Antibacterial Drug Discovery & Development

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 AntiBac 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 of the bacterial electron transport chain (doi:10.1021/acs.jmedchem.2c01493). Current collaborative research efforts are focused on the optimisation of TriSLa drug like properties (ADMET/PK), characterising TriSLa efficacy in infection models, developing and evaluating the efficacy of TriSLa based combination regimens and characterising the antibiotic efficacy of TriSLa against non-tuberculous mycobacteria such as M. abscessus and M. avium.

Key AntiBac team members involve: Dr. Vien Ho, Dr. Kamel Djaout, Jonathan Chatagnon, Hind Oulkfif, Dr. Elizabeth Pradel and Dr. Ernesto Anoz-Carbonell (Past: Dr Sushovan Dam)

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 AntiBac lab, studies on antibiotic production by a soil bacterium led to the discovery of 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.

Key AntiBac team members involve: Dr. Ernesto Anoz-Carbonell, Dr. Ravil Petrov, Dr. Shahriar Safari (Past: Dr. Thibault Caradec & Dr Iullia Ustimenko)

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/), the national reference centre for Enterobacterales (Dr. R. Bonnet) and infection model specialist, Dr. L. Van Maele (CIIL), the AntiBac team is developing a new class of Pyridylpiperazines (PyrPips) based EPIs that are 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). Current effort focus on deciphering the in vitro and in vivo impact of EPIs on the treatment of multidrug-resistant clinical strains, with the aim of defining the optimal means of using such EPIs to revert antibiotic resistance.

Key AntiBac team members involve: Dr. Elizabeth Pradel, Cécilia Sobieski, Léa Lèbre, Jonathan Chatagnon (Past: Dr. Coline Plé, Dr. Juan Carlos Jiménez-Castellanos)