New strains of superbugs are discovered at an alarming rate due to human negligence of antibiotics (misuse or overuse) and acquisition of new mutations leading to rapidly evolving bacterial strains. This burden is estimated at USD 1.3 to 2.7 billion in the USA and USD 1.5 billion in the EU per year. Infected individuals also face significant health and economic consequences. The last decade has shown that antibiotic resistance is one of the most pressing issues in the healthcare system, causing a financial burden on hospitals and societies due to the prolongation of illness and subsequent treatment. We also discuss innate bacterial defense systems and how bacteriophages have evolved to tackle them. This review aims to provide a detailed overview of how bacteria acquire resistance against these non-antibiotic factors. Although the number of novel approaches for tackling the antimicrobial resistance crisis is snowballing, it is still unclear if any proposed solutions would provide a long-term remedy. Recently, bacteriophage-based treatments are also gaining momentum due to their high bactericidal activity and specificity. Nanoparticles (unmodified or in combination with toxic compounds) are also applied to circumvent in vivo drug resistance mechanisms in bacteria. Specifically, physical factors (e.g., pressure, temperature, UV light) are increasingly used for industrial sterilization. Many new antibiotic-free approaches are being developed while the old ones are being revised, resulting in creating unique solutions that arise at the interface of physics, nanotechnology, and microbiology.

Antimicrobial resistance is a significant threat to human health worldwide, forcing scientists to explore non-traditional antibacterial agents to support rapid interventions and combat the emergence and spread of drug resistant bacteria.

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