The emergence of infections caused by antimicrobial resistant microorganisms (AMRs) is currently one of the most important challenges to public and animal health. More than 23,000 deaths have been attributed to infections from AMRs in the United States; and an estimated 10 million people may die every year by 2050 around the globe due to increased resistance. With microorganisms acquiring antibiotic resistance, previously potent antibiotics are becoming ineffective and antibiotics are unable to sustain the demand to effectively treat microorganisms. Consequently, the choices of antibiotics used to treat human and animal pathogens are decreasing, leading to a health crisis. The number of AMRs is increasing and will continue to increase due to the slow development of new antibiotics and lack of alternative therapy for infectious diseases. However, developing new antibiotics in the 21st century has slowed down considerably after the over-screening of microorganisms. In addition, advanced antibiotic discovery programs including genomics, high-tech chemical approaches, and high-throughput screening methods have not been successful to develop new antibiotics and many companies have halted their antibiotic research programs. In this presentation, I will summarize major antibacterial targets and pathways and mechanisms by which AMRs survive in the presence of antibiotics. Current efforts to discover and develop antibiotics using unculturable microorganisms and new antibiotic molecular frameworks as well as development of biological therapy with bacterial phages. In addition, I will present some of our own studies that evaluated the efficacy of nanoparticles in antimicrobial activity. Our findings suggested that CM, derived from natural biopolymer chitosan, can treat infectious diseases caused by AMRs and CM harbored strong antimicrobial activity against both gram-positive and gram-negative bacteria in different environments due to broad targets, including OmpA and LPS in gram-negative bacteria and teichoic acid in gram-positive bacteria. Furthermore, risk assessment of CM revealed by the normal function of the rumen indicates that CM unlikely cause side effects. In addition, we found CM exerted antimicrobial activity in cows with metritis, resulting in cure of this disease. These studies emphasize options for alternative treatment to both human and animal disease caused by bacterial infections.