Chemical biology of antibiotics
INSERM U1019 – CNRS UMR9017 – Lille University – CHU Lille – Institut Pasteur de Lille
Antibiotic (multi)drug resistance is a large and growing global health problem, particularly for tuberculosis and numerous nosocomial bacterial infections. In support of this, the World Health Organisation has proclaimed that research and drug development to combat these drug resistant bacteria is of critical priority. The CBA team investigates a series of novel strategies aimed to combat antibiotic resistant bacteria with current research focussing on the discovery and development of novel antibiotics and the development of innovate strategies that improve antibiotic penetration into bacteria.
The CBA team aims to impact on the fight against antibiotic drug resistance by discovering and developing novel classes of antibiotic drugs and develop technology to improve the entry of antibiotics into bacteria. A selection of current research programs is listed below.
- ANTIBIOCLICKS : This research program investigates a novel bioinspired technology that allows molecules to be conjugated together in a novel manner, with the specific aim of using this technology to connect antibiotics to siderophores to form Trojan horse antibiotics with improved bacterial penetration (so called sideromycin). Using this technology it is feasible that vectorise antibiotics that otherwise do not enter bacteria, and deliver them specifically into selected Gram-negative bacteria or M. tuberculosis. ANTIBIOCLICKS is a research program supported by the European Research Council (ERC consolidator Grant).
- EFFORT : This French-German collaborative research program aims to develop a novel class of bacterial efflux pump inhibitors. Antibiotic efflux pumps of Gram-negative bacteria are their primary defence mechanism to antibiotics, and a major hurdle for antibiotic drug discovery. The EFFORT consortium is developing a newly discovered class of Efflux Pump Inhibitors that can boost the activity of a plethora of antibiotics, making them much more effective. EFFORT consortium partners are experts in medicinal chemistry (Pr M. Flipo, U1177), bacterial efflux pumps and structure/functional biology (Pr. M. Pos, University of Frankfurt, Germany) and in cryo-electron tomography (Pr. A. Frangakis, University of Frankfurt, Germany). The EFFORT consortium is funded by an international – French (ANR) and German (FRDE) call for projects on antimicrobial resistance.
- NL4TB / SMART-lab : This drug discovery program is developing a new class of very potent anti-tuberculosis molecules discovered in the team. In collaboration with the U1177 medicinal chemistry team (Pr. Willand and Pr B. Villemagne) we are developing these chemical leads to achieve in vivo efficacy and help the fight against tuberculosis infections. This work has been supported by ATIP-Avenir, the SMART-Lab (private public partnership) and CTRL-CPER.
- ProActiv : This research program investigates the potential of chemically modulating pathogenic bacteria to force them to activate otherwise inactive prodrug antibiotics. With proof of concept data already obtained, research now focusses on understanding and exploiting these findings for potential clinical application. This is a collaborative research program with members of U1177 (Pr. N. Willand) and members the CIIL (Dr. A. Baulard and Dr. R. Antoine) and it supported by the CPER-CTRL.
Valderrama K, Pradel E, Firsov AM, Drobecq H, Bauderlique-le Roy H, Villemagne B, Antonenko YN, Hartkoorn RC. (2019)
Pyrrolomycins Are Potent Natural Protonophores.
Antimicrob Agents Chemother. Sep 23;63(10)
Singh V, Dhar N, Pató J, Kolly GS, Korduláková J, Forbak M, Evans JC, Székely R, Rybniker J, Palčeková Z, Zemanová J, Santi I, Signorino-Gelo F, Rodrigues L, Vocat A, Covarrubias AS, Rengifo MG, Johnsson K, Mowbray S, Buechler J, Delorme V, Brodin P, Knott GW, Aínsa JA, Warner DF, Kéri G, Mikušová K, McKinney JD, Cole ST, Mizrahi V, Hartkoorn RC.(2017)
Identification of aminopyrimidine-sulfonamides as potent modulators of Wag31-mediated cell elongation in mycobacteria.
Mol Microbiol. 2017 Jan; 03(1):13-25.
Hartkoorn RC, Uplekar S, Cole ST (2014).
Cross-resistance between Clofazimine and Bedaquiline through Up-regulation of MmpL5 in Mycobacterium tuberculosis.
Antimicrob Agents Chemother 58(5):2979-81
Hartkoorn RC, Pojer F, Read JA, Gingell H, Neres J, Horlacher OP, Altmann KH, Cole ST (2014).
Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA.
Nat Chem Biol 10: 96–98
Hartkoorn RC, Sala C, Neres J, Pojer F, Magnet S, Mukherjee R, Uplekar S, Boy-Rottger S, Altmann KH, Cole ST (2012).
Towards a new tuberculosis drug: pyridomycin – nature’s isoniazid.
EMBO Mol Med 4: 1032-1042
Antibiotics ; Antibiotics resistance ; Resistance ; Drug development ; Efflux pumps ; Sideromycin