Faculty Appointments
Assistant Professor of Medicine
Assistant Professor of Pathology, Microbiology and Immunology
Education
Ph.D., University of Maryland, Baltimore, MarylandM.D., Medicine, University of Maryland, Baltimore, MarylandB.S., University of Virginia, Charlottesville, Virginia
Office Address
1161 21st Ave
Nashville, TN 37232
Nashville, TN 37232
Research Description
My primary research goal is to better understand antibiotic treatment failure during bacterial infections. Broadly speaking, antibiotic treatment failure refers to any undesirable outcome when treating an infection. Its causes are multifactorial, and they include a combination of both patient-specific (host-specific) factors and factors specific to the infecting bacteria (pathogen-specific). My research focuses on pathogen-driven mechanisms such as antibiotic resistance, antibiotic tolerance, and biofilm growth with additional interest in how these mechanisms occur within a host in the presence of an immune response. I am particularly interested in antibiotic treatment failure during Staphylococcus aureus infections. S. aureus is the most common bacterial cause of mortality in the United States and is associated with very high rates of antibiotic failure. Current research projects include 1) investigating the connection between amino acid metabolism in S. aureus and induction of antibiotic tolerance and 2) utilizing clinical S. aureus isolates to understand the connection between treatment failure, tolerance to combination antibiotic therapy, and daptomycin resistance. In addition to taking a translational approach by incorporating the study of clinical bacterial isolates, I am also using a combination of molecular biology, microbial genetics, immunology, and animal models to answer these questions. This research aims to not only better understand the mechanisms driving antibiotic treatment failure, but also to develop simple solutions to reverse it.
Research Keywords
Infectious Diseases, Antimicrobial Resistance, Antibiotic tolerance, Antibiotic Treatment Failure, Staphylococcus aureus, Biofilm, Biofilm Infections, Host-Pathogen Interaction, Microbiology, Microbiology and Immunology, Molecular Microbiology, Bacterial Metabolism, Bacteriology, Bacterial Pathogenesis, Endocarditis, Bacteremia, Bloodstream Infections
Clinical Research Keywords
Infectious Diseases, Antimicrobial Resistance, Antibiotic Treatment Failure, Staphylococcus aureus, Biofilm Infections, Endocarditis, Bacteremia, Bloodstream Infections, Antimicrobial Stewardship
Publications
Freiberg JA, Wright PW. What's Hot This Year in Infectious Diseases Clinical Science. Clin Infect Dis. 2025 Jul 7/18/2025; 80(6): 1216-20. PMID: 39891904, PMCID: PMC12272839, PII: 7994646, DOI: 10.1093/cid/ciaf037, ISSN: 1537-6591.
Munneke MJ, Freiberg JA, Skaar EP. The nucleobase analog 4-thiouracil hijacks the pyrimidine salvage pathway to inhibit Staphylococcus aureus growth. Microbiol Spectr [print-electronic]. 2025 Jul; 13(7): e0064025. PMID: 40422278, PMCID: PMC12210855, DOI: 10.1128/spectrum.00640-25, ISSN: 2165-0497.
Tao L, Freiberg JA, Humphries R. "Friends" that come with man's best friend: Capnocytophaga canimorsus sepsis and meningitis in an immunocompromised patient. ASM Case Rep. 2025 Mar; 1(2): PMID: 41244312, PMCID: PMC12530220, PII: asmcr00085-24, DOI: 10.1128/asmcr.00085-24, ISSN: 2996-2684.
Freiberg JA, Siemann JK, Qian ET, Ereshefsky BJ, Hennessy C, Stollings JL, Rali TM, Harrell FE, Gatto CL, Rice TW, Nelson GE, . Swab Testing to Optimize Pneumonia treatment with empiric Vancomycin (STOP-Vanc): study protocol for a randomized controlled trial. Trials. 2024 Dec 12/28/2024; 25(1): 854. PMID: 39732716, PMCID: PMC11682620, PII: 10.1186/s13063-024-08705-6, DOI: 10.1186/s13063-024-08705-6, ISSN: 1745-6215.
Freiberg JA, Reyes Ruiz VM, Gimza BD, Murdoch CC, Green ER, Curry JM, Cassat JE, Skaar EP. Restriction of arginine induces antibiotic tolerance in Staphylococcus aureus. Nat Commun. 2024 Aug 8/7/2024; 15(1): 6734. PMID: 39112491, PMCID: PMC11306626, PII: 10.1038/s41467-024-51144-9, DOI: 10.1038/s41467-024-51144-9, ISSN: 2041-1723.
Djambazova KV, Gibson-Corley KN, Freiberg JA, Caprioli RM, Skaar EP, Spraggins JM. MALDI TIMS IMS Reveals Ganglioside Molecular Diversity within Murine S. aureus Kidney Tissue Abscesses. J Am Soc Mass Spectrom [print-electronic]. 2024 Aug 8/7/2024; 35(8): 1692-701. PMID: 39052897, PMCID: PMC11311236, DOI: 10.1021/jasms.4c00089, ISSN: 1879-1123.
Reyes Ruiz VM, Freiberg JA, Weiss A, Green ER, Jobson M-E, Felton E, Shaw LN, Chazin WJ, Skaar EP. Coordinated adaptation of Staphylococcus aureus to calprotectin-dependent metal sequestration. MBio [print-electronic]. 2024 Jul 7/17/2024; 15(7): e0138924. PMID: 38920392, PMCID: PMC11253595, DOI: 10.1128/mbio.01389-24, ISSN: 2150-7511.
Freiberg JA, Wright PW. What's Hot This Year in Infectious Diseases Clinical Science. Clin Infect Dis. 2024 May 5/15/2024; 78(5): 1170-4. PMID: 38170287, PMCID: PMC11093670, PII: 7505444, DOI: 10.1093/cid/ciad789, ISSN: 1537-6591.
Freiberg JA, Tao L, Manuel C, Mike LA, Nelson GE, Harris BD, Mathers AJ, Talbot TR, Skaar EP, Humphries RM. A multi-species outbreak of VIM-producing carbapenem-resistant bacteria in a burn unit and subsequent investigation of rapid development of cefiderocol resistance. Antimicrob Agents Chemother [print-electronic]. 2024 Apr 4/3/2024; 68(4): e0150723. PMID: 38376188, PMCID: PMC10989021, DOI: 10.1128/aac.01507-23, ISSN: 1098-6596.
Rivera ES, Weiss A, Migas LG, Freiberg JA, Djambazova KV, Neumann EK, Van de Plas R, Spraggins JM, Skaar EP, Caprioli RM. Imaging mass spectrometry reveals complex lipid distributions across Staphylococcus aureus biofilm layers. J Mass Spectrom Adv Clin Lab. 2022 Nov; 26: 36-46. PMID: 36388058, PMCID: PMC9641601, PII: S2667-145X(22)00037-2, DOI: 10.1016/j.jmsacl.2022.09.003, ISSN: 2667-145X.
Beavers WN, Munneke MJ, Stackhouse AR, Freiberg JA, Skaar EP. Host Polyunsaturated Fatty Acids Potentiate Aminoglycoside Killing of Staphylococcus aureus. Microbiol Spectr [print-electronic]. 2022 Apr 4/27/2022; 10(2): e0276721. PMID: 35377191, PMCID: PMC9045252, DOI: 10.1128/spectrum.02767-21, ISSN: 2165-0497.
Freiberg JA, Deri CR, Nesbitt WJ, Humphries RM, Nelson GE. Identification and Antibiotic Susceptibility Patterns of Clinical Blood Culture Isolates Not Identified by a Rapid Microarray Diagnostic System. Microbiol Spectr [print-electronic]. 2021 Sep 9/3/2021; 9(1): e0017521. PMID: 34190590, PMCID: PMC8552754, DOI: 10.1128/Spectrum.00175-21, ISSN: 2165-0497.
Freiberg JA, Le Breton Y, Harro JM, Allison DL, McIver KS, Shirtliff ME. The Arginine Deiminase Pathway Impacts Antibiotic Tolerance during Biofilm-Mediated Streptococcus pyogenes Infections. MBio. 2020 Jul 7/7/2020; 11(4): PMID: 32636245, PMCID: PMC7343988, PII: mBio.00919-20, DOI: 10.1128/mBio.00919-20, ISSN: 2150-7511.
Harro JM, Achermann Y, Freiberg JA, Allison DL, Brao KJ, Marinos DP, Sanjari S, Leid JG, Shirtliff ME. Clearance of Staphylococcus aureus from In Vivo Models of Chronic Infection by Immunization Requires Both Planktonic and Biofilm Antigens. Infect Immun [electronic-print]. 2019 Dec 12/17/2019; 88(1): PMID: 31712267, PMCID: PMC6921670, PII: IAI.00586-19, DOI: 10.1128/IAI.00586-19, ISSN: 1098-5522.
Khan MM, Chattagul S, Tran BQ, Freiberg JA, Nita-Lazar A, Shirtliff ME, Sermswan RW, Ernst RK, Goodlett DR. Temporal proteomic profiling reveals changes that support Burkholderia biofilms. Pathog Dis. 2019 Mar 3/1/2019; 77(2): PMID: 30759239, PMCID: PMC6482045, PII: 5318610, DOI: 10.1093/femspd/ftz005, ISSN: 2049-632X.
Freiberg JA, Saharia KK, Morales MK. An unusual case of Nocardia cyriacigeorgica presenting with spinal abscesses in a renal transplant recipient and a review of the literature. Transpl Infect Dis [print-electronic]. 2019 Feb; 21(1): e13025. PMID: 30414295, DOI: 10.1111/tid.13025, ISSN: 1399-3062.
Le Breton Y, Belew AT, Freiberg JA, Sundar GS, Islam E, Lieberman J, Shirtliff ME, Tettelin H, El-Sayed NM, McIver KS. Genome-wide discovery of novel M1T1 group A streptococcal determinants important for fitness and virulence during soft-tissue infection. PLoS Pathog. 2017 Aug; 13(8): e1006584. PMID: 28832676, PMCID: PMC5584981, PII: PPATHOGENS-D-17-01298, DOI: 10.1371/journal.ppat.1006584, ISSN: 1553-7374.
Freiberg JA. The mythos of laudable pus along with an explanation for its origin. J Community Hosp Intern Med Perspect. 2017 Jul; 7(3): 196-8. PMID: 28808517, PMCID: PMC5538214, PII: 1343077, DOI: 10.1080/20009666.2017.1343077, ISSN: 2000-9666.
Maldarelli GA, Piepenbrink KH, Scott AJ, Freiberg JA, Song Y, Achermann Y, Ernst RK, Shirtliff ME, Sundberg EJ, Donnenberg MS, von Rosenvinge EC. Type IV pili promote early biofilm formation by Clostridium difficile. Pathog Dis [print-electronic]. 2016 Aug; 74(6): PMID: 27369898, PMCID: PMC5985507, PII: ftw061, DOI: 10.1093/femspd/ftw061, ISSN: 2049-632X.
Freiberg JA, Le Breton Y, Tran BQ, Scott AJ, Harro JM, Ernst RK, Goo YA, Mongodin EF, Goodlett DR, McIver KS, Shirtliff ME. Global Analysis and Comparison of the Transcriptomes and Proteomes of Group A Streptococcus Biofilms. MSystems. 2016; 1(6): PMID: 27933318, PMCID: PMC5141267, PII: mSystems00149-16, DOI: 10.1128/mSystems.00149-16, ISSN: 2379-5077.
Schlecht LM, Peters BM, Krom BP, Freiberg JA, Hänsch GM, Filler SG, Jabra-Rizk MA, Shirtliff ME. Systemic Staphylococcus aureus infection mediated by Candida albicans hyphal invasion of mucosal tissue. Microbiology (Reading) [print-electronic]. 2015 Jan; 161(Pt 1): 168-81. PMID: 25332378, PMCID: PMC4274785, DOI: 10.1099/mic.0.083485-0, ISSN: 1465-2080.
Freiberg JA, McIver KS, Shirtliff ME. In vivo expression of Streptococcus pyogenes immunogenic proteins during tibial foreign body infection. Infect Immun [print-electronic]. 2014 Sep; 82(9): 3891-9. PMID: 25001603, PMCID: PMC4187806, PII: IAI.01831-14, DOI: 10.1128/IAI.01831-14, ISSN: 1098-5522.
Bugrysheva J, Froehlich BJ, Freiberg JA, Scott JR. Serine/threonine protein kinase Stk is required for virulence, stress response, and penicillin tolerance in Streptococcus pyogenes. Infect Immun [print-electronic]. 2011 Oct; 79(10): 4201-9. PMID: 21788381, PMCID: PMC3187266, PII: IAI.05360-11, DOI: 10.1128/IAI.05360-11, ISSN: 1098-5522.
Bugrysheva JV, Froehlich BJ, Freiberg JA, Scott JR. The histone-like protein Hlp is essential for growth of Streptococcus pyogenes: comparison of genetic approaches to study essential genes. Appl Environ Microbiol [print-electronic]. 2011 Jul; 77(13): 4422-8. PMID: 21531823, PMCID: PMC3127713, PII: AEM.00554-11, DOI: 10.1128/AEM.00554-11, ISSN: 1098-5336.
Munneke MJ, Freiberg JA, Skaar EP. The nucleobase analog 4-thiouracil hijacks the pyrimidine salvage pathway to inhibit Staphylococcus aureus growth. Microbiol Spectr [print-electronic]. 2025 Jul; 13(7): e0064025. PMID: 40422278, PMCID: PMC12210855, DOI: 10.1128/spectrum.00640-25, ISSN: 2165-0497.
Tao L, Freiberg JA, Humphries R. "Friends" that come with man's best friend: Capnocytophaga canimorsus sepsis and meningitis in an immunocompromised patient. ASM Case Rep. 2025 Mar; 1(2): PMID: 41244312, PMCID: PMC12530220, PII: asmcr00085-24, DOI: 10.1128/asmcr.00085-24, ISSN: 2996-2684.
Freiberg JA, Siemann JK, Qian ET, Ereshefsky BJ, Hennessy C, Stollings JL, Rali TM, Harrell FE, Gatto CL, Rice TW, Nelson GE, . Swab Testing to Optimize Pneumonia treatment with empiric Vancomycin (STOP-Vanc): study protocol for a randomized controlled trial. Trials. 2024 Dec 12/28/2024; 25(1): 854. PMID: 39732716, PMCID: PMC11682620, PII: 10.1186/s13063-024-08705-6, DOI: 10.1186/s13063-024-08705-6, ISSN: 1745-6215.
Freiberg JA, Reyes Ruiz VM, Gimza BD, Murdoch CC, Green ER, Curry JM, Cassat JE, Skaar EP. Restriction of arginine induces antibiotic tolerance in Staphylococcus aureus. Nat Commun. 2024 Aug 8/7/2024; 15(1): 6734. PMID: 39112491, PMCID: PMC11306626, PII: 10.1038/s41467-024-51144-9, DOI: 10.1038/s41467-024-51144-9, ISSN: 2041-1723.
Djambazova KV, Gibson-Corley KN, Freiberg JA, Caprioli RM, Skaar EP, Spraggins JM. MALDI TIMS IMS Reveals Ganglioside Molecular Diversity within Murine S. aureus Kidney Tissue Abscesses. J Am Soc Mass Spectrom [print-electronic]. 2024 Aug 8/7/2024; 35(8): 1692-701. PMID: 39052897, PMCID: PMC11311236, DOI: 10.1021/jasms.4c00089, ISSN: 1879-1123.
Reyes Ruiz VM, Freiberg JA, Weiss A, Green ER, Jobson M-E, Felton E, Shaw LN, Chazin WJ, Skaar EP. Coordinated adaptation of Staphylococcus aureus to calprotectin-dependent metal sequestration. MBio [print-electronic]. 2024 Jul 7/17/2024; 15(7): e0138924. PMID: 38920392, PMCID: PMC11253595, DOI: 10.1128/mbio.01389-24, ISSN: 2150-7511.
Freiberg JA, Wright PW. What's Hot This Year in Infectious Diseases Clinical Science. Clin Infect Dis. 2024 May 5/15/2024; 78(5): 1170-4. PMID: 38170287, PMCID: PMC11093670, PII: 7505444, DOI: 10.1093/cid/ciad789, ISSN: 1537-6591.
Freiberg JA, Tao L, Manuel C, Mike LA, Nelson GE, Harris BD, Mathers AJ, Talbot TR, Skaar EP, Humphries RM. A multi-species outbreak of VIM-producing carbapenem-resistant bacteria in a burn unit and subsequent investigation of rapid development of cefiderocol resistance. Antimicrob Agents Chemother [print-electronic]. 2024 Apr 4/3/2024; 68(4): e0150723. PMID: 38376188, PMCID: PMC10989021, DOI: 10.1128/aac.01507-23, ISSN: 1098-6596.
Rivera ES, Weiss A, Migas LG, Freiberg JA, Djambazova KV, Neumann EK, Van de Plas R, Spraggins JM, Skaar EP, Caprioli RM. Imaging mass spectrometry reveals complex lipid distributions across Staphylococcus aureus biofilm layers. J Mass Spectrom Adv Clin Lab. 2022 Nov; 26: 36-46. PMID: 36388058, PMCID: PMC9641601, PII: S2667-145X(22)00037-2, DOI: 10.1016/j.jmsacl.2022.09.003, ISSN: 2667-145X.
Beavers WN, Munneke MJ, Stackhouse AR, Freiberg JA, Skaar EP. Host Polyunsaturated Fatty Acids Potentiate Aminoglycoside Killing of Staphylococcus aureus. Microbiol Spectr [print-electronic]. 2022 Apr 4/27/2022; 10(2): e0276721. PMID: 35377191, PMCID: PMC9045252, DOI: 10.1128/spectrum.02767-21, ISSN: 2165-0497.
Freiberg JA, Deri CR, Nesbitt WJ, Humphries RM, Nelson GE. Identification and Antibiotic Susceptibility Patterns of Clinical Blood Culture Isolates Not Identified by a Rapid Microarray Diagnostic System. Microbiol Spectr [print-electronic]. 2021 Sep 9/3/2021; 9(1): e0017521. PMID: 34190590, PMCID: PMC8552754, DOI: 10.1128/Spectrum.00175-21, ISSN: 2165-0497.
Freiberg JA, Le Breton Y, Harro JM, Allison DL, McIver KS, Shirtliff ME. The Arginine Deiminase Pathway Impacts Antibiotic Tolerance during Biofilm-Mediated Streptococcus pyogenes Infections. MBio. 2020 Jul 7/7/2020; 11(4): PMID: 32636245, PMCID: PMC7343988, PII: mBio.00919-20, DOI: 10.1128/mBio.00919-20, ISSN: 2150-7511.
Harro JM, Achermann Y, Freiberg JA, Allison DL, Brao KJ, Marinos DP, Sanjari S, Leid JG, Shirtliff ME. Clearance of Staphylococcus aureus from In Vivo Models of Chronic Infection by Immunization Requires Both Planktonic and Biofilm Antigens. Infect Immun [electronic-print]. 2019 Dec 12/17/2019; 88(1): PMID: 31712267, PMCID: PMC6921670, PII: IAI.00586-19, DOI: 10.1128/IAI.00586-19, ISSN: 1098-5522.
Khan MM, Chattagul S, Tran BQ, Freiberg JA, Nita-Lazar A, Shirtliff ME, Sermswan RW, Ernst RK, Goodlett DR. Temporal proteomic profiling reveals changes that support Burkholderia biofilms. Pathog Dis. 2019 Mar 3/1/2019; 77(2): PMID: 30759239, PMCID: PMC6482045, PII: 5318610, DOI: 10.1093/femspd/ftz005, ISSN: 2049-632X.
Freiberg JA, Saharia KK, Morales MK. An unusual case of Nocardia cyriacigeorgica presenting with spinal abscesses in a renal transplant recipient and a review of the literature. Transpl Infect Dis [print-electronic]. 2019 Feb; 21(1): e13025. PMID: 30414295, DOI: 10.1111/tid.13025, ISSN: 1399-3062.
Le Breton Y, Belew AT, Freiberg JA, Sundar GS, Islam E, Lieberman J, Shirtliff ME, Tettelin H, El-Sayed NM, McIver KS. Genome-wide discovery of novel M1T1 group A streptococcal determinants important for fitness and virulence during soft-tissue infection. PLoS Pathog. 2017 Aug; 13(8): e1006584. PMID: 28832676, PMCID: PMC5584981, PII: PPATHOGENS-D-17-01298, DOI: 10.1371/journal.ppat.1006584, ISSN: 1553-7374.
Freiberg JA. The mythos of laudable pus along with an explanation for its origin. J Community Hosp Intern Med Perspect. 2017 Jul; 7(3): 196-8. PMID: 28808517, PMCID: PMC5538214, PII: 1343077, DOI: 10.1080/20009666.2017.1343077, ISSN: 2000-9666.
Maldarelli GA, Piepenbrink KH, Scott AJ, Freiberg JA, Song Y, Achermann Y, Ernst RK, Shirtliff ME, Sundberg EJ, Donnenberg MS, von Rosenvinge EC. Type IV pili promote early biofilm formation by Clostridium difficile. Pathog Dis [print-electronic]. 2016 Aug; 74(6): PMID: 27369898, PMCID: PMC5985507, PII: ftw061, DOI: 10.1093/femspd/ftw061, ISSN: 2049-632X.
Freiberg JA, Le Breton Y, Tran BQ, Scott AJ, Harro JM, Ernst RK, Goo YA, Mongodin EF, Goodlett DR, McIver KS, Shirtliff ME. Global Analysis and Comparison of the Transcriptomes and Proteomes of Group A Streptococcus Biofilms. MSystems. 2016; 1(6): PMID: 27933318, PMCID: PMC5141267, PII: mSystems00149-16, DOI: 10.1128/mSystems.00149-16, ISSN: 2379-5077.
Schlecht LM, Peters BM, Krom BP, Freiberg JA, Hänsch GM, Filler SG, Jabra-Rizk MA, Shirtliff ME. Systemic Staphylococcus aureus infection mediated by Candida albicans hyphal invasion of mucosal tissue. Microbiology (Reading) [print-electronic]. 2015 Jan; 161(Pt 1): 168-81. PMID: 25332378, PMCID: PMC4274785, DOI: 10.1099/mic.0.083485-0, ISSN: 1465-2080.
Freiberg JA, McIver KS, Shirtliff ME. In vivo expression of Streptococcus pyogenes immunogenic proteins during tibial foreign body infection. Infect Immun [print-electronic]. 2014 Sep; 82(9): 3891-9. PMID: 25001603, PMCID: PMC4187806, PII: IAI.01831-14, DOI: 10.1128/IAI.01831-14, ISSN: 1098-5522.
Bugrysheva J, Froehlich BJ, Freiberg JA, Scott JR. Serine/threonine protein kinase Stk is required for virulence, stress response, and penicillin tolerance in Streptococcus pyogenes. Infect Immun [print-electronic]. 2011 Oct; 79(10): 4201-9. PMID: 21788381, PMCID: PMC3187266, PII: IAI.05360-11, DOI: 10.1128/IAI.05360-11, ISSN: 1098-5522.
Bugrysheva JV, Froehlich BJ, Freiberg JA, Scott JR. The histone-like protein Hlp is essential for growth of Streptococcus pyogenes: comparison of genetic approaches to study essential genes. Appl Environ Microbiol [print-electronic]. 2011 Jul; 77(13): 4422-8. PMID: 21531823, PMCID: PMC3127713, PII: AEM.00554-11, DOI: 10.1128/AEM.00554-11, ISSN: 1098-5336.