**Background:** Antibiotic resistance in bacteria is a major global health problem, costing 55 billion USD annually in the United States. Silver has been used as an antimicrobial agent for millennia, from ancient preservation of food and water to modern medical applications. This review examines the roles and forms of silver, particularly silver nanoparticles (AgNPs), and their potential to combat antibiotic-resistant bacteria, with emphasis on ESKAPE pathogens and pathogens of greatest human health concern according to the World Health Organization.
**Methods:** This is a narrative review that synthesizes published literature on the history, fabrication, physicochemical characterization, antibacterial mechanisms, and synergistic effects of AgNPs and AgNP–antibiotic conjugates. The paper discusses fabrication methods (physical, chemical, and biological), characterization techniques (e.g., UV-Vis, TEM, DLS, FT-IR, Raman, SERS), and antibacterial testing methods (Kirby–Bauer disk diffusion, solution-based growth inhibition, colony counting). Synergy is quantified using the fractional inhibitory concentration (FIC) index, where an FIC value of 0.5 is considered synergistic.
**Key Results:** The review describes multiple antibacterial mechanisms of AgNPs: cell membrane damage (depolarization, altered permeability, osmotic collapse, leakage of K+ ions), DNA damage (denaturation, breaks, mutations in repair genes), and collateral damage (ROS production, protein and ribosome denaturation). Smaller AgNPs (≤10 nm) have enhanced antibacterial activity due to larger surface area. Positively charged AgNPs exhibit greater attraction to bacterial cells than negatively charged ones. AgNP–antibiotic conjugates show synergistic effects against both resistant and non-resistant bacteria. For example, AgNP–ceftriaxone reduced MIC by 250-fold (from 1024 μg/mL to 4 μg/mL) against *Acinetobacter baumannii*. AgNP–methicillin conjugates reduced MIC from 250 μg/mL to 7.8 μg/mL against MDR *S. epidermidis*. AgNP–ampicillin conjugates had MIC values of 3–28 μg/mL compared to ampicillin alone (12–720 μg/mL) or AgNPs alone (280–640 μg/mL). AgNP–gentamycin conjugates reduced the original MIC of gentamicin by 32-fold with an FIC of 0.39 against *E. coli*. Positively charged amine-capped AgNP–vancomycin had MIC of 5.7 fmol/mL against *S. aureus*, compared to 97 nmol/mL for negatively charged citrate-capped conjugates. The review also notes that AgNPs are toxic to eukaryotic cells in vitro and in vivo, affecting mitochondria, endoplasmic reticulum, lysosomes, and causing accumulation in organs (liver, lung, brain, skin). In vivo studies show AgNPs can cross the blood–brain barrier, placental barrier, and blood–testis barrier in animal models.
**Clinical Implications:** AgNPs and AgNP–antibiotic conjugates hold promise as next-generation antibacterial agents, particularly against multidrug-resistant pathogens. Their multifactorial mechanisms of action reduce the likelihood of resistance development. Synergistic effects allow lower antibiotic doses, potentially reducing side effects and slowing resistance emergence. However, clinical translation is limited by few FDA-approved treatments. Key challenges include improving batch-to-batch reproducibility, developing dose–response relationships, advancing in vitro and in vivo studies, and addressing toxicity concerns. Targeted delivery strategies (antibody, aptamer) could reduce dosage and limit toxicity. The review emphasizes the need for more research on long-term safety and environmental impacts before widespread clinical use.