Paul S. Hoffman

Professor Emeritus, Medicine- Infectious Diseases and International Health

Primary Location

Box 801340
Charlottesville, VA 22908

Primary Phone Number

434.924.2893

Bio & Overview

My research program focuses on molecular mechanisms of microbial pathogenesis by Legionella pneumophila (the agent of Legionnaires' disease) and the stomach ulcer causing bacterium Helicobacter pylori. Legionella pneumophila is an intracellular parasite of fresh water amoeba that when transmitted by aerosol to humans often causes severe pneumonia. We discovered that DsbA2 is a novel periplasmic disulfide bond oxidoreductase that catalyzes both the formation of disulfide bonds and corrects disulfide bonding mistakes to aid protein folding that are important in the assembly of macromolecular structures. This new family of bifunctional proteins is required for the proper formation and function of Type IV secretion virulence systems (T4SS) in many intracellular pathogens. Many of these pathogens, like L. pneumophila, are dimorphic and display a developmental cycle that ends in formation of infectious cyst-like forms that are important in transmission of disease. We hypothesize that L. pneumophila cysts are pre-programmed to activate their T4SS following contact with a suitable host cells and that DsbA2 delivers reducing equivalents to activate the Dot/Icm T4SS of L. pneumophila. Legionella is a model system for the study of obligate intracellular pathogens such as Chlamydia and Coxiella.
Helicobacter pylori colonizes the gastric mucosa of humans, a niche that is hostile to other microbes. In the absence of niche competition, how much regulation does a microbe need? We and others have shown that H. pylori contains few transcription factors and that regulation is not a strong on/off, as seen with regulators in E. coli. There are two essential transcription factors ArsR and HP1043 and while ArsR is associated with responses to acid, the function of HP1043 is unknown. Our studies connect HP1043 to oxidative stress and to redox toxicity of prodrugs like metronidazole. Using proteomics and qPCR techniques, we have identified members of the HP1043 regulon using a mutant form of the protein. We have also identified a non-coding regulatory RNA upstream of HP1043 that cooperates with HP1043 in regulating many genes of the regulon. These ncRNAs are abundant in H. pylori and appear to be important in modulating expression of many gene systems.
My laboratory has been involved in the study of drug resistance and in the development of new genomic/ bioinformatic based strategies for identifying new microbial targets to aid the discovery of new therapeutics. We have synthesized a novel antibiotic Amixicile that is a potent inhibitor of pyruvate ferredoxin oxidoreductase (PFOR) and related alpha keto acid decarboxylases common to all strictly anaerobic bacteria, anaerobic human parasites and to microaerobic human pathogens Helicobacter pylori and Campylobacter jejuni. The target is not found in humans or probiotic beneficial microorganisms. Amixicle shows efficacy against Clostridium difficile and Helicobacter pylori in mouse infection models. Related analogues with different chemistries show efficacy against biofilm producing bacteria and against Legionella pneumophila, Bacillus anthracis and MRSA strains of Staphylococcus aureus.

Academic Information

Department: Medicine- Infectious Diseases and International Health

Academic Title: Professor

Primary Education

BS, Biology, Virginia Polytechnic Institute and State University, 1972
MS, Bacteriology, Iowa State University, 1974
PhD, Microbiology, Virginia Polytechnic Institute and State University, 1977

Other Appointments

Professor, Microbiology, Immunology, and Cancer Biology

Other Affiliations

Professor, BIMS

Research Interests

Molecular mechanisms of microbial pathogenesis and antibiotic development

Selected Publications

Cheruvanky A, Stoesser N, Sheppard AE, Crook DW, Hoffman PS, Weddle E, Carroll J, Sifri CD, Chai W, Barry K, Ramakrishnan G, Mathers AJ, Enhanced Klebsiella pneumoniae Carbapenemase Expression from a Novel Tn4401Deletion., 2017; Antimicrobial agents and chemotherapy. 61(6) . PMID: 28373185 | PMCID: PMC5444142

Hutcherson JA, Sinclair KM, Belvin BR, Gui Q, Hoffman PS, Lewis JP, Amixicile, a novel strategy for targeting oral anaerobic pathogens., 2017; Scientific reports. 7(1) 10474. PMID: 28874750 | PMCID: PMC5585216

Qu Y, Olsen JR, Yuan X, Cheng PF, Levesque MP, Brokstad KA, Hoffman PS, Oyan AM, Zhang W, Kalland KH, Ke X, Small molecule promotes β-catenin citrullination and inhibits Wnt signaling in cancer., 2017; Nature chemical biology. 14(1) 94-101. PMID: 29083417

Chahales P, Hoffman PS, Thanassi DG, Nitazoxanide Inhibits Pilus Biogenesis by Interfering with Folding of the Usher Protein in the Outer Membrane., 2016; Antimicrobial agents and chemotherapy. 60(4) 2028-38. PMID: 26824945 | PMCID: PMC4808142

Kennedy AJ, Bruce AM, Gineste C, Ballard TE, Olekhnovich IN, Macdonald TL, Hoffman PS, Synthesis and Antimicrobial Evaluation of Amixicile-Based Inhibitors of the Pyruvate-Ferredoxin Oxidoreductases of Anaerobic Bacteria and Epsilonproteobacteria., 2016; Antimicrobial agents and chemotherapy. 60(7) 3980-7. PMID: 27090174 | PMCID: PMC4914612

Hoffman PS, Bruce AM, Olekhnovich I, Warren CA, Burgess SL, Hontecillas R, Viladomiu M, Bassaganya-Riera J, Guerrant RL, Macdonald TL, Preclinical studies of amixicile, a systemic therapeutic developed for treatment of Clostridium difficile infections that also shows efficacy against Helicobacter pylori., 2014; Antimicrobial agents and chemotherapy. 58(8) 4703-12. PMID: 24890599 | PMCID: PMC4136022

Kpadeh ZZ, Day SR, Mills BW, Hoffman PS, Legionella pneumophila utilizes a single-player disulfide-bond oxidoreductase system to manage disulfide bond formation and isomerization., 2014; Molecular microbiology. 95(6) 1054-69. PMID: 25534767 | PMCID: PMC4415175

Olekhnovich IN, Vitko S, Valliere M, Hoffman PS, Response to Metronidazole and Oxidative Stress is Mediated Through Homeostatic Regulator HsrA (HP1043) in Helicobacter pylori., 2013; Journal of bacteriology. () . PMID: 24296668 | PMCID: PMC3911170

Olekhnovich IN, Vitko S, Chertihin O, Hontecillas R, Viladomiu M, Bassaganya-Riera J, Hoffman PS, Mutations to essential orphan response regulator HP1043 of Helicobacter pylori result in growth-stage regulatory defects., 2013; Infection and immunity. 81(5) 1439-49. PMID: 23429531 | PMCID: PMC3647984

Kpadeh ZZ, Jameson-Lee M, Yeh AJ, Chertihin O, Shumilin IA, Dey R, Day SR, Hoffman PS, Disulfide bond oxidoreductase DsbA2 of Legionella pneumophila exhibits protein disulfide isomerase activity., 2013; Journal of bacteriology. 195(8) 1825-33. PMID: 23435972 | PMCID: PMC3624562

Warren CA, van Opstal E, Ballard TE, Kennedy A, Wang X, Riggins M, Olekhnovich I, Warthan M, Kolling GL, Guerrant RL, Macdonald TL, Hoffman PS, Amixicile, a novel inhibitor of pyruvate: ferredoxin oxidoreductase, shows efficacy against Clostridium difficile in a mouse infection model., 2012; Antimicrobial agents and chemotherapy. 56(8) 4103-11. PMID: 22585229 | PMCID: PMC3421617

Dey R, Hoffman PS, Glomski IJ, Germination and amplification of anthrax spores by soil-dwelling amoebas., 2012; Applied and environmental microbiology. 78(22) 8075-81. PMID: 22983962 | PMCID: PMC3485947

Martínez-Júlvez M, Rojas AL, Olekhnovich I, Espinosa Angarica V, Hoffman PS, Sancho J, Structure of RdxA--an oxygen-insensitive nitroreductase essential for metronidazole activation in Helicobacter pylori., 2012; The FEBS journal. 279(23) 4306-17. PMID: 23039228 | PMCID: PMC3504637

Warren CA, van Opstal EJ, Riggins MS, Li Y, Moore JH, Kolling GL, Guerrant RL, Hoffman PS, Vancomycin treatment's association with delayed intestinal tissue injury, clostridial overgrowth, and recurrence of Clostridium difficile infection in mice., 2012; Antimicrobial agents and chemotherapy. 57(2) 689-96. PMID: 23147742 | PMCID: PMC3553708

Day SR, Sifri CD, Hoffman PS, Infection of nonphagocytic host cells by legionella., 2012; Methods in molecular biology (Clifton, N.J.). 954() 463-78. PMID: 23150414

Jameson-Lee M, Garduño RA, Hoffman PS, DsbA2 (27 kDa Com1-like protein) of Legionella pneumophila catalyses extracytoplasmic disulphide-bond formation in proteins including the Dot/Icm type IV secretion system., 2011; Molecular microbiology. 80(3) 835-52. PMID: 21375592 | PMCID: PMC3086132

Ballard TE, Wang X, Olekhnovich I, Koerner T, Seymour C, Salamoun J, Warthan M, Hoffman PS, Macdonald TL, Synthesis and antimicrobial evaluation of nitazoxanide-based analogues: identification of selective and broad spectrum activity., 2011; ChemMedChem. 6(2) 362-77. PMID: 21275058 | PMCID: PMC3089805

Costa LB, JohnBull EA, Reeves JT, Sevilleja JE, Freire RS, Hoffman PS, Lima AA, Oriá RB, Roche JK, Guerrant RL, Warren CA, Cryptosporidium-malnutrition interactions: mucosal disruption, cytokines, and TLR signaling in a weaned murine model., 2011; The Journal of parasitology. 97(6) 1113-20. PMID: 21711105 | PMCID: PMC3247658