Antibiotics have a history of more than 70 years, during which they have saved the lives of millions of individuals. However, the golden era of so called miracle bullets is over now-antibiotic resistance to almost every class of antibiotics particularly in Gram negative microbes has rippled the fear that we may enter to pre-antibiotic era. The situation is gruesome as eventually diarrhea would be difficult to treat because it has already developed resistance to treatment of last resort and in enterobacteriaceae, which comprises of diarrheal pathogens-the multi-drug resistance genes are present on plasmids associated with integrons and transposons that aid in dissemination of resistance genes to unrelated species. It is imperative to reverse the resistance mechanism by overwhelming those microbial enzymes that degrade the antibiotics, by increasing the uptake of antibiotics by bacterial cells, by blocking drug efflux, by discovering new natural products having antimicrobial potential and most importantly through development of nano-antibiotics.