Fighting bacterial persistence: Current and emerging anti-persister strategies and therapeutics

Defraine, Valerie; Fauvart, Maarten; Michiels, Jan

doi:10.1016/j.drup.2018.03.002

Cited by 223Bacterial Genetics and BiotechnologyBacterial biofilms and quorum sensingAntimicrobial Resistance in Staphylococcus

Fighting bacterial persistence: Current and emerging anti-persister strategies and therapeutics

Defraine, Valerie, Fauvart, Maarten, Michiels, Jan·2018·Drug Resistance Updates

DOI 10.1016/j.drup.2018.03.002

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Abstract

In addition to the well-known strategies of antibiotic resistance and biofilm formation, bacterial populations possess an additional survival strategy to endure hostile environments or antibiotic exposure. A small fraction of transiently antibiotic-tolerant phenotypical variants, called persister cells, is capable of surviving treatment with high doses of antibiotics. When antibiotic pressure drops, persisters that switch back to a normal phenotype can resume growth, ensuring survival of the bacterial population. Persister cells have been identified in every major pathogen, contribute to the antibiotic tolerance observed in biofilms, and are responsible for the recalcitrant nature of chronic infections. Also, evidence is accumulating that persister cells can contribute to the emergence of antibiotic resistance. Consequently, effective treatment of persister cells could greatly improve patient outcome. The small number of persisters and the redundancy in mechanisms of persister formation impede target-based development of anti-persister therapies. Nonetheless, the armory of anti-persister molecules is increasing. This review presents a comprehensive overview of anti-persister molecules and strategies described in literature to date and offers perspectives on potential anti-persistence targets and methods for the development of future therapies. Furthermore, we highlight in vivo model systems for pre-clinical testing and summarize ongoing clinical trials of candidate anti-persister therapeutics.

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Persistence is always linked to cell dormancy, a state in which cellular metabolism temporarily ceases.
“Persistence is always linked to cell dormancy, a state in which the cellular metabolism temporarily ceases [111,123,124].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [123]

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Tolerance and resistance of microbial biofilms
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The global preclinical antibacterial pipeline
Theuretzbacher, U., Outterson, K., Engel, A., & Karlén, A. (2019) · Nature Reviews Microbiology · doi:10.1038/s41579-019-0288-0 · Cited by 744 · see citing works
Tolerance and Resistance of Pseudomonas aeruginosa Biofilms to Antimicrobial Agents—How P. aeruginosa Can Escape Antibiotics
Ciofu, O., & Tolker‐Nielsen, T. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.00913 · Cited by 733 · see citing works
Bacterial persisters: molecular mechanisms and therapeutic development
Niu, H., Gu, J., & Zhang, Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01866-5 · Cited by 334 · see citing works
“Encouragingly, with the advancement of our understanding of mechanisms and characteristics of persisters, several anti-persister compounds have been discovered 89,372,373 (Table 2).”
Background
Relationship between the Viable but Nonculturable State and Antibiotic Persister Cells
Ayrapetyan, M., Williams, T. C., & Oliver, J. D. (2018) · Journal of Bacteriology · doi:10.1128/jb.00249-18 · Cited by 286 · see citing works
Bacterial Persisters and Infection: Past, Present, and Progressing
Gollan, B., Grabe, G. J., Michaux, C., & Hélaine, S. (2019) · Annual Review of Microbiology · doi:10.1146/annurev-micro-020518-115650 · Cited by 274 · see citing works
Salmonella persisters promote the spread of antibiotic resistance plasmids in the gut
Bakkeren, E., Huisman, J. S., Fattinger, S. A., Hausmann, A., Furter, M., Egli, A., Slack, E. M. C., Sellin, M. E., Bonhoeffer, S., Regoes, R. R., et al. (2019) · Nature · doi:10.1038/s41586-019-1521-8 · Cited by 258 · see citing works
Bacterial Heterogeneity and Antibiotic Survival: Understanding and Combatting Persistence and Heteroresistance
Dewachter, L., Fauvart, M., & Michiels, J. J. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.09.028 · Cited by 229 · see citing works
Self-citation
Evolutionary causes and consequences of bacterial antibiotic persistence
Bakkeren, E., Diard, M., & Hardt, W. (2020) · Nature Reviews Microbiology · doi:10.1038/s41579-020-0378-z · Cited by 226 · see citing works
Mechanism of Drug Tolerant Persister Cancer Cells: The Landscape and Clinical Implication for Therapy
Mikubo, M., Inoue, Y., Liu, G., & Tsao, M. (2021) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2021.07.017 · Cited by 213 · see citing works
Dormant, quiescent, tolerant and persister cells: Four synonyms for the same target in cancer
Vallette, F. M., Olivier, C., Lézot, F., Oliver, L., Cochonneau, D., Lalier-Bretaudeau, L., Cartron, P., & Heymann, D. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.11.004 · Cited by 184 · see citing works
“Similar observations in bacteria and yeast also suggested that the dormancy/quiescence/tolerance/persistence phenomenon is a dynamic process with different genes playing roles of variable significance at different times [71,72].”
Background
The Global Challenge of Antimicrobial Resistance: Mechanisms, Case Studies, and Mitigation Approaches
Nazir, A., Nazir, A., Zuhair, V., Aman, S., Sadiq, S. U. R., Hasan, A. H., Tariq, M., Rehman, L. U., Mustapha, M. J., & Bulimbe, D. B. (2025) · Health Science Reports · doi:10.1002/hsr2.71077 · Cited by 178 · see citing works
“Persister cells have been detected across all significant pathogens and are a leading factor behind chronic infections [69].”
Clinical Escherichia coli: From Biofilm Formation to New Antibiofilm Strategies
Ballén, V., Cepas, V., Ratia, C., Gabasa, Y., & Soto, S. M. (2022) · Microorganisms · doi:10.3390/microorganisms10061103 · Cited by 141 · see citing works
Fucoidan-Stabilized Gold Nanoparticle-Mediated Biofilm Inhibition, Attenuation of Virulence and Motility Properties in Pseudomonas aeruginosa PAO1
Khan, F., Manivasagan, P., Lee, J.-W., Pham, D. T. N., Oh, J., & Kim, Y. (2019) · Marine Drugs · doi:10.3390/md17040208 · Cited by 119 · see citing works
The antimicrobial peptide LI14 combats multidrug-resistant bacterial infections
Shi, J., Chen, C., Wang, D., Wang, Z., & Liu, Y. (2022) · Communications Biology · doi:10.1038/s42003-022-03899-4 · Cited by 116 · see citing works
Tolerance and Persistence of Pseudomonas aeruginosa in Biofilms Exposed to Antibiotics: Molecular Mechanisms, Antibiotic Strategies and Therapeutic Perspectives
Soares, A., Alexandre, K., & Etienne, M. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.02057 · Cited by 115 · see citing works
How antibiotics work together: molecular mechanisms behind combination therapy
Sullivan, G. J., Delgado, N. N., Maharjan, R. P., & Cain, A. K. (2020) · Current Opinion in Microbiology · doi:10.1016/j.mib.2020.05.012 · Cited by 107 · see citing works
Eradicating Bacterial Persisters with Combinations of Strongly and Weakly Metabolism-Dependent Antibiotics
Zheng, E. J., Stokes, J. M., & Collins, J. J. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.08.015 · Cited by 104 · see citing works
“As a result, there has been growing interest in the discovery of treatments whose efficacy is unaffected by perturbations in metabolic state (Defraine et al., 2018).”
Background
The current drug discovery landscape for trypanosomiasis and leishmaniasis: Challenges and strategies to identify drug targets
Altamura, F., Rajesh, R., Catta‐Preta, C. M. C., Moretti, N. S., & Cestari, I. D. S. (2020) · Drug Development Research · doi:10.1002/ddr.21664 · Cited by 101 · see citing works
Persistence against benzalkonium chloride promotes rapid evolution of tolerance during periodic disinfection
Nordholt, N., Kanaris, O., Schmidt, S. B. I., & Schreiber, F. (2021) · Nature Communications · doi:10.1038/s41467-021-27019-8 · Cited by 98 · see citing works
Fast bacterial growth reduces antibiotic accumulation and efficacy
Łapińska, U., Voliotis, M., Lee, K. K., Campey, A., Stone, M. R. L., Tuck, B., Phetsang, W., Zhang, B., Tsaneva-Atanasova, K. T., Blaskovich, M. A. T., et al. (2022) · eLife · doi:10.7554/elife.74062 · Cited by 92 · see citing works
In Vitro Studies of Persister Cells
Kaldalu, N., Hauryliuk, V., Turnbull, K. J., Mensa, A. L., Putrinš, M., & Tenson, T. (2020) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00070-20 · Cited by 88 · see citing works
“Despite that, several of them are enrolled in clinical trials (180).”
Background
Recent Progress in Natural-Product-Inspired Programs Aimed To Address Antibiotic Resistance and Tolerance
Abouelhassan, Y., Garrison, A. T., Yang, H., Chávez‐Riveros, A., Burch, G. M., & Huigens, R. W. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00370 · Cited by 83 · see citing works
Link Between Antibiotic Persistence and Antibiotic Resistance in Bacterial Pathogens
Eisenreich, W., Rudel, T., Heesemann, J., & Goebel, W. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.900848 · Cited by 83 · see citing works
“Metaphilic” Cell-Penetrating Polypeptide-Vancomycin Conjugate Efficiently Eradicates Intracellular Bacteria via a Dual Mechanism
Jiang, Y., Han, M., Yang, B., Yujun, F., Li, W., Wu, J. R., Song, Z., Zhao, Z., Tan, Z., Chen, Y., et al. (2020) · ACS Central Science · doi:10.1021/acscentsci.0c00893 · Cited by 76 · see citing works
Multidrug Resistance (MDR) and Collateral Sensitivity in Bacteria, with Special Attention to Genetic and Evolutionary Aspects and to the Perspectives of Antimicrobial Peptides—A Review
Fodor, A., Abate, B. A., Deák, P., Fodor, L., Gyenge, E., Klein, M. G., Koncz–Kálmán, Z., Muvevi, J., Otvos, L. J., Székely, G., et al. (2020) · Pathogens · doi:10.3390/pathogens9070522 · Cited by 78 · see citing works
Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies
Zheng, E. J., Andrews, I. W., Grote, A., Manson, A. L., Alcantar, M. A., Earl, A. M., & Collins, J. J. (2022) · Nature Communications · doi:10.1038/s41467-022-30272-0 · Cited by 70 · see citing works
Forming and waking dormant cells: The ppGpp ribosome dimerization persister model
Wood, T. K., & Song, S. (2020) · Biofilm · doi:10.1016/j.bioflm.2019.100018 · Cited by 68 · see citing works
Persister cells: formation, resuscitation and combative therapies
Wainwright, J., Hobbs, G., & Nakouti, I. (2021) · Archives of Microbiology · doi:10.1007/s00203-021-02585-z · Cited by 67 · see citing works
“As antibiotic targets involve the corruption of synthesis products; one proposed method of exterminating persisters is to encourage resuscitation within the dormant population so that these targets are actively produced (Defraine et al. 2018).”
BackgroundInfluential
When antibiotics fail: a clinical and microbiological perspective on antibiotic tolerance and persistence of Staphylococcus aureus
Küehl, R., Morata, L., Meylan, S., Mensa, J., & Soriano, À. (2019) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkz559 · Cited by 62 · see citing works
Treatment strategies targeting persister cell formation in bacterial pathogens
Khan, F., Pham, D. T. N., Tabassum, N., Oloketuyi, S. F., & Kim, Y. (2020) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2020.1822278 · Cited by 63 · see citing works
“These subpopulations exhibit tolerance against antibiotics by first stopping growth to survive the antimicrobial pressure, and then resuming to grow once the pressure drops (Defraine et al. 2018).”
BackgroundInfluential
Power-law tail in lag time distribution underlies bacterial persistence
Şimşek, E., & Kim, M. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1903836116 · Cited by 59 · see citing works
L-lysine potentiates aminoglycosides against Acinetobacter baumannii via regulation of proton motive force and antibiotics uptake
Deng, W., Fu, T., Zhang, Z., Jiang, X. Y., Xie, J., Sun, H., Hu, P., Ren, H., Zhou, P., Liu, Q., et al. (2020) · Emerging Microbes & Infections · doi:10.1080/22221751.2020.1740611 · Cited by 60 · see citing works
“eus survived from a lethal dose of penicillin as persisters [47].”
Background
Biofilm tolerance, resistance and infections increasing threat of public health
Yang, S., Li, X., Cang, W., Mu, D., Ji, S., An, Y., Wu, R., & Wu, J. (2023) · Microbial Cell · doi:10.15698/mic2023.11.807 · Cited by 60 · see citing works
The Antimicrobial and Wound Healing Potential ofOpuntia ficus indica L. inermisExtracted Oil from Tunisia
Khémiri, I., Essghaier, B., Sadfi‐Zouaoui, N., Gdara, N. B., & Bitri, L. (2019) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2019/9148782 · Cited by 59 · see citing works
Ecology and evolution of antibiotic persistence
Verstraete, L., den Bergh, B. V., Verstraeten, N., & Michiels, J. J. (2021) · Trends in Microbiology · doi:10.1016/j.tim.2021.10.001 · Cited by 58 · see citing works
Self-citation
Quorum sensing controls persistence, resuscitation, and virulence of Legionella subpopulations in biofilms
Personnic, N., Striednig, B., & Hilbi, H. (2020) · The ISME Journal · doi:10.1038/s41396-020-00774-0 · Cited by 59 · see citing works
Discovery of antibiotics that selectively kill metabolically dormant bacteria
Zheng, E. J., Valeri, J. A., Andrews, I. W., Krishnan, A., Bandyopadhyay, P., Anahtar, M. N., Herneisen, A. L., Schulte, F., Linnehan, B., Wong, F. J., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.10.026 · Cited by 57 · see citing works
“Since many known anti-persister compounds target the bacterial membrane, 24 we directly tested whether our short-listed compounds disrupt the mammalian cell membrane us-ing a red blood cell hemolysis assay.”
Background
Targeting Type II Toxin–Antitoxin Systems as Antibacterial Strategies
Równicki, M., Lasek, R., Trylska, J., & Bartosik, D. (2020) · Toxins · doi:10.3390/toxins12090568 · Cited by 56 · see citing works
Understanding Metabolic Regulation Between Host and Pathogens: New Opportunities for the Development of Improved Therapeutic Strategies Against Mycobacterium tuberculosis Infection
Park, J.-H., Shim, D., Kim, K. E. S., Lee, W., & Shin, S. J. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.635335 · Cited by 56 · see citing works
“In addition to antibiotic resistance and biofilm formation, the bacteria’s survival strategy form drug-resistant persistent cells to survive hostile environments or antibiotic stress (Fisher et al., 2017; Defraine et al., 2018).”
Background
Antimicrobial, Antibiofilm, and Anti-persister Activities of Penfluridol Against Staphylococcus aureus
Liu, Y., She, P., Xu, L., Chen, L., Li, Y., Liu, S., Li, Z., Hussain, Z. B., & Wu, Y. C. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.727692 · Cited by 56 · see citing works
Killing of Staphylococcus aureus persisters by a multitarget natural product chrysomycin A
Jia, J., Zheng, M., Zhang, C., Li, B., Lu, C., Bai, Y., Tong, Q., Hang, X., Ge, Y., Zeng, L., et al. (2023) · Science Advances · doi:10.1126/sciadv.adg5995 · Cited by 55 · see citing works
“Recently, growing data showed that the production of intracellular ROS implies a vital effector role in persister cell death (51).”
BackgroundInfluential
Increased energy demand from anabolic-catabolic processes drives β-lactam antibiotic lethality
Lobritz, M. A., Andrews, I. W., Braff, D., Porter, C. B. M., Gutierrez, A., Furuta, Y., Cortes, L. B. G., Ferrante, T. C., Bening, S. C., Wong, F. J., et al. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2021.12.010 · Cited by 48 · see citing works
“Our study contributes toadeveloping understandingof the role that bacterial metabolism plays in antibiotic efficacy and how these insights could be utilized to develop improved antibacterial therapeutic strategies (Defraine et al., 2018; Meylan et al., 2018; Stokes et al., 2019; Van Acker and Coenye, 2017).”
Background
Combatting persister cells: The daunting task in post-antibiotics era
Zhou, Y., Liao, H., Pei, L., & Pu, Y. (2023) · Cell Insight · doi:10.1016/j.cellin.2023.100104 · Cited by 50 · see citing works
“Furthermore, antimicrobial peptides (AMPs) secreted by host immune system, such as defensins and cathelicidins, can efficiently disrupt bacterial cell membrane in a growth-independent manner, thus having activity against persisters (Defraine et al., 2018; Mohammad et al., 2015).”
Background
Specific Enrichment and Proteomics Analysis ofEscherichia coliPersisters from Rifampin Pretreatment
Sulaiman, J. E., Hao, C., & Lam, H. (2018) · Journal of Proteome Research · doi:10.1021/acs.jproteome.8b00625 · Cited by 50 · see citing works
Multiple potential strategies for the application of nisin and derivatives
Khan, F., Singh, P., Joshi, A. S., Tabassum, N., Jeong, G., Bamunuarachchi, N. I., Mijakovic̀, I., & Kim, Y. (2022) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2022.2112650 · Cited by 49 · see citing works
“Several natural and synthetic active compounds have been developed to treat persister cells (Defraine et al. 2018; Khan et al. 2020).”
Background
Persistence of Intracellular Bacterial Pathogens—With a Focus on the Metabolic Perspective
Eisenreich, W., Rudel, T., Heesemann, J., & Goebel, W. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.615450 · Cited by 47 · see citing works
“For recent reviews, see (Defraine et al., 2018; Thakur et al., 2019; Wilmaerts et al., 2019).”
Ribosome dependence of persister cell formation and resuscitation
Wood, T. K., Song, S., & Yamasaki, R. (2019) · The Journal of Microbiology · doi:10.1007/s12275-019-8629-2 · Cited by 47 · see citing works
Impact of bacterial persisters on their host
Moldoveanu, A. L., Rycroft, J. A., & Helaine, S. (2021) · Current Opinion in Microbiology · doi:10.1016/j.mib.2020.07.006 · Cited by 44 · see citing works
Advances in antibacterial activity of zinc oxide nanoparticles against Staphylococcus aureus (Review)
Hao, Y., Wang, Y., Zhang, L., Liu, F., Jin, Y., Long, J., Chen, S., Duan, G., & Yang, H. (2024) · Biomedical Reports · doi:10.3892/br.2024.1849 · Cited by 45 · see citing works
“…strategies to fight against S. aureus infections, such as bacteriophage (6,7), vaccines (8‑10), monoclonal antibodies (11,12), recombinant endolysins (13), anti‑persistent bacteria therapies (14), antibacterial peptide (15,16), natural plant components (17‑19) and nanoparticles (NPs) (20,21).”
Background
Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents
Huigens, R. W., Abouelhassan, Y., & Yang, H. (2019) · ChemBioChem · doi:10.1002/cbic.201900116 · Cited by 43 · see citing works
Recent Advances in Bacterial Persistence Mechanisms
Pan, X., Liu, W., Du, Q., Zhang, H., & Han, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241814311 · Cited by 40 · see citing works
“From another perspective, stimulating antibiotic influx could change the membrane permeabilization to improve the effectiveness of antibiotics [82].”
Background
Designer co-beta-peptide copolymer selectively targets resistant and biofilm Gram-negative bacteria
Si, Z., Li, J., Ruan, L., Reghu, S., Ooi, Y. J., Li, P., Zhu, Y., Hammond, P. T., Verma, C. S., Bazan, G. C., et al. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2023.122004 · Cited by 39 · see citing works
Diversity of Bacteria and Bacterial Products as Antibiofilm and Antiquorum Sensing Drugs Against Pathogenic Bacteria
Khan, F., Oloketuyi, S. F., & Kim, Y. (2019) · Current Drug Targets · doi:10.2174/1389450120666190423161249 · Cited by 39 · see citing works
Bactericidal Activity of Usnic Acid-Chitosan Nanoparticles against Persister Cells of Biofilm-Forming Pathogenic Bacteria
Khan, F., Yu, H., & Kim, Y. (2020) · Marine Drugs · doi:10.3390/md18050270 · Cited by 40 · see citing works
“[4], due to the varied nature and diversity in their occurrence, there is still the need to explore more anti‐persister agents.”
BackgroundInfluential
A Quantitative Survey of Bacterial Persistence in the Presence of Antibiotics: Towards Antipersister Antimicrobial Discovery
Salcedo-Sora, J. E., & Kell, D. B. (2020) · Antibiotics · doi:10.3390/antibiotics9080508 · Cited by 34 · see citing works
Preexisting variation in DNA damage response predicts the fate of single mycobacteria under stress
Manina, G., Griego, A., Singh, L. K., McKinney, J. D., & Dhar, N. (2019) · The EMBO Journal · doi:10.15252/embj.2019101876 · Cited by 33 · see citing works
“…to low-metabolic states and expression of detoxifying enzymes and efflux systems are recognized causes of phenotypic drug tolerance, whose common trait is their inherent stochasticity (Adams et al , 2011; Dhar et al , 2016; Pu et al , 2016; Bergmiller et al , 2017; Defraine et al , 2018).”
Antibiotic resilience: a necessary concept to complement antibiotic resistance?
Carvalho, G., Forestier, C., & Mathias, J. (2019) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2019.2408 · Cited by 35 · see citing works
“The involvement of biological mechanisms related to antibiotic resilience in the emergence of antibiotic resistance is gaining concern in the scientific community [6,38,70], and the development of strategies to oppose these mechanisms with specific molecules is in progress [43,58,71].”
Background
Effect of colistin-based antibiotic combinations on the eradication of persister cells in Pseudomonas aeruginosa
Baek, M. S., Chung, E. S., Jung, D. S., & Ko, K. S. (2019) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkz552 · Cited by 35 · see citing works
Intestinal biofilms: pathophysiological relevance, host defense, and therapeutic opportunities
Jandl, B., Dighe, S. N., Gasché, C., Makristathis, A., & Muttenthaler, M. (2024) · Clinical Microbiology Reviews · doi:10.1128/cmr.00133-23 · Cited by 35 · see citing works
“Interfering with mechanisms that support persister cell formation is another approach (426), as well as waking persister cells through sugar treatment (427) to reconstruct antibiotic targets followed by antibiotic treatment (426).”
Synergistic effect of antibiotic combinations on Staphylococcus aureus biofilms and their persister cell populations
Kamble, E. E., Sanghvi, P., & Pardesi, K. R. (2022) · Biofilm · doi:10.1016/j.bioflm.2022.100068 · Cited by 34 · see citing works
Antibacterial, antibiofilm, and antipersister cells formation of green synthesis silver nanoparticles and graphene nanosheets against Klebsiella pneumoniae
Aziz, S. N., Marjani, M. F. A., Rheima, A. M., & Al-Kadmy, I. M. S. (2021) · Reviews in Medical Microbiology · doi:10.1097/mrm.0000000000000280 · Cited by 33 · see citing works
“[16], there is still the need to seek other useful antipersister cell materials.”
Background
Identification of a potent indigoid persister antimicrobial by screening dormant cells
Song, S., Gong, T., Yamasaki, R., Kim, J., & Wood, T. K. (2019) · Biotechnology and Bioengineering · doi:10.1002/bit.27078 · Cited by 33 · see citing works
How preclinical infection models help define antibiotic doses in the clinic
Tängdén, T., Lundberg, C. V., Friberg, L. E., & Huttner, A. C. (2020) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2020.106008 · Cited by 33 · see citing works
“Conversely, bacterial persistence may not be captured in vitro, making laboratory results potentially incongruent with clinical eﬃcacy studies assessing antibiotics with a mechanism of action that relies on active bacterial replication [27] .”
Background
Antibiotic tolerance: targeting bacterial survival
Boeck, L. (2023) · Current Opinion in Microbiology · doi:10.1016/j.mib.2023.102328 · Cited by 31 · see citing works
Current and Emerging Therapies to Combat Cystic Fibrosis Lung Infections
Manos, J. (2021) · Microorganisms · doi:10.3390/microorganisms9091874 · Cited by 30 · see citing works
“Additionally, the existence of subpopulations of persister cells, cells with increased tolerance to antibiotics, complicates antibiotic treatment [78].”
Background
Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms
Zhang, S., Qu, X., Jiao, J., Tang, H., Wang, M., Wang, Y., Yang, H., Yuan, W., & Yue, B. (2021) · Bioactive Materials · doi:10.1016/j.bioactmat.2021.11.019 · Cited by 31 · see citing works
“Persisters are a subpopulation of dormant bacteria that can survive under high doses of antibiotics and resume growth after the antibiotic pressure drops [11].”
Background
Plausible role of bacterial toxin–antitoxin system in persister cell formation and elimination
Paul, P., Sahu, B. R., & Suar, M. (2019) · Molecular Oral Microbiology · doi:10.1111/omi.12258 · Cited by 29 · see citing works
Bacterial biofilms: their role in chronical infection processes and the means to combat them
Ilyina, T. S., & Romanova, Y. M. (2021) · Molecular Genetics Microbiology and Virology (Russian) · doi:10.17116/molgen20213902114 · Cited by 28 · see citing works
Oxidative imbalance in Candida tropicalis biofilms and its relation with persister cells
da Silva, M. A., Baronetti, J. L., Páez, P. L., & Paraje, M. G. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.598834 · Cited by 28 · see citing works
Antipersister strategies against stress induced bacterial persistence
Kaushik, V., Sharma, S., Tiwari, M., & Tiwari, V. (2022) · Microbial Pathogenesis · doi:10.1016/j.micpath.2022.105423 · Cited by 26 · see citing works
Targeting mycobacterial membranes and membrane proteins: Progress and limitations
Kumar, G., & Kapoor, S. (2023) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2023.117212 · Cited by 26 · see citing works
Antibiotic-recalcitrant Salmonella during infection
Giorgio, R. T., & Hélaine, S. (2024) · Nature Reviews Microbiology · doi:10.1038/s41579-024-01124-z · Cited by 25 · see citing works
“A group has identified three main categories of anti-persister treatment strategies: resensitization of persister cells to an antibiotic, identification of drugs that kill irrespective of growth status, and interference with persister formation 117 .”
The protected physiological state of intracellular Salmonella enterica persisters reduces host cell-imposed stress
Schulte, M., Olschewski, K., & Hensel, M. (2021) · Communications Biology · doi:10.1038/s42003-021-02049-6 · Cited by 25 · see citing works
Antimicrobial peptide DvAMP combats carbapenem-resistant Acinetobacter baumannii infection
Yang, L., Gao, Y., Zhang, J., Tian, C., Lin, F., Song, D., Zhou, L., Peng, J., & Guo, G. (2024) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2024.107106 · Cited by 24 · see citing works
The classification of bacterial survival strategies in the presence of antimicrobials
Chebotar, I. V., Emelyanova, M., Bocharova, Y. A., Mayanskiy, N. A., Kopantseva, E., & Mikhailovich, V. M. (2021) · Microbial Pathogenesis · doi:10.1016/j.micpath.2021.104901 · Cited by 23 · see citing works
Amphiphilic azobenzenes: Antibacterial activities and biophysical investigation of their interaction with bacterial membrane lipids
Franche, A., Fayeulle, A., Lins, L., Billamboz, M., Pezron, I., Deleu, M., & Léonard, E. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.103399 · Cited by 24 · see citing works
“The emergence of nosocomial multi-drug resistant (MDR) bacterial strains is a growing concern in hospitals and underlines the urgent need for the development of novel antibacterial agents [1,2].”
Background
Growth Mode and Physiological State of Cells Prior to Biofilm Formation Affect Immune Evasion and Persistence of Staphylococcus aureus
Savijoki, K., Miettinen, I., Nyman, T. A., Kortesoja, M., Hanski, L. L., Varmanen, P., & Fallarero, A. (2020) · Microorganisms · doi:10.3390/microorganisms8010106 · Cited by 23 · see citing works
“Bactericidal antibiotics quickly kill most of a bacterial population, leaving a small fraction of cells that survive by entering a persister state; however, the presence of such survivors is not considered when initiating treatment [10].”
Background
Persister control by leveraging dormancy associated reduction of antibiotic efflux
Roy, S., Bahar, A. A., Gu, H., Nangia, S., Sauer, K., & Ren, D. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1010144 · Cited by 23 · see citing works
“Persister cells are growth-arrested, but can restart growth when the external stress is removed, causing relapse of infection [5,10,11].”
Background
Phylogeny Reveals Novel HipA-Homologous Kinase Families and Toxin-Antitoxin Gene Organizations
Gerdes, K., Bærentsen, R. L., & Brodersen, D. E. (2021) · mBio · doi:10.1128/mbio.01058-21 · Cited by 22 · see citing works
“Importantly, persistence is believed to contribute to the recalcitrance of bacterial infections and may thus pose a significant medical problem (30, 33-35).”
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Influential
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Authors: Defraine, V., Fauvart, M., & Michiels, J.
Affiliations: Vlaams Instituut voor Biotechnologie (BE)
Corresponding author: Michiels, Jan
ORCID: Fauvart, Maarten
Michiels, Jan
Venue: Drug Resistance Updates
Publisher: Elsevier BV
Published: 2018-05
Volume: 38
Pages: 12-26
ISSN: 1368-7646 (ISSN-L)
DOI: 10.1016/j.drup.2018.03.002
OpenAlex: W2796472927
Cited by: 222
References: 167
Citations by year: 2026: 14 · 2025: 26 · 2024: 25 · 2023: 26 · 2022: 20 · 2021: 35 · 2020: 36 · 2019: 33 · 2018: 7
FWCI: 3.82
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Drug Resistance Updates (publishedVersion)
PubMed (publishedVersion)
Lirias (KU Leuven) (submittedVersion)
Funders: Agency for Innovation through Science and Technology (IWT)
KU Leuven Center of Excellence (PF/2010/07)
KU Leuven Research Council (PF/10/010)
Belgian Science Policy Office (BELSPO) (IAP P7/28)
Fund for Scientific Research
Flanders (FWO) (G047112N, G0B2515N, G055517N)
Flemish Institute for Biotechnology (VIB)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
Keywords: bacterial persistence, persister cells, antibiotic tolerance, biofilm, antibiotic resistance emergence, chronic infection
MeSH terms: Animals, Anti-Bacterial Agents, Bacteria, Bacterial Proteins, Genotype, Humans, Phenotype, Drug Design, Signal Transduction, Gene Expression Regulation, Bacterial, Biofilms, Drug Resistance, Bacterial, Microbial Viability

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Fighting bacterial persistence: Current and emerging anti-persister strategies and therapeutics

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