This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Since their discovery in the 1940s, the tetracycline class of antibiotics has been widely used against a broad range of Gram positive, Gram negative and more unusual targets such as Chlamydia and mycoplasmas. In addition to classic medicinal applications, chlortetracycline and oxytetracycline are commonly used at sub-therapeutic levels in animal feed as growth. As the tetracyclines have risen to become the most widely produced antibiotic, the number of resistant bacteria has increased to the point that they are nearly ubiquitous in clinical and agricultural settings. Resistance is typically conferred by either efflux of the drug (tetA) or ribsomal protection (tetM and tetO). Recently, a new enzymatic mechanism of resistance was discovered through drug inactivation (tetX). We have found crystallization conditions for tetX and are requesting beamtime for the collection of a MAD data set. Very small native crystals diffracted to 2.6 A at CHESS F1 (the crystal was shot by a colleague but was unable to collect data because of poor freezes). These freezing issues have since been resolved. We would like to collect both a native and MAD data set of the tetX protein as well as a soak of the drug-complex. Our studies are particularly relevant as one of the most recent antibiotics approved by the FDA is Tygacil or tigilcycline, a member of the tetracycline class is readily inactivated by tetX.
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