**2. Factors associated with antibiotic resistance in** *Escherichia coli*

It is absolutely clear to us today that the antibiotic resistance of *E. coli* and some other bacteria involves a combination of different factors [20]. Drugresistant *E. coli* can be transmitted to human beings from the environment through direct or indirect contact (e.g., consumption of contaminated food and water) [21]. The uncontrolled use of antibiotics in domestic animals, as well as dietary supplements, could be one of the main reasons for high antimicrobial resistance [22]. In addition, colonization of healthy adult workers with extendedspectrum β-lactamases (ESBLs) producing *E. coli* may be related to consumption of food and water contaminated with ESBL-producing bacteria [23].

The main causes of antibiotic resistance may involve aimless antibiotic use, deficiencies in health centers and infection-control programs in hospitals, insufficient staff training, poor hygiene and other preventive measures in veterinary medicine, and lack of right management steps in animal farms, that may cause a high frequency of ESBL producing *E. coli* isolates in human (42%) and animal sample (63%) [24].

According to the worldwide antibiotic sales database, comparing antibiotic use for the years 2000 to 2015, an evident rise from about 11 doses per 1000 inhabitants per day to almost 16 is noticed [25]. Analyzing research findings with the statistics demonstrates that the mean value of antibiotic consumption was largely impacted by mid-income and low-income countries [26]. The highest number of MDR bacterial infections were observed in these countries [20]. In the past 10 years, a growing number of resistance genes have been identified in *E. coli* isolates, and many of these resistance genes were received by horizontal gene transfer. *E. coli* acts as a donor and a recipient of resistance genes in the enterobacterial gene pool, and as a result can acquire resistance genes from other bacteria but can also pass on its resistance genes to other bacteria. AMR in *E. coli* is considered one of the most important disputes in both animals and humans on a global scale as a real public health concern [20].

According to research studies, proper monitoring of disposal processes in hospitals, systematic surveillance of hospital-associated infections, monitoring the consumption of antibiotics in animals, evaluation and monitoring of antibiotic-sensitivity patterns, and preparation of safe antibiotic strategies may ease more corrective steps for the control and inhibition of *E. coli* infections in all around the world [24].

The three most common manners by which Gram-negative bacteria develop antibiotic resistance are: (i) cleaving the antibiotic drugs such as β-lactam in the periplasmic space by secretion of enzymes like β-lactamase [27]; (ii) decreasing the size and number of the porins that facilitate drug transport [12]; and, (iii) changing the selective permeation and electrostatic field within the constriction zones of porins where the antibiotic docks first and then translocate inside the cells [28]. In attention to these facts, it seems the nature charge of the OM plays definitive roles in the interactions of electrostatic binding, charged molecules transportation, and drugs killing/inhibitory actions of wild-type and antibiotic-resistant species [29].
