- A.B., 1968, Rice University, Biochemistry.
- Ph.D., 1975, University of Texas, Dallas, Molecular Biology.
- Postdoctoral research: Harvard University Medical School.
Joined the department in 1987.
Awards: College of Agriculture and Life Sciences Dean’s Outstanding Achievement in Faculty Mentoring, 2015.
Molecular Mechanisms of Host Cell Lysis
The Young laboratory is primarily focused on the molecular mechanisms by which bacteriophages, or bacterial viruses, accomplish host cell lysis. Bacteria have a sturdy cell wall made up of a cross-linked polysaccharide derivative called the peptidoglycan. This incredibly strong and rigid structure keeps the membrane sac of the cell from blowing up like an overfilled balloon, yet it is also growing dynamically, allowing E. coli to double in length every 20 minutes in rich medium. A bacterial virus must accomplish at least local degradation of the cell wall in order to cause cell lysis and release of the progeny virus particles.
The main strategy for cell lysis, and indeed, the strategy employed by all double-stranded DNA bacteriophages, is to synthesize an enzyme, generically called an endolysin, which can degrade the peptidoglycan. The essential point is that the enzyme must not only get out of the cell to attack the cell wall but also do so at the proper time; i.e., when there have been sufficient numbers of progeny virions assembled in the infected cell. We work on a remarkable class of small membrane proteins which we have called ‘holins’, because they form ‘holes’ in the cell membrane to let out the endolysin. More than 60 different holins have been identified by scanning the genomes of different bacteriophages. We are focusing on the molecular properties of these proteins which permit them form holes in the membrane and also, perhaps even more importantly, on the ‘clock’ which allows the proteins to form the holes at the precisely correct time. In collaboration with Mike Manson of Biology, our lab showed that the holins accumulate utterly harmlessly in the membrane until they suddenly “trigger” to disrupt the membrane and kill the cell. A few seconds later, the cell explodes because the endolysins have been released and attacked the cell wall.
Another way to achieve lysis is to subvert the delicate biochemical pathways by which cell walls grow and form separations between progeny cells. We have discovered that, unlike dsDNA phages, small ssRNA and ssDNA bacteriophages, which have only room for 3 – 10 genes, synthesize a protein called an ‘amurin’ that inhibits a specific step in cell wall synthesis. As a result, just as if the cell wall synthesis had been blocked by a chemical antibiotic like penicillin, when the cell tries to divide and make a new cell wall between the daughter cells, it fails and lyses. This discovery may lead to a completely new class of antibiotics that mimic the molecular action of the amurins.
Our lab is also interested in phage genomics and in applications of phage biology to antibacterial therapy, prophylaxis and diagnosis. Please visit the lab web page for information on these efforts.
- Yao, GW, Duarte, I, Le, TT, Carmody, L, LiPuma, JJ, Young, R et al.. A Broad Host Range Tailocin from Burkholderia cenocepacia. Appl. Environ. Microbiol. 2017; :. doi: 10.1128/AEM.03414-16. PubMed PMID:28258146 .
- Cahill, J, Rajaure, M, O'Leary, C, Sloan, J, Marrufo, A, Holt, A et al.. Genetic Analysis of the Lambda Spanins Rz and Rz1: Identification of Functional Domains. G3 (Bethesda). 2017;7 (2):741-753. doi: 10.1534/g3.116.037192. PubMed PMID:28040784 PubMed Central PMC5295617.
- Gorzelnik, KV, Cui, Z, Reed, CA, Jakana, J, Young, R, Zhang, J et al.. Asymmetric cryo-EM structure of the canonical Allolevivirus Qβ reveals a single maturation protein and the genomic ssRNA in situ. Proc. Natl. Acad. Sci. U.S.A. 2016;113 (41):11519-11524. doi: 10.1073/pnas.1609482113. PubMed PMID:27671640 PubMed Central PMC5068298.
- Chen, Y, Young, R. The Last r Locus Unveiled: T4 RIII Is a Cytoplasmic Antiholin. J. Bacteriol. 2016;198 (18):2448-57. doi: 10.1128/JB.00294-16. PubMed PMID:27381920 PubMed Central PMC4999926.
- Guardia, A, Gulten, G, Fernandez, R, Gómez, J, Wang, F, Convery, M et al.. N-Benzyl-4-((heteroaryl)methyl)benzamides: A New Class of Direct NADH-Dependent 2-trans Enoyl-Acyl Carrier Protein Reductase (InhA) Inhibitors with Antitubercular Activity. ChemMedChem. 2016;11 (7):687-701. doi: 10.1002/cmdc.201600020. PubMed PMID:26934341 .
- Fan, X, Duan, X, Tong, Y, Huang, Q, Zhou, M, Wang, H et al.. The Global Reciprocal Reprogramming between Mycobacteriophage SWU1 and Mycobacterium Reveals the Molecular Strategy of Subversion and Promotion of Phage Infection. Front Microbiol. 2016;7 :41. doi: 10.3389/fmicb.2016.00041. PubMed PMID:26858712 PubMed Central PMC4729954.
- Young, R, Gill, JJ. MICROBIOLOGY. Phage therapy redux--What is to be done?. Science. 2015;350 (6265):1163-4. doi: 10.1126/science.aad6791. PubMed PMID:26785457 .
- Liu, M, Gill, JJ, Young, R, Summer, EJ. Bacteriophages of wastewater foaming-associated filamentous Gordonia reduce host levels in raw activated sludge. Sci Rep. 2015;5 :13754. doi: 10.1038/srep13754. PubMed PMID:26349678 PubMed Central PMC4563357.
- Liu, M, Bischoff, KM, Gill, JJ, Mire-Criscione, MD, Berry, JD, Young, R et al.. Bacteriophage application restores ethanol fermentation characteristics disrupted by Lactobacillus fermentum. Biotechnol Biofuels. 2015;8 :132. doi: 10.1186/s13068-015-0325-9. PubMed PMID:26339290 PubMed Central PMC4558781.
- Das, M, Bhowmick, TS, Ahern, SJ, Young, R, Gonzalez, CF. Control of Pierce's Disease by Phage. PLoS ONE. 2015;10 (6):e0128902. doi: 10.1371/journal.pone.0128902. PubMed PMID:26107261 PubMed Central PMC4479439.