PhD position in natural products

-This thesis will be carried out at ICSN, in the Plant Metabolites team, under the supervision of Fanny Roussi, in collaboration with a team from the University of Malaya in Malaysia and the CNR (Centre National de Référence pour la Résistance aux Antibiotique-CNR, Kremlin Bicêtre).
The Institut de Chimie des Substances Naturelles (ICSN, UPR 2301 of the CNRS) is located in Gif-sur-Yvette and is part of the University of Paris-Saclay. It consists of thirteen research teams grouped into four departments. The Plant Metabolites team is specialised in the study and valorisation in medicinal chemistry of metabolites produced by plants.

The objectives of this thesis project will be to identify and develop molecules, derived from Malaysian plants, capable of inhibiting antibiotic resistance mechanisms.
Currently, more and more pathogenic micro-organisms are resistant to most antibiotics. Furthermore, the discovery and commercialisation of new antibiotics has become a rare, risky, slow and expensive process (1, 2). For example, only two new classes of antibiotics have been marketed since the 1960s, whereas more than 20 classes of antibiotics were marketed between 1940 and 1960 (4). The discovery of new antibiotics seems to be increasingly difficult, while multiple resistance to anti-infectives leads to therapeutic impasses (3). Both situations constitute a major global public health problem. New approaches to antimicrobial control are therefore needed to regain a therapeutic arsenal to effectively treat multidrug-resistant infections.
In 2017, WHO published a list of pathogens for which new therapeutic approaches are needed. The pathogens of greatest concern are carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa and Enterobacterales resistant to carbapenems and third-generation cephalosporins.
Carbapenems, used to treat many hospital-acquired infections, are the antibiotics with the broadest spectrum of activity. They are the treatments of last resort for infections with antibiotic-resistant germs. Thus, the emergence of resistance to carbapenems, mainly due to the expression of carbapenemases (enzymes that hydrolyse carbapenems), is one of the most important problems posed by antibiotic resistance because there are few therapeutic alternatives.
Thierry Naas' team at the Kremlin Bicêtre Hospital has set up biochemical screening tests for the main carbapenemases KPC-2, NDM-1 and OXA-48 found in enterobacteria, as well as tests on multi-resistant enterobacteria.
The objective of the student will be (1) to screen the 436 Malaysian plant extracts from the ICSN's extract library using the CNR's biochemical tests, (2) to carry out guided bio- and mass-purification of the 3 most promising extracts in order to identify the molecules responsible for the inhibitory activity of the carbapenemase(s), (3) to validate the activity of the pure molecules on multi-resistant strains of enterobacteria, (4) to elaborate by synthesis/hemisynthesis analogues of the most original chemical series in order to carry out a structure-activity relationship study.
1- Perspect. Med. Chem. 2014, 6, 25; 2- J. Antibio. 65, 385; 3- . P T. 2015, 40(4), 277; 4- Br J Pharmacol. 2011, 163(1), 184