A
BSTRACT
The global antimicrobial resistance crisis demands innovative therapeutics, as pathogens such as methicillin-resistant
Staphylococcus aureus
and multidrug-resistant
Pseudomonas aeruginosa
continue to outpace drug development efforts, collectively driving approximately 1.27 million deaths annually. Beyond resistance, conventional antibiotics cause collateral damage to beneficial microbiota, immune effector cells, and tissue-resident progenitor populations, a fundamental limitation that demands a paradigm shift. This review introduces the concept of “regenerative antibiotics,” a therapeutic framework in which mesenchymal stem/stromal cells (MSCs) and their bioactive secretome serve not merely as tissue repair agents, but as active, programmable antimicrobial platforms. We trace this field’s evolution across six historical events from early immunomodulatory characterizations of MSCs (2000–2010) to the landmark discovery of LL-37-mediated bacterial killing in 2010, and through to the current era of regulatory engagement (2024–2026). The molecular mechanisms underlying MSC antimicrobial activity are examined in depth, including direct bactericidal peptide secretion (LL-37, β-defensins, and hepcidin), biofilm disruption, tryptophan deprivation via indoleamine 2,3-dioxygenase (IDO), and senotherapeutic remodeling of the infected tissue microenvironment. Five therapeutic delivery strategies are critically evaluated: antibiotic-MSC combination therapy, MSCs as targeted drug carriers, cell-free extracellular vesicle platforms, biomaterial-integrated delivery systems, and genetically engineered MSCs with amplified secretomes. Evidence from
in- vitro
, preclinical, and early veterinary studies demonstrates a tripartite action of bacterial clearance, biofilm disruption, and tissue regeneration, which is unachievable by any single antibiotic. Furthermore, the thematic understanding of MSC-based regenerative antibiotics is discussed from a practical neurological infection perspective. This review positions regenerative antibiotics as a compelling, clinically translatable paradigm for the postantibiotic era.