Antimicrobial resistance is conventionally regarded as the primary mechanism by which bacteria survive antibiotic exposure, named as genotypic resistance. However, increasing evidence suggests that phenotypic tolerance, including persistence and tolerance, collectively referred to as recalcitrance, also plays a critical role in bacterial survival. In this review, researchers systematically examine bacterial persistence from multiple dimensions, covering persister identification, formation mechanisms, host–pathogen interactions, emerging detection technologies, and novel countermeasures, providing an updated roadmap for understanding and combating persistent infections.
The review highlights that the formation and persistent depth of persisters are complex and diverse, involving toxin-antitoxin system, metabolism, SOS response and DNA damage repair, stringent response and RpoS, efflux pump system, trans-translation, QS system and others. Meanwhile, the review also highlights the growing recognition that bacterial persistence is deeply intertwined with host–pathogen interactions. Evidence from pathogens such as Staphylococcus aureus , Escherichia coli , Klebsiella pneumoniae , and Pseudomonas aeruginosa suggests that persistence can be maintained through genomic adaptation, metabolic reprogramming, biofilm formation, and intracellular survival. These adaptations allow bacteria to persist within host tissues, contributing to chronic, recurrent, and difficult-to-treat infections. The authors argue that understanding persistence requires moving beyond antibiotic-centered models and considering the complex biological dialogue between pathogens and their hosts.
One of the major challenges in persistence research has been the difficulty of identifying and characterizing persister cells. The review summarizes novel methodologies, including single-cell RNA sequencing, flow cytometry and fluorescence labeling, and single-cell raman spectroscopy (SCRS). These technologies provide unprecedented resolution for investigating bacterial heterogeneity and offer new opportunities to monitor persistence at the single-cell level.
Researchers are also exploring innovative approaches to eliminate persisters that survive conventional antibiotic treatment. According to the review, emerging strategies include phage-derived therapies, rational combination treatments, metabolic interventions, and host-informed anti-persister approaches. Rather than relying solely on increasing antibiotic potency, these strategies aim to target the crucial persistent features to eliminate persister cells.
Professors Cao Bin and Lu Binghuai from China-Japan Friendship Hospital (National Center for Respiratory Medicine) serve as the corresponding authors. Zhang Feilong and Yang Lin from Peking Union Medical College, together with Wang Xuelian from the Clinical Research Institute of China-Japan Friendship Hospital, are the co-first authors. This review was supported by the National Key R&D Program for Major Chronic Non-communicable Diseases of China and the Beijing Natural Science Foundation.
Science Bulletin
Literature review