Mario F. Feldman, Ph.D.

Professor
Molecular Microbiology

Molecular Microbiology and Microbial Pathogenesis Program
Plant and Microbial Biosciences Program

  • 314-747-4473

  • 314-362-1262

  • mfeldman@wusm.wustl.edu

  • Pathogenesis of multidrug resistant bacteria and biogenesis of bacterial vesicles in the human gut

Research Abstract:

Acinetobacter baumannii (Ab), the highest ranked Gram-negative bacterium warranting research and development of novel therapeutics. Initially, our work focused on the glycobiology of the Ab cell surface, exploring capsule biosynthesis and protein glycosylation, both of which are considered the primary virulence factors of Ab. This work was the foundation for subsequent research addressing Ab bacterial secretion systems. In fact, our group was the first to demonstrate the functionality of multiple secretion systems and to determine their contribution to Ab virulence in various models of infection. Indeed, we have developed a murine model system to investigate uropathogenesis by Ab, which was urgently needed as ~20% of the modern Ab clinical isolates come from urinary sources. In most of our pathogenesis studies we employ recent clinical isolates. Through these studies, we identified novel virulence factors that are absent in traditional lab isolates, such some CUP pili and the glycoprotease CpaA, among others. We have also shown that novel clinical Ab isolates are able to replicate within macrophages. In addition, we have discovered novel strategies involved in the dissemination of multidrug resistance in Ab. Our contributions to the field of Acinetobacter pathogenesis have been published in Nature Communications, PNAS, Science Advances, mBio and PLoS pathogens. My longterm goal is to contribute to the development of novel therapeutic and preventative interventions against Ab. For the last 10 years, my team has employed biochemistry, molecular biology, and mass spectrometry to investigate membrane vesiculation across diverse bacterial species uncovering important molecular aspects of vesicle biogenesis, and because of this work, I am regarded as a world-leader in the study of bacterial vesiculation. Furthermore, we have also utilized our expertise in bacterial membrane vesiculation to engineer membrane vesicles as novel vaccine delivery platforms. Although, bacterial vesicles play several different roles during both, pathogenesis and symbiosis, their biogenesis mechanisms are not well-understood. We demonstrated that, unlike other species, gut bacteria selectively pack proteins, most of them involved in degradation of glycans, into their vesicles. Using these proteins as molecular markers, we recently employed videomicroscopy to, for the first time, visualize outer membrane vesicle (OMV) formation in Bacteroides. These findings put my team in a privileged position to elucidate the mechanisms of OMV biogenesis, which have been elusive for more than five decades. Work on this topic in my lab is currently supported by an R21grant (see below). My long term goal is to develop novel vaccine and antimicrobials against bacterial pathogens and to further employ engineered OMV for vaccine and therapeutic applications.

Selected Publications:

2. Le NH, Pinedo V, Lopez J, Cava F, Feldman MF. Killing of Gram-negative and Gram-positive bacteria by a bifunctional cell wall-targeting T6SS effector. Proc Natl Acad Sci U S A. 2021 Oct 5;118(40):e2106555118. doi: 10.1073/pnas.2106555118. PMID: 34588306.

3. Benomar S, Di Venanzio G, Feldman MF. Plasmid-Encoded H-NS Controls Extracellular Matrix Composition in a Modern Acinetobacter baumannii Urinary Isolate. J Bacteriol. 2021 Oct 12;203(21):e0027721. doi: 10.1128/JB.00277-21. PMID: 34398664.

4. Lopez J, Le NH, Moon KH, Salomon D, Bosis E, Feldman MF. Formylglycine-Generating Enzyme-Like Proteins Constitute a Novel Family of Widespread Type VI Secretion System Immunity Proteins. J Bacteriol. 2021 Oct 12;203(21):e0028121. doi: 10.1128/JB.00281-21. Aug 16. PMID: 34398661.

5. Sycz G, Di Venanzio G, Distel JS, Sartorio MG, Le NH, Scott NE, Beatty WL, Feldman MF. Modern Acinetobacter baumannii clinical isolates replicate inside spacious vacuoles and egress from macrophages. PLoS Pathog. 2021 Aug 9;17(8):e1009802. doi: 10.1371/journal.ppat.1009802. PMID: 34370792


6. Talyansky Y, Nielsen TB, Yan J, Carlino-Macdonald U, Di Venanzio G, Chakravorty S, Ulhaq A, Feldman MF, Russo TA, Vinogradov E, Luna B, Wright MS, Adams MD, Spellberg B. Capsule carbohydrate structure determines virulence in Acinetobacter baumannii. PLoS Pathog. 2021 Feb 2;17(2):e1009291. doi: 10.1371/journal.ppat.1009291. eCollection 2021 Feb.PMID: 33529209

7. Haurat MF, Scott NE, Di Venanzio G, Lopez J, Pluvinage B, Boraston AB, Ferracane MJ, Feldman MF. The Glycoprotease CpaA Secreted by Medically Relevant Acinetobacter Species Targets Multiple O-Linked Host Glycoproteins. mBio. 2020 Oct 6;11(5):e02033-20. doi: 10.1128/mBio.02033-20. PMID: 33024038.

8. Le NH, Peters K, Espaillat A, Sheldon JR, Gray J, Di Venanzio G, Lopez J, Djahanschiri B, Mueller EA, Hennon SW, Levin PA, Ebersberger I, Skaar EP, Cava F, Vollmer W, Feldman MF. Peptidoglycan editing provides immunity to Acinetobacter baumannii during bacterial warfare, Science Advances, 2020. Jul 22;6(30):eabb5614. doi: 10.1126/sciadv.abb5614. eCollection 2020 Jul.
9. Ruiz FM, Lopez J, Ferrara CG, Santillana E, Espinosa YR, Feldman MF, Romero A.Structural Characterization of TssL from Acinetobacter baumannii: a Key Component of the Type VI Secretion System. J Bacteriol. 2020 Aug 10;202(17). pii: e00210-20. doi: 10.1128/JB.00210-20. Print 2020 Aug 10. PMID: 32571965

10. Wenzel CQ, Mills DC, Dobruchowska JM, Vlach J, Nothaft H, Nation P, Azadi P, Melville SB, Carlson RW, Feldman MF, Szymanski CM. An atypical lipoteichoic acid from Clostridium perfringens elicits a broadly cross-reactive and protective immune response. J Biol Chem. 2020 Jul 10;295(28):9513-9530. doi: 10.1074/jbc.RA119.009978. Epub 2020 May 18. PMID: 32424044

11. Lopez J, Ly PM, Feldman MF. The Tip of the VgrG Spike Is Essential to Functional Type VI Secretion System Assembly in Acinetobacter baumannii. mBio. 2020 Jan 14;11(1). pii: e02761-19. doi: 10.1128/mBio.02761-19. PMID: PMID: 31937641

12. Vorkapic D, Mitterer F, Pressler K, Leitner DR, Anonsen JH, Liesinger L, Mauerhofer LM, Kuehnast T, Toeglhofer M, Schulze A, Zingl FG, Feldman MF, Reidl J, Birner-Gruenberger R, Koomey M, Schild S. A Broad Spectrum Protein Glycosylation System Influences Type II Protein Secretion and Associated Phenotypes in Vibrio cholerae. Front Microbiol. 2019 Dec 3;10:2780. doi: 10.3389/fmicb.2019.02780. eCollection 2019. PMID: 31849912

13. Calix JJ, Burnham JP, Feldman MF. Comparison of the Clinical Characteristics of Hospital-Acquired and Non-Hospital-Acquired Acinetobacter calcoaceticus-baumannii Complex in a Large Midwest US Health Care System. Open Forum Infect Dis. 2019 Oct 4;6(10):ofz423. doi: 10.1093/ofid/ofz423. eCollection 2019 Oct. PMID: 31660377.

14. Feldman MF, Mayer AE, Scott NE, Vinogradov E, McKee SR, Chavez SM, Twentyman J, Stallings CL, Rosen DA, Harding CM. A promising bioconjugate vaccine against hypervirulent Klebsiella pneumoniae. Proc Natl Acad Sci U S A. 2019. doi/10.1073/pnas.1907833116


15. * Urusova DV, Kinsella RL, Salinas ND, Haurat MF, Feldman MF, Tolia NH. The structure of Acinetobacter secreted protease CpaA complexed with its chaperone CpaB reveals a novel mode of a T2SS chaperone-substrate interaction. J Biol Chem. 2019 Jul 18. pii: jbc.RA119.009805. doi: 10.1074/jbc.RA119.009805.

16. * Di Venanzio G, Flores-Mireles AL, Calix JJ, M Haurat MF, Scott NE, Palmer LD, Potter RF, Hibbing ME, Friedman L, Wang B, Dantas G, Skaar EP, Hultgren SJ, Feldman MF. Urinary tract colonization is enhanced by a plasmid that regulates uropathogenic Acinetobacter baumannii chromosomal genes Nature Communications. 10: 2763 (2019).

17. Burnham JP, Feldman MF, Calix JJ. Seasonal Changes in the Prevalence of Antibiotic-Susceptible Acinetobacter calcoaceticus-baumannii Complex Isolates Result in Increased Multidrug Resistance Rates During Winter Months. Open Forum Infect Dis. 2019 May 22;6(6):ofz245. doi: 10.1093. PMID: 31214631

18. * Harding CM, Nasr MA, Scott NE, Goyette-Desjardins G, Nothaft H, Mayer AE, Chavez SM, Huynh JP, Kinsella RL, Szymanski CM, Stallings CL, Segura M, Feldman MF. A platform for glycoengineering a polyvalent pneumococcal bioconjugate vaccine using E. coli as a host. Nat Commun. 2019 Feb 21;10(1):891. doi: 10.1038/s41467-019-08869-9.

19. * Di Venanzio G, Moon KH, Weber BS, Lopez J, Ly PM, Potter RF, Dantas G, Feldman MF. Multidrug-resistant plasmids repress chromosomally encoded T6SS to enable their dissemination. Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1378-1383. doi: 10.1073/pnas.1812557116.

20. * Valguarnera E, Scott NE, Azimzadeh P, Feldman MF. Surface Exposure and Packing of Lipoproteins into Outer Membrane Vesicles Are Coupled Processes in Bacteroides. mSphere. 2018 Nov 7;3(6). pii: e00559-18. doi: 10.1128/mSphere.00559-18.
21. * Harding CM, Haurat MF, Vinogradov E, Feldman MF. Distinct amino acid residues confer one of three UDP-sugar substrate specificities in Acinetobacter baumannii PglC phosphoglycosyltransferases. Glycobiology. 2018 Apr 13. doi: 10.1093/glycob/cwy037.

22. * Lopez J, Feldman MF. Expanding the molecular weaponry of bacterial species. J Biol Chem. 2018 Feb 2;293(5):1515-1516. doi: 10.1074/jbc.H118.001463. Epub 2018 Feb 2. PMID: 29292211.

23. * Kinsella RL, Lopez J, Palmer LD, Salinas ND, Skaar EP, Tolia NH, Feldman MF. Defining the interaction of the protease CpaA with its type II secretion chaperone CpaB and its contribution to virulence in Acinetobacter species.J Biol Chem. 2017 Dec 1;292(48):19628-19638. doi: 10.1074/jbc.M117.808394. Epub 2017 Oct 5.PMID: 28982978.
24. * Valguarnera E, Feldman MF. Glycoengineered Outer Membrane Vesicles as a Platform for Vaccine Development.Methods Enzymol. 2017;597:285-310. doi: 10.1016/bs.mie.2017.06.032. Epub 2017 Aug 18.

25. Lazzaro M, Feldman MF, García Véscovi E. A Transcriptional Regulatory Mechanism Finely Tunes the Firing of Type VI Secretion System in Response to Bacterial Enemies. MBio. 2017 Aug 22;8(4). pii: e00559-17. doi: 10.1128/mBio.00559-17.PMID: 28830939

26. * Moon KH, Weber BS, Feldman MF. Subinhibitory concentrations of trimethoprim and sulfamethoxazole prevent biofilm formation by Acinetobacter baumannii through inhibition of Csu pili expression. Antimicrob Agents Chemother. 2017 Jul 3. pii: AAC.00778-17. doi: 10.1128/AAC.00778-17.

27. * Harding CM, Pulido MR, Di Venanzio G, Kinsella RL, Webb AI, Scott NE, Pachón J, Feldman MF. Pathogenic Acinetobacter species have a functional type I secretion system and contact-dependent inhibition systems. J Biol Chem. 2017 Jun 2;292(22):9075-9087. doi: 10.1074/jbc.M117.781575. Epub 2017 Apr 3.

28. Rangarajan M, Aduse-Opoku J, Hashim A, McPhail G, Luklinska Z, Haurat MF, Feldman MF, Curtis MA. LptO (PG0027) Is Required for Lipid A 1-Phosphatase Activity in Porphyromonas gingivalis W50. J Bacteriol. 2017 May 9;199(11). pii: e00751-16. doi: 10.1128/JB.00751-16. Print 2017 Jun 1.

Last Updated: 10/21/2021 4:17:01 PM

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