An inhibited state of bacterial RNA polymerase as a framework for antibiotic design.

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Successfully managing bacterial infections in humans and in animals has been possible through the use of antibiotics, agents that kill the bacteria and or stop them from growing. Resistance to these compounds is now wide spread, in part because bacteria mutate to evade the actions of these agents and in part because for all known natural antibiotics, a resistance mechanism is genetically encoded in the organism which makes the anti bacterial compound. These intrinsic resistance mechanisms are portable and can transfer between bacteria to help spread drug resistance.Recently we have unraveled, in great detail, how one natural protein inhibitor works to prevent an essential bacterial machinery from functioning. This machine accesses and converts the genetic information stored in DNA in a process called transcription which eventually allows proteins to be made. Proteins carry out the majority of cellular activities. Therefore, without the proper function of this essential machine, the bacteria can't survive. Interestingly this machine is relatively conserved among bacteria but very different from humans and animals, so it is a good target for broad spectrum antibiotics to work. We plan to use our newly acquired in-depth knowledge to design new non-native compounds that will inhibit and/or kill bacteria. To do so we will use methods that allow us to look at how these molecules are organized in 3-dimension to understand the exact detailed interactions at the molecular and atomic levels, and use this information to design small inhibitors of this essential machinery. We have a wide range of methods to study in mechanistic details this essential machinery, called the bacterial multi-subunit RNA polymerase, and so can work out how best to inhibit it based on our knowledge of a novel naturally occurring factor which normally inhibits the machine. This approach has not been previously taken, rather naturally occuring small molecules have been sought which inhibit the RNA polymerase machine.