Multidrug resistant tuberculosis and gram +ve and -ve nosocomial bacteria are posing an ever increasing burden to global healthcare systems with high levels of associated mortality and morbidity. A major cause is that the antibiotics pipeline over the last 40 years has produced very few novel classes of antibiotics. To prevent us from entering a “post-antibiotic” era, it essential that concerted efforts are made, to both discovery novel antibiotics compounds, but also novel antibiotic drug targets. NAT-4-MDR will strive to address this pertinent problem and establish research to discover new small molecule and natural product antibacterials, and to elucidate novel vulnerable and drugable antibiotic targets in bacteria. In addition NAT-4-MDR will develop novel lines of research to address the rational modifications of natural products to exploit their potential as drugs. NAT-4-MDR is divided into three linked work-packages that are designed to tackle the antibiotic problem at different stages and from different angles. Work-package I, is setup to identify novel compounds with antibiotic activity (M. tuberculosis, S. aureus, and E. coli), either through the screening of locally available 73000 small molecules compound library, and through the targeted awakening of novel natural product antibiotics from cryptic biosynthetic gene clusters in the rare actinomycetes. The objective of work package 2 is to identify novel antibiotic targets using published potent antibiotic natural products. The elucidation of the mechanism of action of these natural products will uncover new vulnerable and drug-able targets in bacteria. In the final work-package, a rational approach to generate analogues of the natural product pyridomycin (by de novo chemistry and mutasynthesis) will seek to improve its drug-like qualities, and to investigate its potential in targeting various other targets in bacteria (here called target-switching). These work packages of NAT-4-MDR will establish a number of innovative and technical approaches in the field of antibiotics discovery and natural products that are currently not widely studied in France. This multidisciplinary approach tackles the issue of novel antibiotic development from a variety of angles, an approach considered essential to maximize the potential impact of the research. This work is clearly in line with the ambitions of the Institut Pasteur de Lille, which has the desire to investigate and act on the increasing burden of antimicrobial drug resistance. My personal experience in drug discovery for M. tuberculosis and target deconvolution within this bacterium give me the necessary expertise to drive this project. Personal preliminary data also strongly supports the feasibility of the proposed work and minimize the risk associated. Uniquely to France, and important for the proposed research is that Institut Pateur de Lille has a 73,000 small compound library, a state-of-the-art screening platform that allows for the automated nanolitre dispensing and biosafety 3 facilities that allows for the efficient screening and manipulation of M. tuberculosis. Close association of the Institut Pasteur de Lille and the University of Lille (Drugs and Molecules for Living Systems) also allows for efficient collaboration for the needed chemistry, while a strong collaboration with Prof. K-H Altmann (ETH Zurich in Switzerland) will allow for de novo chemistry of natural products (particularly pyridomycin). Overall therefore, NAT-4-MDR represents a unique package for France, with an ideally matched research project and local research infrastructure and knowledge that will maximize the potential and impact of this work.