**Abstract**

An important feature complicating the treatment of infections caused by *E. coli* is the increase in resistance to different antibiotics, even to last resort antibiotics. When resistant bacteria spread to the community, resistance creates comprehensive infection control issues, increasing morbidity for non-hospitalized patients of all ages and sexes. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This chapter reviews different mechanisms of *E. coli* resistance against different classes of last resort antibiotics such as fosfomycin, nitrofurantoin, and polymixins. In addition, *E. coli* vaccines, epidemiology, and novel approaches to combat antibiotic resistance will be discussed throughout the chapter. In the age of antibiotic resistance and precise microbial genome engineering, many new strategies are now being used to combat multidrug-resistant bacteria, hoping to be our end game weapon. These strategies include CRISPR-Cas antimicrobials, nanobiotics, phage therapy, and probiotics, which promise to have a substantial impact on the way we treat diseases in the future, as we will discuss in the chapter.

**Keywords:** multidrug-resistant *E. coli*, colistin resistance, *mcr-1*, hospitals, fosfomycin, plasmid, ARGs, probiotics, CRISPR-Cas
