To effectively address antibiotic resistance, we need to discover new antibiotics and antimicrobial strategies. Our group is approaching this in several ways with an emphasis of using Chemical Biology and Chemical Genetics strategies and in particular emphasizing microbial natural products as sources of new bioactive chemical matter. We are focused on bacterial, fungal and malarial parasite pathogens to this end.
Compounds that improve the activity of antibiotics for example increasing potency, blocking resistance, etc. are termed antibiotic adjuvants. We are screening synthetic and natural product compounds for their ability potentiate antibiotics in a number of assays including direct inhibition of known resistance mechanisms, increasing activity of antibiotics against Gram negative bacteria among others.
Authors: Cox G, Sieron A, King AM, De Pascale G, Pawlowski AC, Koteva K, Wright GD.
Reference: Cell Chem Biol. 2016 Nov 29. pii: S2451-9456(16)30434-2. doi: 10.1016/j.chembiol.2016.11.011.
Authors: Nicole Robbins, Michaela Spitzer, Tennison Yu, Robert P Cerone, Anna K Averette, Yong-Sun Bahn, Joseph Heitman, Donald C Sheppard, Mike Tyers, Gerard D Wright
Reference: Cell Rep. 2015 Nov 17;13(7):1481-92. doi: 10.1016/j.celrep.2015.10.018.
Authors: Andrew M King, Sarah A Reid-Yu, Wenliang Wang, Dustin T King, Gianfranco De Pascale, Natalie C Strynadka, Timothy R Walsh, Brian K Coombes, Gerard D Wright
Reference: Nature. 2014 Jun 26;510(7506):503-6. doi: 10.1038/nature13445.
Antibiotics that kill a broad spectrum of bacteria are not the only strategy to treat infection. Reducing the virulence of pathogens, improving the reactivity of the host innate immune response, and the discovery of highly narrow spectrum antimicrobials are others. Here we are screening natural products in particular and combinations of agents for these desired phenotypes.
Authors: Robbins N, Spitzer M, Wang W, Waglechner N, Patel DJ, O'Brien JS, Ejim L, Ejim O, Tyers M, Wright GD.
Reference: Cell Chem Biol. 2016 Nov 17;23(11):1383-1394. doi: 10.1016/j.chembiol.2016.08.015.
Authors: Perry JA, Koteva K, Verschoor CP, Wang W, Bowdish DM, Wright GD.
Reference: J Antibiot (Tokyo). 2015 Jan;68(1):40-6. doi: 10.1038/ja.2014.83.
Natural products are proven to be excellent leads for new antibiotics and other therapeutics. They represent privileged chemical matter with intrinsic bioactivity. Exploring and expanding this chemical matter is readily amenable to synthetic biology strategies. We are exploring antimicrobial natural product biosynthetic mechanism and endeavoring to use tailoring enzymes to expand the chemical diversity of several scaffolds.
Authors: G Yim, W Wang, MN Thaker, S Tan, GD Wright
Reference: ACS Infect. Dis., 2016, 2 (9), pp 642–650 DOI: 10.1021/acsinfecdis.6b00105
Authors: Maulik N Thaker, Wenliang Wang, Peter Spanogiannopoulos, Nicholas Waglechner, Andrew M King, Ricardo Medina, Gerard D Wright
Reference: Nat Biotechnol. 2013 Oct;31(10):922-7. doi: 10.1038/nbt.2685.
Living organisms have proven to be the most reliable source of bioactive chemicals with antimicrobial activity. Environmental microbes continue to be outstanding resources for the identification of new chemical scaffolds that perturb microbial biology. We are searching for new bioactive agents derived from these sources as starting points for new antimicrobial agents and to facilitate this we have established the Wright Actinomycete Collection (WAC). This library includes approximately 10,000 strains collected from a myriad of environments and includes over 25 distinct genera.