wall of bacteria is a formidable xenobiotic penetration barrier and a major hurdle in antibiotic drug development. One approach observed in nature to overcome this penetration barrier is to hijack the iron acquisition machinery of bacteria for uptake. To acquire iron, bacteria synthesise and export small molecules, called siderophores. Siderophores effectively scavenge iron from the environment and are then actively taken up to internalise the iron. Some bacterial natural products are composed of an antibiotic coupled to a siderophore. In the bacterial interspecies warfare, these molecules hijack the iron uptake machinery of another species to achieve intracellular antibiotic delivery. Such natural systems have inspired the chemical synthesis of mimetic siderophore-antibiotic conjugates with improved bacterial penetration. In the CBA lab, studies on antibiotic production by a soil bacterium led to the discovery a new siderophore-antibiotic conjugate, and importantly, identified a novel means of coupling siderophores to antibiotics (doi:10.1021/acscentsci.3c00965). In an ERC-COG supported program named Antibioclicks, this mechanism of macromolecular conjugation is now being exploited to generate, characterise and develop bioinspired Trojan horse antibiotics to target the WHO priority bacterial pathogens.

In addition to their physiological role, bacterial efflux pumps are extremely efficient at expelling antibiotics out of bacteria. 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) could serve as adjuvants to improve antibiotic activity, and fight acquired drug resistance). In a collaborative program with medicinal chemists (particularly Dr. M. Flipo, U1177, ,https://www.deprezlab.fr/) and infection model specialist, Dr. L. Van Maele (CIIL), the CBA team is developing a new class of Pyridylpiperazines (PyrPips) based EPI that are potent potentiators of antibiotic activity in Enterobacterales (doi: 10.1038/s41467-021-27726-2, 10.1093/jacamr/dlad112, 10.1016/j.ejmech.2023.115630, 10.1038/s44321-023-00007-9). The team’s objective is to help develop these EPIs for clinical use to revert antibiotic resistance in multidrug-resistant clinical strains.