Antibiotic Persistence: Surviving Treatment & New Therapeutic Strategies

Antibiotic Persistence: Why Infections Relapse and What Can Be Done

Antibiotic-resistant (AMR) bacteria pose a growing global health threat, but resistance isn’t the only way bacteria survive treatment. A subpopulation of bacteria, known as ‘persisters,’ can survive antibiotic exposure by entering a dormant state, leading to treatment failure, relapse, and chronic infections. Researchers are now uncovering the mechanisms behind persistence and exploring new strategies to combat these resilient bacteria.

Resistance vs. Persistence: Key Differences

Antibiotic resistance arises from genetic changes that allow bacteria to grow and multiply even in the presence of antibiotics. These changes can include alterations in bacterial cell walls, the production of enzymes that inactivate antibiotics, or modifications to the antibiotic’s target site.¹ Commonly recognized resistant species include Enterococcus faecium, Staphylococcus aureus, Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter species.¹

In contrast, antibiotic persistence is a phenotypic adaptation, not a genetic mutation. Persister cells are a small fraction of a bacterial population that temporarily tolerate antibiotics without any change in their susceptibility. They don’t actively resist the drug; they survive it in a dormant or slow-growing state. When antibiotic pressure is removed, persisters can ‘wake up’ and re-establish the infection.^1,2 Persistence is best understood as a form of antibiotic tolerance, distinct from resistance, and is influenced by environmental factors like pH, oxidative stress, and nutrient availability.^1,3

Biological Mechanisms Underlying Persistence

Research has identified several mechanisms driving antibiotic persistence. The hipA7 allele in E. Coli is a well-studied example, promoting persistence by inhibiting glutamyl-tRNA synthetase and activating the stringent response, leading to growth arrest.¹

Toxin-antitoxin (TA) systems also play a crucial role. These systems inhibit essential bacterial processes when activated by stress, allowing persisters to survive antibiotic exposure.^1,4 Environmental stressors, such as nutrient limitation, heat, and oxidative stress, trigger the production of alarmones like (p)ppGpp, which activate stress responses and TA modules.^1,6,8 Reduced ATP levels further contribute to antibiotic tolerance by downregulating essential cellular functions.¹

Biofilm formation is strongly linked to persistence. Biofilms provide a protective environment for bacteria, and the gradients of oxygen and nutrients within biofilms can promote the formation of persister cells.^3,4 Intracellular bacterial communities and quiescent intracellular reservoirs also contribute to persistence by shielding bacteria from both antibiotics and the host’s immune system.⁴

Clinical Consequences of Persistence

Currently, standard clinical microbiology labs primarily focus on detecting antibiotic resistance, not persistence. Antibiotic tolerance, including persistence, is typically assessed using time-consuming and variable killing assays.² This can lead to misdiagnosis, where persistence is mistaken for resistance, prompting inappropriate escalation to broad-spectrum antibiotics.²

This misdiagnosis has significant consequences. Unnecessary broad-spectrum antibiotic use damages the host microbiome and can accelerate the development of antibiotic resistance.² Persisters are particularly problematic in chronic, relapsing, and device-associated infections, as they can survive therapy, reseed infection, and serve as a reservoir for the emergence of resistant mutants.^1,2,4,5,7

Research Advances and Therapeutic Strategies

Even as new antibiotic development has slowed, researchers are exploring alternative strategies to combat persistent bacteria. Machine learning has aided in the discovery of halicin, a novel antibiotic that disrupts bacterial membrane potential.⁷ Bacteriophage therapy, using viruses to infect and kill bacteria, is also being investigated, though challenges remain regarding specificity and immune interactions.¹

Targeting persister cells directly is a promising approach. Strategies include using phage-derived endolysins to kill persisters, employing membrane-active compounds to increase antibiotic uptake, and utilizing anti-persister adjuvants like diosgenin to disrupt persister formation.^1,7,8 Preventing persister formation by targeting the stringent and SOS responses is another area of research.⁷ Combining antibiotics with agents that sensitize persisters by increasing cell stress or enhancing antibiotic accumulation is also being explored.^7,8

A deeper understanding of the interplay between antibiotic resistance and persistence, coupled with the development of diagnostics to differentiate between these mechanisms, is crucial for improving treatment outcomes and combating the growing threat of antibiotic resistance.

References

1. Huemer, M., Mairpady Shambat, S., Brugger, S. D., & Zinkernagel, A. S. (2020). Antibiotic resistance and persistence – Implications for human health and treatment perspectives. EMBO Reports 21(12). DOI
2. Lalitha, S. J., Sujitha, R. K., & Srinivas, K. (2025). Antibiotic Persistence Unveiled: Mechanisms of Dormancy and Resilience. Journal of Mycology and Infection 18-24. DOI
3. Gangar, T., & Patra, S. (2023). Antibiotic persistence and its impact on the environment. 3 Biotech 13(12). DOI
4. Choi, C., Kim, D. DS., Choi, J. B., et al. (2026). Mechanisms and clinical implications of bacterial persistence in recurrent urinary tract infections. Investigative and Clinical Urology 67(2); 123-130. DOI
5. Eisenreich, W., Rudel, T., Heesemann, J., & Goebel, W. (2022). Link Between Antibiotic Persistence and Antibiotic Resistance in Bacterial Pathogens. Frontiers in Cellular and Infection Microbiology 12. DOI
6. Pan, X., Liu, W., Du, Q., et al. (2023). Recent Advances in Bacterial Persistence Mechanisms. International Journal of Molecular Sciences 24(18); 14311. DOI
7. Hashemi, M. J., Dhaouadi Khattab, Y., & Ren, D. (2025). Mini review: Persister cell control strategies. Frontiers in Pharmacology 16. DOI
8. Seo, Y., Kim, M., & Kim, T. (2025). Inhibition of (p)ppGpp Synthesis and Membrane Fluidity Modulation by Diosgenin: A Strategy to Suppress Staphylococcus aureus Persister Cells. International Journal of Molecular Sciences 26(13); 6335. DOI
9. Antimicrobial Resistance Collaborators. (2022). Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet 399(10325); 629-655. DOI