Current Research in Microbial Sciences 2 (2021) 100047 Available online 7 July 2021 2666-5174/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Bacterial toxin-antitoxin modules: classifcation, functions, and association with persistence Garima Singh 1, # , Mohit Yadav 1, # , Chaitali Ghosh 2 , Jitendra Singh Rathore 1, * 1 School of Biotechnology, Gautam Buddha University, Greater Noida, Yamuna Expressway, Uttar Pradesh, India 2 Department of Zoology Gargi College, University of Delhi, New Delhi, India A R T I C L E INFO Keywords: Toxin-Antitoxin modules Promoter Translation Persistence Bioflms PSK Antibacterial artifcial activation ABSTRACT Toxin-antitoxin (TA) modules are ubiquitous gene loci among bacteria and are comprised of a toxin part and its cognate antitoxin part. Under normal physiological conditions, antitoxin counteracts the toxicity of the toxin whereas, during stress conditions, TA modules play a crucial role in bacterial physiology through involvement in the post-segregational killing, abortive infection, bioflms, and persister cell formation. Most of the toxins are proteinaceous that affect translation or DNA replication, although some other intracellular molecular targets have also been described. While antitoxins may be a protein or RNA, that generally neutralizes its cognate toxin by direct interaction or with the help of other signaling elements and thus helps in the TA module regulation. In this review, we have discussed the current state of the multifaceted TA (type I–VIII) modules by highlighting their classifcation and specifc targets. We have also discussed the presence of TA modules in the various pathogens and their role in antibiotic persistence development as well as bioflm formation, by infuencing the different cellular processes. In the end, assembling knowledge about ubiquitous TA systems from pathogenic bacteria facilitated us to propose multiple novel antibacterial strategies involving artifcial activation of TA modules. 1. Introduction Earlier, it was found that antibiotics, which have the potency to kill bacteria, are not successful to sterilize cultures (Bigger, 1944; Hobby et al., 1942). Later, Bigger observed a distinct subpopulation of bacteria that manage and survive in an intensive antibiotic environment and he called them persisters. Numerous bacterial infections like Staphylococcus aureus in prosthetic implant infections, Mycobacterium tuberculosis in pulmonary infections, etc. are major life-threatening health issues and are related to the antibiotic treatment defeat due to bacterial persistence (Fauvart et al., 2011). Persisters are not only resistant to antibiotics but also often protected from the immune defense of hosts. For example, they may hide in different niches like the stomach (Helicobacter pylori), central nervous system (Treponema pallidum), bioflms (Pseudomonas aeruginosa), macrophages or granulomas (Mycobacterium tuberculosis), and gallbladder (Salmonella typhi) (Jayaraman, 2008). A streak of sig- nifcant investigations regarding bacterial persistence was done and it was deduced that the involvement was of intrinsic genetic factors like toxin-antitoxin (TA) modules (D¨ orr et al., 2010; Gutierrez et al., 2017; Moyed & Bertrand, 1983). Therefore, it becomes much important to investigate the functions of TA modules in various pathogenic bacterial strains. Bacterial TA modules are primarily associated with various physio- logical activities like apoptosis, growth arrest, gene regulation, and survival (Buts et al., 2005; Gerdes et al., 2005; Hayes & Van, 2011; Kim et al., 2018). In 1983, TA modules were discovered on the Escherichia coli plasmid (Ogura & Hiraga, 1983). As an addiction module, these systems were involved in the maintenance of the genetic element. TA modules are formed with a toxin part associated with an antitoxin part and are encoded on the extrachromosomal unit or chromosomal unit. Extrachromosomal encoded TA modules belong to plasmid stabilization and cell viability (Magnuson, 2007; Monti et al., 2007), while chromo- somal encoded TA modules are involved in bioflm formation, persister cell formation, growth arrest, and multidrug tolerance (Korch & Hill, 2006; Vazquez et al., 2006; Wang & Wood, 2011; Yamaguchi et al., 2011). A host cell is infuenced by the toxin part which inhibits DNA * Corresponding author: Jitendra Singh Rathore, School of Biotechnology, Gautam Buddha University, Yamuna Expressway, Gautam Buddha Nagar, Greater Noida, Uttar Pradesh 201312, India E-mail address: jitendra@gbu.ac.in (J.S. Rathore). # Equal Contribution Contents lists available at ScienceDirect Current Research in Microbial Sciences journal homepage: www.sciencedirect.com/journal/current-research-in-microbial-sciences https://doi.org/10.1016/j.crmicr.2021.100047 Received 6 May 2021; Received in revised form 4 July 2021; Accepted 5 July 2021