Rifampin phosphotransferase is an unusual antibiotic resistance kinase

Peter J. Stogios, Georgina Cox, Peter Spanogiannopoulos, Monica C. Pillon, Nicholas Waglechner, Tatiana Skarina, Kalinka Koteva, Alba Guarné, Alexei Savchenko () and Gerard D. Wright ()
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Peter J. Stogios: University of Toronto
Georgina Cox: M.G. DeGroote Institute for Infectious Disease Research, McMaster University
Peter Spanogiannopoulos: M.G. DeGroote Institute for Infectious Disease Research, McMaster University
Monica C. Pillon: McMaster University
Nicholas Waglechner: M.G. DeGroote Institute for Infectious Disease Research, McMaster University
Tatiana Skarina: M.G. DeGroote Institute for Infectious Disease Research, McMaster University
Kalinka Koteva: M.G. DeGroote Institute for Infectious Disease Research, McMaster University
Alba Guarné: McMaster University
Alexei Savchenko: University of Toronto
Gerard D. Wright: M.G. DeGroote Institute for Infectious Disease Research, McMaster University

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Rifampin (RIF) phosphotransferase (RPH) confers antibiotic resistance by conversion of RIF and ATP, to inactive phospho-RIF, AMP and Pi. Here we present the crystal structure of RPH from Listeria monocytogenes (RPH-Lm), which reveals that the enzyme is comprised of three domains: two substrate-binding domains (ATP-grasp and RIF-binding domains); and a smaller phosphate-carrying His swivel domain. Using solution small-angle X-ray scattering and mutagenesis, we reveal a mechanism where the swivel domain transits between the spatially distinct substrate-binding sites during catalysis. RPHs are previously uncharacterized dikinases that are widespread in environmental and pathogenic bacteria. These enzymes are members of a large unexplored group of bacterial enzymes with substrate affinities that have yet to be fully explored. Such an enzymatically complex mechanism of antibiotic resistance augments the spectrum of strategies used by bacteria to evade antimicrobial compounds.

Date: 2016
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DOI: 10.1038/ncomms11343

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