An integrated approach to understand the emergence and spread of extensively resistant Gram-negative bacteria in China

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Since the discovery of penicillin in 1928 more than 100 antimicrobial agents have been identified and used to treat bacterial infections. This led to the near-eradication of some infectious diseases such as tuberculosis in the developed world. This advance in scientific discovery comes with a caveat, as microbes have acquired the ability to resist the toxic effects of these antimicrobial agents.The majority of bacteria that constitute antimicrobial threats are facultative, opportunistic pathogens which are found in great numbers in the environment and readily exchange genes with a variety of other microbes. Such elements include virulence factors, which allow them to infect animals and elude the host's immune system, and antimicrobial resistance genes that render them resistant to drugs. Over recent years, the biggest emerging antimicrobial resistance threat is represented by Gram-negative bacteria, which are increasingly breaching the last-resort drugs.With the advent of genome sequencing, we have learned a lot about the genes which make bacteria pathogenic and the ones that allow them to become resistant to drugs. However, we currently do not have the required computational tools to identify the routes through which "mobile elements" move between lineages of bacteria, or even quantify the extent of these exchanges. This in turn greatly limits our ability to block such transfer of resistance elements.We have assembled a multidisciplinary team to address three integrated issues. First, we will generate an extensive database of complete genomes of unprecedented quality for three major antimicrobial threats, Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii. This will represent the first such high-quality microbial genomic database ever and will constitute a precious resource for the development of future diagnostic and prognostic tools. In a second step we will develop new computational tools to reconstruct the acquisition and spread of resistance in lineages of these three species in China. These tools will be flexible enough to be applied to genetic sequence data of any microbe and will allow us to reconstruct emergence and sread of resistance in these three species.Finally, we will perform functional validation in the lab to corroborate the findings from the bioinformatics and computational analyses. This work will also allow establishing the complex link between the genetic makeup of different lineages and their level of resistance to the three most important last-resort drugs carbapenem, tigecycline and colistin. The significance of this study lies in the multipronged approach to describe and characterise antimicrobial resistance in the most threatening Gram-negative bacteria in China. This effort will culminate in the identification of the key genetic and environmental factors that facilitate the proliferation and transmission of multi drug resistant pathogens. Such information should in turn lead to essential information on how to optimise antimicrobial stewardship both to the benefit of the patients and to stem the spread of resistance in the future.