Synergistic drug combinations for tuberculosis therapy identified by a novel high-throughput screen
Open accessAbstract
Therapeutic options for tuberculosis (TB) are limited and notoriously ineffective despite the wide variety of potent antibiotics available for treating other bacterial infections. We investigated an approach that enables an expansion of TB therapeutic strategies by using synergistic combinations of drugs. To achieve this, we devised a high-throughput synergy screen (HTSS) of chemical libraries having known pharmaceutical properties, including thousands that are clinically approved. Spectinomycin was used to test the concept that clinically available antibiotics with limited efficacy against Mycobacterium tuberculosis might be used for TB treatment when coadministered with a synergistic partner compound used as a sensitizer. Screens using Mycobacterium smegmatis revealed many compounds in our libraries that acted synergistically with spectinomycin. Among them, several families of antimicrobial compounds, including macrolides and azoles, were also synergistic against M. tuberculosis in vitro and in a macrophage model of M. tuberculosis infection. Strikingly, each sensitizer identified for synergy with spectinomycin uniquely enhanced the activities of other clinically used antibiotics, revealing a remarkable number of unexplored synergistic drug combinations. HTSS also revealed a novel activity for bromperidol, a butyrophenone used as an antipsychotic drug, which was discovered to be bactericidal and greatly enhanced the activities of several antibiotics and drug combinations against M. tuberculosis . Our results suggest that many compounds in the currently available pharmacopoeia could be readily mobilized for TB treatment, including disease caused by multi- and extensively drug-resistant strains for which there are no effective therapies.
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Neuroleptics aripiprazole and bromperidol can inhibit biofilm formation by Candida spp.
“The neuroleptics aripiprazole and bromperidol can inhibit biofilm formation by Candida spp., but the second was found to work synergistically with spectinomycin to inhibit the growth of Mycobacterium smegmatis and M. tuberculosis [55,75].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [75]
Bromperidol works synergistically with spectinomycin to inhibit the growth of Mycobacterium smegmatis and M. tuberculosis.
“The neuroleptics aripiprazole and bromperidol can inhibit biofilm formation by Candida spp., but the second was found to work synergistically with spectinomycin to inhibit the growth of Mycobacterium smegmatis and M. tuberculosis [55,75].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [75]
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Sorted by citations
Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications
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- Authors
- Ramón-García, S., Ng, C., Anderson, H., Chao, J. D., Zheng, X., Pfeifer, T., Av-Gay, Y., Roberge, M., & Thompson, C. J.
- Affiliations
- Department of Microbiology and Immunology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
- University of British Columbia (CA)
- Centre for Drug Research and Development (CA)
- Corresponding author
- Thompson, Charles J.
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2011-08
- Volume
- 55
- Issue
- 8
- Pages
- 3861-3869
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC3147639
- OpenAlex
- W2100266438
- Cited by
- 185
- References
- 45
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 21 · 2023: 21 · 2022: 15 · 2021: 17 · 2020: 12 · 2019: 8 · 2018: 9 · 2017: 8 · 2016: 10 · 2015: 13 · 2014: 7 · 2013: 7 · 2012: 8
- FWCI
- 5.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- British Columbia Centre for Disease Control
- Canadian Institutes of Health Research (82745_1, MOP-82855)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- tuberculosis, Mycobacterium tuberculosis, drug synergy, spectinomycin, macrolides, azoles, bromperidol, butyrophenones, Mycobacterium smegmatis, macrophage infection model, drug-resistant tuberculosis, antibacterial activity
- MeSH terms
- Spectinomycin, Antitubercular Agents, Drug Synergism, Drug Therapy, Combination, Haloperidol, Humans, Macrophages, Mycobacterium tuberculosis, Tuberculosis, Mycobacterium smegmatis, High-Throughput Screening Assays
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