Persister Cell–Mediated Phenotypic Antibiotic Tolerance in Biofilm-Forming Bacteria: Mechanisms and Clinical Implications

The persistence of bacterial infections despite antibiotic susceptibility represents a major challenge in modern medicine, largely driven by phenotypic antibiotic tolerance mediated by persister cells within biofilm-forming populations. Basically, persister cells represent a temporary, non-inheritable subpopulation of bacteria whose dormancy or low metabolism makes them capable to evade the killing effect of antibiotics that normally eliminate the bacteria. By forming biofilms, bacteria not only protect persister cells through physical barriers to antibiotics but also further strengthen this tolerance, since biofilms create a nutrient-limited microenvironment with oxygen gradients and make it difficult for antibiotics to penetrate. In fact, the three factors together lead to a lifestyle of persister cells, which explains why the treatment is ineffective and the infection comes back. The pathways that lead to the production of persister cells are quite complex, as they involve several different cellular mechanisms and processes, such as toxin-antitoxin modules, generation of the stringent response through (p)ppGpp signaling, drop in the levels of ATP, and different stress-response routes. What is more, the system of quorum sensing leading to cell-cell communication and signalling inside biofilms is of utmost importance in the regulation of persistence and the survival of the community at the same time. In contrast to antibiotic resistance, which is the result of genetic mutations, the state of tolerance mediated by persisters is transient and capable of reversal, so when the antibiotic pressure is not there, cells can grow again. From a clinical perspective, persister cells cause infections that continue over a long time or keep coming back, like urinary tract infections, tuberculosis, and infections related to medical devices. They make it very difficult to treat with medicines. Unfortunately, the treatment methods we have today still fall short of eliminating these cells. However, new techniques are being researched that may improve clinical outcomes, including bacteriophage therapy, anti-persister medications, biofilm destruction, stimulation of persister cell metabolism, and nanotechnology-based treatments. Therefore, developing novel treatments for persistent bacterial infections requires a deep understanding of the biology of persister cells.

Persister cells, Biofilms, Antibiotic tolerance, Chronic infections, Toxin-antitoxin systems, Quorum sensing

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