**1. Introduction**

By the discovery of penicillin in 1928, the twentieth century was the golden age of antibiotics based on small molecule natural products, for instance, tetracyclines, β-lactams, and aminoglycosides [1]. These products were successful in the treatment of infectious diseases, and they saved the lives of many human beings from different types of bacterial infections. However, common antibiotics have become ineffective due to the constant evolution of most bacterial strains against them [2]. These bacterial strains can spread all around the world and lead to fatal infectious diseases because of antimicrobial resistance (AMR), which is currently one of the most crucial global health concerns [3]. Not only the antibiotics misuse and overuse have an important role in increasing AMR, but also the relatively slow pace of the development of novel antibiotics has aggravated this problem [4]. The latter reason, the

so-called "discovery void," occurred because no major class of antibiotics has been introduced since the introduction of lipopeptide antibiotics (e.g., daptomycin) in the mid-1980s. While in over 50 years no new class of antibiotics has been approved, the antibacterial treatments for Gram-negative bacteria become more difficult [2–5]. In 2016, multidrug resistance (MDR) was announced as one of the major health challenges of that time by the World Economic Forum (WEF). The foundation believed without urgent action, the estimated global death because of MDR could reach 10 million by 2050 [6]. Hence, the design and synthesis of new antibiotics with new antimicrobial mechanisms is evident [7]. According to the literature, bacterial cell membranes have a critical role in modulating antibiotic resistance, during recent years, studies on bacterial cell membranes perturbed by new compounds to overcome antibiotic resistance have been developed [8].

In comparison to Gram-positive bacteria, all Gram-negative bacteria have an extra membrane that surrounds them and is called the outer membrane (OM) (**Figure 1**) [8]. Unlike the cytoplasmic membrane (CM), the OM is very asymmetric, containing phospholipids on the inner leaflet, and lipopolysaccharides (LPSs) on the outer leaflet [9]. LPSs are the major constituents on the OM of Gramnegative bacteria which have zwitterionic oligosaccharides as core [10], zwitterionic phospholipid head groups on saturated fatty acid chains [11], and lipid A with anionic phosphate groups [12].

The OM is essential for cell viability and prevents the entry of harmful toxic substances by blocking permeability. LPSs play a central role in the selective permeability and integrity of OM. While many hydrophobic molecules are able to limit diffusion [13], LPSs play an important factor in providing selectivity to them. Because of the anionic phosphate groups, LPS molecules are able to form intermolecular electrostatic bonds with neighbors. The cross-bridging of neighboring LPS molecules significantly contributes to the resistance against hydrophobic antimicrobial agents. The anionic nature of lipid A seems to be the Achilles heel for OM integrity. The OM of *E. coli* is composed not only of LPS but also outer membrane proteins (OMP), lipoproteins (LPP), and porins [14–16]. Porins are charged proteins that allow the penetration of drugs, nutrients, and small molecules inside bacterial cells [17].

So far, intracellular processes are the target of many antibiotics to create holes in the bacterial cell envelope. In particular, there is a formidable barrier on the outer membrane (OM) of Gram-negative bacteria that must be overcome by antibiotics. There are two different pathways that help antibiotics to take through the OM, which are general diffusion porins for hydrophilic antibiotics and a lipid-mediated pathway for hydrophobic antibiotics. Some outer membrane structures such as

#### **Figure 1.**

*Comparing gram-positive and gram-negative bacterial cell membranes.*

*Antibiotic Resistance among* Escherichia coli *Isolates, Antimicrobial Peptides and Cell Membrane… DOI: http://dx.doi.org/10.5772/intechopen.101936*

protein and lipid, and their modifications have a striking influence on the bacterial antibiotics sensitivity and resistance [18]. The ability of OM disruption to change the rules of Gram-negative entry, overcome pre-existing and spontaneous resistance. Disruption of the OM expands the threshold of hydrophobicity compatible with Gram-negative activity to include hydrophobic molecules. Together, OM disruption overcomes many of the traditional hurdles encountered during antibiotic treatment and is a high-priority approach for further development [19].
