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Biochemistry. 2009 Sep 22;48(37):8776-86. doi: 10.1021/bi9009083.

Chemical tools for dissecting bacterial physiology and virulence.

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Infectious Disease Initiative, The Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.


Increasingly, chemical biology is being used in the context of bacterial virulence and the host-pathogen interaction, as small molecule inhibitors provide a number of unique advantages for the study of bacterial pathogens that complement powerful, existing classical genetic approaches. Small molecules have the potential to inhibit targets rapidly and reversibly, with a high degree of specificity. They are therefore well suited for studying the role of essential genes in bacterial physiology and virulence in both genetically tractable and intractable organisms, with the capacity to reveal novel phenotypes and insights into the function of essential factors during infection. The use of small molecule inhibitors during infection is also deepening our understanding of the role that host factors play in bacterial pathogenesis. In the future, the utility of chemical biology will grow as technologies for rapid identification of targets of interesting bioactive small molecules are developed. In this review, we highlight recent work in which small molecule inhibitors are used to study essential genes and genetically intractable organisms, to reveal novel phenotypes related to bacterial physiology, and to probe the role of bacterial and host factors during infection. In addition, we review recent advances in biochemical, genetic, and genomic techniques for target identification.

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