Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library
Open accessAbstract
Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2–4 week antibiotic treatment, 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive oxygen species production are more active against the B. burgdorferi persisters than the commonly used antibiotics that inhibit macromolecule biosynthesis. Future studies are needed to evaluate and optimize the promising active hits in drug combination studies in vitro and also in vivo in animal models. These studies may have implications for developing more effective treatments of Lyme disease.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Wormser, G. P., Dattwyler, R. J., Shapiro, E. D., HALPERIN, J. J., Steere, A. C., Klempner, M. S., Krause, P. J., Bakken, J., Strle, F., Stanek, G., et al. (2006) · Clinical Infectious Diseases · doi:10.1086/508667 · Cited by 2,084 · see citing works
Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi
Fraser, C. M., Casjens, S., Huang, W. M., Sutton, G. G., Clayton, R. A., Lathigra, R. B., White, O. R., Ketchum, K. A., Dodson, R. J., Hickey, E. K., et al. (1997) · Nature · doi:10.1038/37551 · Cited by 2,083 · see citing works
Lewis, K. (2010) · Annual Review of Microbiology · doi:10.1146/annurev.micro.112408.134306 · Cited by 1,858 · see citing works
The role of glutathione-S-transferase in anti-cancer drug resistance
Townsend, D. M., & Tew, K. D. (2003) · Oncogene · doi:10.1038/sj.onc.1206940 · Cited by 1,353 · see citing works
Chemistry: Chemical con artists foil drug discovery
Baell, J. B., & Walters, M. A. (2014) · Nature · doi:10.1038/513481a · Cited by 1,048 · see citing works
Glutathione: an overview of biosynthesis and modulation
Anderson, M. E. (1998) · Chemico-Biological Interactions · doi:10.1016/s0009-2797(97)00146-4 · Cited by 917 · see citing works
Hurdle, J. G., O’Neill, A. J., Chopra, I., & Lee, R. E., Jr. (2010) · Nature Reviews Microbiology · doi:10.1038/nrmicro2474 · Cited by 871 · see citing works
Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes
Radolf, J. D., Caimano, M. J., Stevenson, B., & Hu, L. T. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2714 · Cited by 747 · see citing works
Zhang, Y. (2003) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkg446 · Cited by 477 · see citing works
Self-citationLyme Disease Testing by Large Commercial Laboratories in the United States
Hinckley, A. F., Connally, N. P., Meek, J. I., Johnson, B. J. B., Kemperman, M. M., Feldman, K. A., White, J. L., & Mead, P. S. (2014) · Clinical Infectious Diseases · doi:10.1093/cid/ciu397 · Cited by 386 · see citing works
Effects of common ophthalmic preservatives on ocular health
Noecker, R. J. (2001) · Advances in Therapy · doi:10.1007/bf02853166 · Cited by 304 · see citing works
Health Care Costs, Utilization and Patterns of Care following Lyme Disease
Adrion, E., Aucott, J. N., Lemke, K., & Weiner, J. P. (2015) · PLoS ONE · doi:10.1371/journal.pone.0116767 · Cited by 233 · see citing works
Persisters, persistent infections and the Yin–Yang model
Zhang, Y. (2014) · Emerging Microbes & Infections · doi:10.1038/emi.2014.3 · Cited by 231 · see citing works
Self-citationPersistence of Borrelia burgdorferi in experimentally infected dogs after antibiotic treatment
Straubinger, R. K., Summers, B. A., Chang, Y., & Appel, M. J. G. (1997) · Journal of Clinical Microbiology · doi:10.1128/jcm.35.1.111-116.1997 · Cited by 218 · see citing works
Bacterial neuraminidase facilitates mucosal infection by participating in biofilm production
Soong, G. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27920 · Cited by 214 · see citing works
Translational strategies for cancer prevention in liver
Kensler, T. W., Qian, G.-S., Chen, J., & Groopman, J. D. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1076 · Cited by 213 · see citing works
Embers, M. E., Barthold, S. W., Borda, J. T., Bowers, L. C., Doyle, L. A., Hodzic, E., Jacobs, M. B., Hasenkampf, N. R., Martin, D. S., Narasimhan, S., et al. (2013) · PLoS ONE · doi:10.1371/annotation/f84663e3-0a2c-4243-8f97-3a58133c1b0f · Cited by 205 · see citing works
Embers, M. E., Barthold, S. W., Borda, J. T., Bowers, L. C., Doyle, L. A., Hodzic, E., Jacobs, M. B., Hasenkampf, N. R., Martin, D. S., Narasimhan, S., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029914 · Cited by 197 · see citing works
Persistence of Borrelia burgdorferi following Antibiotic Treatment in Mice
Hodzic, E., Feng, S., Holden, K., Freet, K. J., & Barthold, S. W. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01050-07 · Cited by 186 · see citing works
Borrelia burgdorferi, the Causative Agent of Lyme Disease, Forms Drug-Tolerant Persister Cells
Sharma, B., Brown, A. V., Matluck, N. E., Hu, L. T., & Lewis, K. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00864-15 · Cited by 175 · see citing works
Aucott, J. N., Rebman, A. W., Crowder, L. A., & Kortte, K. B. (2012) · Quality of Life Research · doi:10.1007/s11136-012-0126-6 · Cited by 154 · see citing works
Daull, P., Lallemand, F., & Garrigue, J. (2013) · Journal of Pharmacy and Pharmacology · doi:10.1111/jphp.12075 · Cited by 139 · see citing works
Resurgence of Persisting Non-Cultivable Borrelia burgdorferi following Antibiotic Treatment in Mice
Hodzic, E., Imai, D. M., Feng, S., & Barthold, S. W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0086907 · Cited by 132 · see citing works
Xenodiagnosis to Detect Borrelia burgdorferi Infection: A First-in-Human Study
Marques, A. R., Telford, S. R., Turk, S.-P., Chung, E., Williams, C., Dardick, K. R., Krause, P. J., Brandeburg, C., Crowder, C. D., Carolan, H. E., et al. (2014) · Clinical Infectious Diseases · doi:10.1093/cid/cit939 · Cited by 128 · see citing works
Feng, J., Auwaerter, P. G., & Zhang, Y. (2015) · PLoS ONE · doi:10.1371/journal.pone.0117207 · Cited by 124 · see citing works
Self-citationSiles, S. A., Srinivasan, A., Pierce, C. G., Lopez-Ribot, J. L., & Ramasubramanian, A. K. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00680-13 · Cited by 120 · see citing works
Feng, J., Wang, T., Shi, W., Zhang, S., Sullivan, D. J., Auwaerter, P. G., & Zhang, Y. (2014) · Emerging Microbes & Infections · doi:10.1038/emi.2014.53 · Cited by 114 · see citing works
Self-citationFeng, J., Wang, T., Zhang, S., Shi, W., & Zhang, Y. (2014) · PLoS ONE · doi:10.1371/journal.pone.0111809 · Cited by 110 · see citing works
Self-citationIneffectiveness of Tigecycline against Persistent Borrelia burgdorferi
Barthold, S. W., Hodzic, E., Imai, D. M., Feng, S., Yang, X., & Luft, B. J. (2009) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00788-09 · Cited by 108 · see citing works
Stricker, R. B., & Sapi (2011) · Infection and Drug Resistance · doi:10.2147/idr.s19201 · Cited by 92 · see citing works
The γ-Glutamyl Cycle in the Choroid Plexus: Its Possible Function in Amino Acid Transport
Tate, S. S., Ross, L. L., & Meister, A. (1973) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.70.5.1447 · Cited by 79 · see citing works
Phillips, S. E., Mattman, L. H., Hulinska, D., & Moayad, H. (1998) · Infection · doi:10.1007/bf02770837 · Cited by 77 · see citing works
Chan, C.-Y., Prudom, C. E., Raines, S. M., Charkhzarrin, S., Melman, S. D., Haro, L. P. D., Allen, C., Lee, S. A., Sklar, L. A., & Parra, K. J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.321133 · Cited by 54 · see citing works
Feng, J., Shi, W., Zhang, S., & Zhang, Y. (2015) · Emerging Microbes & Infections · doi:10.1038/emi.2015.31 · Cited by 53 · see citing works
Self-citationBayer, M. E., Zhang, L., & Bayer, M. H. (1996) · Infection · doi:10.1007/bf01716077 · Cited by 53 · see citing works
Persister mechanisms in Borrelia burgdorferi: implications for improved intervention
Feng, J., Shi, W., Zhang, S., & Zhang, Y. (2015) · Emerging Microbes & Infections · doi:10.1038/emi.2015.51 · Cited by 45 · see citing works
Self-citationCabo, M. L., Herrera, J. J. R., Crespo, M. D., & Pastoriza, L. (2008) · Food Control · doi:10.1016/j.foodcont.2008.08.002 · Cited by 39 · see citing works
Advances in targeting the vacuolar proton-translocating ATPase (V-ATPase) for anti-fungal therapy
Hayek, S. R., Lee, S. A., & Parra, K. J. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00004 · Cited by 37 · see citing works
Niu, H., Cui, P., Shi, W., Zhang, S., Feng, J., Wang, Y., Sullivan, D. J., Zhang, W., Zhu, B., & Zhang, Y. (2015) · Antibiotics · doi:10.3390/antibiotics4020179 · Cited by 36 · see citing works
Self-citationChiou, J.-F., Wang, Y.-H., Jou, M., Liu, T., & Shiau, C.-Y. (2009) · Free Radical Research · doi:10.3109/10715760903380458 · Cited by 17 · see citing works
Pancewicz, S. A., Skrzydlewska, E., Hermanowska-Szpakowicz, T., Jm, Z., & Kondrusik, M. (2001) · PubMed · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Cao, X., Ding, L., Xie, Z., Yang, Y., Whiteman, M., Moore, P. K., & Bian, J. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7058 · Cited by 409 · see citing works
Phenotypic heterogeneity in persisters: a novel ‘hunker’ theory of persistence
Urbaniec, J., Xu, Y., Hu, Y., Hingley‐Wilson, S., & McFadden, J. (2021) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuab042 · Cited by 80 · see citing works
Wani, K. I., Choudhary, S., Zehra, A., Naeem, M., Weathers, P., & Aftab, T. (2021) · Planta · doi:10.1007/s00425-021-03676-3 · Cited by 74 · see citing works
Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening
Pothineni, V. R., Wagh, D. A., Babar, M. M., Inayathullah, M., Solow-Cordero, D. E., Kim, K., Samineni, A. V., Parekh, M. B., Tayebi, L., & Rajadas, J. (2016) · Drug Design Development and Therapy · doi:10.2147/dddt.s101486 · Cited by 57 · see citing works
Bailly, C. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174661 · Cited by 47 · see citing works
Feng, J., Zhang, S., Shi, W., & Zhang, Y. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.01744 · Cited by 40 · see citing works
Self-citationFeng, J., Weitner, M., Shi, W., Zhang, S., & Zhang, Y. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.00062 · Cited by 36 · see citing works
Self-citationFeng, J., Leone, J., Schweig, S., & Zhang, Y. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00006 · Cited by 36 · see citing works
Self-citationTherapeutic potential of endogenous hydrogen sulfide inhibition in breast cancer (Review)
Li, M., Liu, Y., Deng, Y., Pan, L., Fu, H., Han, X., Li, Y., Shi, H., & Wang, T. (2021) · Oncology Reports · doi:10.3892/or.2021.8019 · Cited by 34 · see citing works
Cabello, F. C., Embers, M. E., Newman, S. A., & Godfrey, H. P. (2022) · mBio · doi:10.1128/mbio.03440-21 · Cited by 31 · see citing works
Identification of FDA-Approved Drugs with Activity against Stationary Phase Bartonella henselae
Li, T., Feng, J., Xiao, S., Shi, W., Sullivan, D. J., & Zhang, Y. (2019) · Antibiotics · doi:10.3390/antibiotics8020050 · Cited by 26 · see citing works
Self-citationCabello, F. C., Godfrey, H. P., Bugrysheva, J. V., & Newman, S. A. (2017) · Environmental Microbiology · doi:10.1111/1462-2920.13897 · Cited by 24 · see citing works
Lyme disease and the pursuit of a clinical cure
Adkison, H., & Embers, M. E. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2023.1183344 · Cited by 23 · see citing works
Zheng, X., Ma, X., Li, T., Shi, W., & Zhang, Y. (2020) · BMC Microbiology · doi:10.1186/s12866-020-01777-9 · Cited by 23 · see citing works
Self-citationActivity of Sulfa Drugs and Their Combinations against Stationary Phase B. burgdorferi In Vitro
Feng, J., Zhang, S., Shi, W., & Zhang, Y. (2017) · Antibiotics · doi:10.3390/antibiotics6010010 · Cited by 21 · see citing works
Self-citationNovel targets and strategies to combat borreliosis
Strnad, M., Grubhoffer, L., & Rego, R. O. M. (2020) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-020-10375-8 · Cited by 19 · see citing works
Screening of NCI-DTP library to identify new drug candidates for Borrelia burgdorferi
Pothineni, V. R., Wagh, D. A., Babar, M. M., Inayathullah, M., Watts, R. E., Kim, K., Parekh, M. B., Gurjarpadhye, A. A., Solow-Cordero, D. E., Tayebi, L., et al. (2016) · The Journal of Antibiotics · doi:10.1038/ja.2016.131 · Cited by 17 · see citing works
Álvarez-Manzo, H. S., Zhang, Y., Shi, W., & Zhang, Y. (2020) · Antibiotics · doi:10.3390/antibiotics9090542 · Cited by 16 · see citing works
Self-citationJian, T.-R., Periasamy, A. P., Hsu, N.-Y., Wu, W., Harroun, S. G., & Chang, H. (2017) · Sensors and Actuators B Chemical · doi:10.1016/j.snb.2017.07.042 · Cited by 9 · see citing works
Horowitz, R. I., & Freeman, P. R. (2022) · Antibiotics · doi:10.3390/antibiotics11070912 · Cited by 8 · see citing works
Hunfeld, K., Kraiczy, P., Norris, D. E., & Lohr, B. (2023) · Pathogens · doi:10.3390/pathogens12101204 · Cited by 6 · see citing works
Herbal Medicine for Lyme Disease and Other Tick-Borne Infections
Yarnell, E. L. (2016) · Alternative and Complementary Therapies · doi:10.1089/act.2016.29085.eya · Cited by 4 · see citing works
Study of intermolecular interactions of antiviral agent tilorone with RNA and nucleosides
Pashynska, V. A., Nm, Z., Kosevich, M. V., Gömöry, Á., Holubiev, P. K., & Marynin, A. I. (2018) · Biophysical Bulletin · doi:10.26565/2075-3810-2018-39-02 · Cited by 4 · see citing works
Horowitz, R. I., Fallon, J., & Freeman, P. R. (2024) · Microorganisms · doi:10.3390/microorganisms12050909 · Cited by 3 · see citing works
Offutt, A., & Breitschwerdt, E. B. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1205545 · Cited by 2 · see citing works
Horowitz, R. I., Fallon, J., & Freeman, P. R. (2023) · Microorganisms · doi:10.3390/microorganisms11092301 · Cited by 2 · see citing works
Drug Repurposing Patent Applications January–March 2017
Mucke, H. A. (2017) · Assay and Drug Development Technologies · doi:10.1089/adt.2017.29057.pq1 · Cited by 2 · see citing works
High Activity of Selective Essential Oils against Stationary Phase Borrelia burgdorferiPreprint
Feng, J., Zhang, S., Shi, W., Zubcevik, N., Miklossy, J., & Zhang, Y. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/130898 · Cited by 2 · see citing works
Self-citationThe Use of Natural Bioactive Nutraceuticals in the Management of Tick-Borne Illnesses
Shor, S. M., & Schweig, S. (2023) · Microorganisms · doi:10.3390/microorganisms11071759 · Cited by 1 · see citing works
Álvarez-Manzo, H. S., Zhang, Y., & Zhang, Y. (2022) · Infectious Microbes & Diseases · doi:10.1097/im9.0000000000000096 · Cited by 1 · see citing works
Self-citationFDA breakthrough—Drug therapy designations for clinical evidence
Madkour, L. H. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-822481-6.00024-4
Álvarez-Manzo, H. S., Zhang, Y., Shi, W., & Zhang, Y. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.04.429852
Self-citation(2020) · Duke University Press eBooks · doi:10.1215/9781478007395-007
(2020) · Duke University Press eBooks · doi:10.1215/9781478007395-004
(2020) · Duke University Press eBooks · doi:10.1215/9781478007395-009
(2020) · Duke University Press eBooks · doi:10.1215/9781478007395-001
MAPPING THE LYME DISEASE CONTROVERSY
(2020) · Duke University Press eBooks · doi:10.1215/9781478007395-002
(2020) · Duke University Press eBooks · doi:10.1215/9781478007395-003
LYME DISEASE, EVIDENCE-BASED MEDICINE, AND THE BIOPOLITICS OF TRUTHMAKING
(2020) · Duke University Press eBooks · doi:10.1215/9781478007395-006
(2020) · Duke University Press eBooks · doi:10.1215/9781478007395-005
(2020) · Duke University Press eBooks · doi:10.1215/9781478007395-008
Al-Dallee, Z. T., Khalaf, K. T., Dawood, Y., & Ramadhan, U. H. (2022) · Basrah Researches Sciences · doi:10.56714/bjrs.48.1.1
A dual-labeling molecule for efficient drug discovery of mitochondrial-lysosomal interactions
Wu, J., Wang, X., Li, X., Zhu, Z., Cui, Z., Zhang, T., Zou, W., & Han, G. (2024) · Molecular and Cellular Probes · doi:10.1016/j.mcp.2024.101968
- Authors
- Feng, J., Weitner, M., Shi, W., Zhang, S., Sullivan, D., & Zhang, Y.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Zhang, Ying
- Venue
- Antibiotics
- Publisher
- MDPI AG
- Published
- 2015-09-16
- Volume
- 4
- Issue
- 3
- Pages
- 397-410
- ISSN
- 2079-6382 (ISSN-L)
- PMC
- PMC4790293
- OpenAlex
- W4240004137
- Cited by
- 43
- References
- 41
- Citations by year
- 2024: 2 · 2023: 5 · 2022: 4 · 2021: 5 · 2020: 14 · 2019: 1 · 2018: 2 · 2017: 5 · 2016: 5
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Antibiotics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Global Lyme Alliance
- National Institutes of Health
- Centers for Disease Control and Prevention
- National Institute of Allergy and Infectious Diseases (R01AI099512, R21AI108535)
- Topics
- Life Sciences › Immunology and Microbiology › Parasitology › Vector-borne infectious diseases
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- Borrelia burgdorferi, Lyme disease, post-treatment Lyme disease syndrome, stationary phase bacteria, antimicrobial activity, rifamycin, quinolones, antifungal agents, antimalarial drugs, antiparasitic drugs, reactive oxygen species, drug repurposing, antibiotic resistance
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
