Resistance to antibiotics is a clinical crisis of global proportion. The ability of microbes to evade antibiotics and the lack of new compounds emerging from the pharmaceutical sector means that we must have a thorough understanding of the mechanisms of resistance and its evolution. We are using a strategy termed Genomic Enzymology to study antibiotic resistance in our lab. In this approach, predicted antibiotic resistance genes are identified from available genome sequences or by direct cloning of new resistance elements based on phenotype. This is followed by rigorous structure/function analysis to understand the molecular details of resistance.
We are studying the mechanisms of resistance to several classes of antibiotics including the aminoglycosides, glycopeptides, tetracyclines, streptogramins, lipopeptides, and rifamycins. This includes understanding the detailed molecular mechanisms and the structures of antibiotic resistance proteins. In particular, we are focused on enzymes that inactivate the compounds or bypass the molecular target. Our goals are to fully understand the molecular details of resistance using protein structure and function approaches. With this information, we can begin to strategize around methods to block or otherwise avoid these resistance mechanisms.
Authors: Peter J Stogios, Georgina Cox, Peter Spanogiannopoulos, Monica C Pillon, Nicholas Waglechner, Tatiana Skarina, Kalinka Koteva, Alba Guarné, Alexei Savchenko, Gerard D Wright
Reference: Nat Commun. 2016 Apr 22;7:11343. doi: 10.1038/ncomms11343.
Authors: Andrew M King, Dustin T King, Shawn French, Eric Brouillette, Abdelhamid Asli, J Andrew N Alexander, Marija Vuckovic, Samarendra N Maiti, Thomas R Parr Jr, Eric D Brown, François Malouin, Natalie CJ Strynadka, Gerard D Wright
Reference: ACS Chem Biol. 2016 Apr 15;11(4):864-8. doi: 10.1021/acschembio.5b00944.
Authors: Georgina Cox, Peter J Stogios, Alexei Savchenko, Gerard D Wright
Reference: MBio. 2015 Jan 6;6(1). pii: e02180-14. doi: 10.1128/mBio.02180-14.
Understanding this process can help track the emergence and spread of resistance mechanisms and help us to comprehend the forces at work in selection for resistance. We approach this in two ways. First, we are searching the genomes of bacteria for genes that encode homologues of resistance enzymes and studying the enzymology of these to assess their fitness as antibiotic inactivators. Second, we are actively screening environmental organisms for novel resistance phenotypes and identifying new mechanisms. This includes collecting organisms from diverse environments and studying the molecular mechanism of resistance.
Authors: Pawlowski AC, Wang W, Koteva K, Barton HA, McArthur AG, Wright GD.
Reference: Nat Commun. 2016 Dec 8;7:13803. doi: 10.1038/ncomms13803.
Authors: Vanessa M D’Costa, Christine E King, Lindsay Kalan, Mariya Morar, Wilson WL Sung, Carsten Schwarz, Duane Froese, Grant Zazula, Fabrice Calmels, Regis Debruyne, G Brian Golding, Hendrik N Poinar, Gerard D Wright
Reference: Nature. 2011 Aug 31;477(7365):457-61. doi: 10.1038/nature10388.
We have termed the collection of all antibiotic resistance genes the “Antibiotic Resistome”. The resistome includes not only the resistance elements associated with pathogens, but also those genes in environmental organisms not usually associated with disease. Furthermore, genes that encode proteins that serve as ancestors of resistance, which we call proto-resistance genes in analogy to the cancer field.
Authors: Julie A Perry, Gerard D Wright
Reference: Bioessays. 2014 Dec;36(12):1179-84. doi: 10.1002/bies.201400128.
Authors: Julie Ann Perry, Erin Louise Westman, Gerard D Wright
Reference: Curr Opin Microbiol. 2014 Oct;21:45-50. doi: 10.1016/j.mib.2014.09.002.
Authors: Vanessa M. D'Costa, Katherine M. McGrann, Donald W. Hughes and Gerard D. Wright
Reference: Science, New Series, Vol. 311, No. 5759 (Jan. 20, 2006), pp. 374-377