**2.2 Resistance to nitrofurantoin**

Nitrofurans are a group of compounds characterized by the presence of one or more nitro-groups on a nitroaromatic or nitroheterocyclic backbone. Examples of compounds belonging to this group include furazolidone, nitrofurazone, and

#### **Figure 2.**

*Proportion of anionic phospholipids in the cytoplasmic membrane is lower in gram-negative bacteria than gram-positive bacteria so the efficiency of the Ca2+-mediated insertion of daptomycin into the cytoplasmic membrane that is required for its antibacterial activity is reduced [16]***.**

nitrofurantoin: drugs that all display antimicrobial activity and are used clinically to treat different types of infections [22].

Nitrofurans need to be activated by *E. coli* nitroreductase reducing activity to show their antibiotic effect. *E. coli* nitroreductase activities may be insensitive to oxygen (type I) or inhibited by oxygen (type II). In type 1, reduction occurs via a sequence of toxic intermediates, including a nitroso and hydroxylamine state, to a biologically inactive end product where one of the intermediates is thought to be responsible for toxicity as it binds and disrupts bacterial DNA and protein. Increasing resistance is accompanied by a decrease in the activity of their reductive capacity [23]**.**

Sequential increase in resistance was genetically shown to result from sequential inactivation of the diverse nitro-reducing activities present in *E. coli*. The mutations were genetically mapped and named *nfs*A and *nfs*B. The direct link between these genes, and the sequential loss of nitro-reducing activity, was established by mutant isolation and sequencing of *nsf*A and *nsf*B. Nitrofuran resistance has been mapped only to type I nitroreductase genes [23, 24].

#### **2.3 Resistance to polymyxin (last defense line)**

Colistin and the other polymyxins are cationic antimicrobial peptides. These agents interfere with the negatively charged outer membrane of gram-negative bacteria. When polymyxins bind to the outer bacterial membrane it will disrupt the membrane. Thereby promotes the killing of the bacteria [25]**.**

The clinicians have reconsidered the value of colistin due to the rising number of hospital outbreaks with carbapenem-resistant gram-negative bacteria along with the deficiency of the development of new antimicrobial agents directed toward such MDR strains. Upon this, colistin systemic administration has been reintroduced as a final treatment option. In the light of this the WHO reclassified colistin in 2012 as a critically essential antibacterial agent for mankind's remedy [26].

Worldwide, the increased use of colistin led to the appearance of colistin resistance. Colistin resistance rates have been noticed to increase more often [27]**.**

#### *2.3.1 Intrinsic resistance*

Colistin resistance occurs normally via alterations n the two-component regulatory system phoPQ-PmrAB, both contain a sensor kinase (PhoQ and PmrB, correspondingly), these kinases sense the signals that originated from the surrounding environment [28].

#### *2.3.2 Acquired resistance*

Similarly, to the chromosomal mechanisms of colistin resistance, the acquired resistance to colistin is mainly involved with lowering the affinity of the colistin to bind to the LPS by decreasing its negative charge. MCR gens (mobile colistin resistance genes) are a member of the phosphor-ethanol-amino transferase enzyme family, with expression of this gene resulting in ethanolamine moiety addition to the lipid A [29].

This plasmid-mediated mechanism of resistance is of special due to the possibility of colistin resistance spreading among a wide range of enteric bacteria in mankind and animals. This type of resistance is resistance is associated with the low level of MIC (4–8 mg/L) [30].

#### **2.4 Plasmid-mediated colistin resistance**

On the 18th of November 2015, **Liu** *et al.* reported the first description of plasmid-mediated colistin resistance (*mcr*-1 gene) among samples from *DOI: http://dx.doi.org/10.5772/intechopen.104955* Escherichia coli *(*E. coli*) Resistance against Last Resort Antibiotics and Novel Approaches…*

food-producing animals, food, and humans in China, the detection of the mcr-1 gene the horizontally transferred plasmid-mediated colistin resistance gene altered the previous idea about the colistin resistance in gram-negative bacteria which stats that Enterobacteriaceae only develop colistin resistance through chromosomal mutations or other adaptive mechanisms. *In vitro* studies on *mcr-1* gene showed self-transfer of the gene from conjugative plasmids [31]. After the first detection of the *mcr*-1 gene in *Enterobacteriaceae* in China, within the 6 months after its first detection, the plasmids which carry the *mcr*-1 gene were found in isolates from animals, food, the environment, and humans worldwide [32]. On 3 March 2016, a literature review published in Euro surveillance showed that during 3 months of its discovery the *mcr*-1 gene had been spread to many parts of the world and found in isolates from different sources of food and environment and also from infected patients as well as asymptomatic human carriers [33]**.** It is worthy to mention that, the *mcr*-1 gene detected in a human was in the U.S on the 26th of May 2016 in an *E. coli* isolate [32].

Although the first detection of *mcr* gene was in 2015 it is believed that this gene was existed among Enterobacterial isolates for many years before, but it wasn't identified and it was transmitted silently for years [29].

Surprisingly, a retrospective study by [34], on isolates from Chicken origin indicated that the emergence of *mcr*-1 gene among enterobacterial isolates was when the colistin was first used in food-producing animals in 1980, but it did not appear again in the isolates from the next 20 years. However, the *mcr*-1 gene was noticed again in random isolates belonged to the period from 2004 to 2006. In isolates from 2009, the outbreak of the presence of *mcr*-1 gene among isolates recovered from the chicken was noted [35].

Until now, there are 8 variants of the *mcr* gene (*mcr*-1, *mcr*-2, *mcr*-3, *mcr*-4, *mcr*-5, *mcr*-6, *mcr*-7 and *mcr*-8). *mcr*-2 gene is a variant of *mcr* gene which share about 76.7% nucleotide (81% amino acid) with *mcr*-1, this gen was first detected in Belgium [25]**.** The *mcr*-3 gene has nucleotide sequence 45.0 and 47.0% identity to *mcr*-1 and *mcr*-2 respectively [29].
