Sandbox Reserved 992: Difference between revisions

Class C β-lactamases, among many other enzyme types, also contain a structural component known as an [http://en.m.wikipedia.org/wiki/Oxyanion_hole oxyanion hole]. This pocket of [http://en.m.wikipedia.org/wiki/Hydrophile hydrophilic] residues directly stabilizes the high-energy [http://en.m.wikipedia.org/wiki/Tetrahedral_carbonyl_addition_compound tetrahedral intermediate], lowering the activation energy and promoting a faster overall reaction.<ref>Albert Lehninger et al. (2008). Principles of Biochemistry (5th ed.). Macmillan. p. 207.</ref><ref>Livermore, David. β-Lactamase mediated resistance and opportunities for its control. J. Antimicrob. Chemother. (1998) 41 (suppl 4): 25-41.</ref>

Since the discovery of penicillin in the late 1920s by [http://en.m.wikipedia.org/wiki/Alexander_Flemming Alexander Flemming]<ref>American Chemical Society International Historic Chemical Landmarks. Discovery and Development of Penicillin. http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html (accessed Feb 26, 2015).</ref> β-lactam antibiotics, characterized by their central chemical structure, the β-lactam ring, have played an important role in human health. Unfortunately, extensive use, and often misuse, of such drugs has led to an increased resistance in many species of bacterium resulting in major clinical treatment dilemmas.  Each year in the United States alone, a minimum of 2 million people are infected with drug-resistant bacteria and of those 2 million, at least 23,000 infections result in fatality.<ref>Antibiotic Resistant Threat Report in the United States, 2013. Centers for Disease Control and Prevention. 16 September, 2013.</ref> Fortunately, fiscal year funding for antibiotic resistance research from the U.S. government has nearly to $1.2 billion, providing a more optimistic outlook for this serious issue in clinical treatment.<ref>ASM Statement on the President’s Proposed 2016 Budget to Combat Antibiotic-resistant Bacteria. American Society for Microbiology. 28 Jan 2015. Web. 22 Feb 2015.</ref>

With the mechanistic knowledge of β-lactamases, there are two apparent options for clinical treatment of β-lactam resistant bacteria. Scientists could either (a) design an entirely new class of antibiotic that are not reliant on the chemical structure of the β-lactam ring, or (b) use the current arsenal of antibiotics in combination with an inhibitor that will deactivate the β-lactamase. A β-lactamase inhibitor is a compound that could form a tight complex to the active site of the enzyme and causes the β-lactamase to be unable to bind and inactivate another antibiotic molecule. Links to examples Class C β-lactamases, both with and without clinical inhibitors bound, are provided.<ref>Powers, Rachel, Hollister C. Swanson, Magdalena A. Taracila, Nicholas W. Florek, Chiara Romagnoli, Emilia Caselli, Fabio Prati, Robert A. Bonomo, and Bradley J. Wallar. Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii. Biochemistry, 2014, 53 (48), 7670-7679.</ref>