sector, wear, and corrosion‐resistant coatings. The engineering of NMs to form lighter, as well as extremely stronger materials has found its application in making hard and strong surface coating over material as resistive coatings, faster acting switches, medicines, storage devices with enhanced storage capacity and in building materials.
1.4.1 Advanced Application of NMs as Antimicrobial Agents
Apart from the above applications, NMs have been employed in the medical field as both theragnostic and diagnostic agents. Gold NPs are well‐known for their application in the medical field whereas silver NPs have found applications as antimicrobial materials. Apart from silver, in recent times, a number of NMs have gained attention as antimicrobial agents in the healthcare sector because of the development of resistant bacteria caused by the uncontrolled usage of antibiotics. Antimicrobial‐resistance is considered one of the critical issues that need an immediate solution. In this regard NMs with unique features and specific functionality have gained interest in combating antimicrobial resistance. In the following sections, we will briefly explain bacterial resistance and the role of NMs in bacterial resistance.
1.5 Bacterial Resistance to Antibiotics
The most serious threat to public health are infectious diseases and mortalities that have resulted from chronic infections. The common causative agents for most infectious diseases are bacteria. Before the discovery of antibiotics, the old treatment modalities involved the use of synthetic compounds such as sulfa drugs, quinolones, and salvarsan as chemotherapeutic agents (Aminov, 2010). Later on, in the twentieth century antibiotics emerged as wonder drugs. However, the wild use of antibiotics with uncontrolled measures led to the emergence of antibiotic‐resistant pathogens and the foremost dangerous multidrug‐resistant strains.
The first antibiotic resistance was reported with the enzyme called penicillinase produced from pathogenic Escherichia coli (Abraham & Chain, 1940). In nature, the organism that produces antibiotics has self‐resistance against its own antibiotic. Most of them have more than one simultaneous mechanism to protect the cells completely from their own bioactive molecules. The most common mechanism of self‐resistance involves antibiotic modification or degradation, antibiotic efflux, antibiotic sequestration, and target modification. In the producer organisms, the genetic code for the self‐resistances are clustered with the antibiotic synthesis gene and hence their expression is co‐regulated. The widespread use of antibiotics and coexistence of antibiotic producer organism with nonproducers led to the origin of antibiotic resistance (Kaur & Peterson, 2018). Since NMs have shown potential to deal with antibiotic resistance, a brief discussion on the mechanism of antibiotic resistance is included in this section.
1.5.1 Mechanism of Antibiotic Resistance
The mechanism of bacterial antibiotic resistance can be categorized into intrinsic and extrinsic. The antibiotic resistance mechanism that fixed in the genetic core of the organisms is an intrinsic mechanism encoded in chromosomes. This may include the enzyme system which inactivates antibiotics, nonspecific efflux pump systems, and permeability barrier mechanisms (Cox & Wright, 2013; Fajardo et al., 2008). AcrAB/TolC efflux pump in E. coli is one of the well‐studied intrinsic resistance systems. These efflux systems are generally very nonspecific and help in exporting different antibiotics, detergents, dyes, and disinfectants (Nikaido & Takatsuka, 2009). Similarly, a mechanism involving permeability barrier in E. coli and other Gram‐negative bacteria for vancomycin is also an intrinsic resistance system where the outer membrane acts as a permeability barrier (Arthur & Courvalin, 1993). On the other hand, the resistance system that is obtained from other organisms such as producers by horizontal gene transfer is called the acquired resistance system. Unlike the intrinsic resistance system, the resistance elements of the acquired systems are generally embedded in plasmids and transposons. Acquired resistance system includes the plasmid‐encoded specific efflux pumps and enzymes that can alter or modify the antibiotics or the target of antibiotics (Bismuth et al., 1990).
According to Wang, Hu, and Shao (2017), the resistance mechanism can be categorized into different subdivisions on the basis of the biochemistry at the protein level target alterations, passive or inactive enzyme generation, active efflux pumps, permeability barrier, biofilm formation, elimination and emergence of certain specific protein. It has been noted that in the same bacterium there may exist two or more simultaneous mechanisms from the aforementioned categories as resistance mechanism such as antagonist induction through metabolic pathway and production of competitive inhibitor to counteract the antibiotics. In general, the molecular mechanisms of antibiotic resistance are divided into three types: (i) antibiotic modification, (ii) antibiotic efflux, and (iii) target modification or bypass or protection mechanisms (Wang et al., 2017).
1.5.1.1 Antibiotics Modification
Antibiotics modification is the common resistance mechanism of pathogenic bacteria against antibiotics of aminoglycosides class. So far, multiple types of aminoglycosides modifying enzymes (AMEs) have been identified in both Gram‐negative and Gram‐positive bacteria (Ramirez and Tolmasky, 2010; Schwarz et al., 2004). The genetic code for these systems is embedded in the mobile genetic elements (MGEs) of pathogenic or resistant bacteria (Ramirez & Tolmasky, 2010). The chromosomal determinants of the aminoglycosides modifying enzymes have been found in the large number of bacteria present in the environment such as Acinetobacter and Providencia. These chromosomal determinants are the sources from where pathogenic strains acquired the genetic codes onto their mobile genetic elements (Schwarz et al., 2004). A well‐known AME is the N‐acetyl transferase, which acetylates the aminoglycosides. Apart from AMEs, chloramphenicol acetyltransferase (CAT) and antibiotic hydrolyzing enzyme β‐lactamases belong to the same group of enzymes that acts on the antibiotics and modifies them (Martinez, 2018; Schwarz et al., 2004).
1.5.1.2 Antibiotic Efflux
The second most common mechanism of antibiotic resistance is antibiotic efflux and permeability barrier. As we discussed earlier, the permeability barrier mechanism is mostly availed by the greatest number of Gram‐negative bacteria. The presence of an extra outer membrane in Gram‐negative bacteria exhibits a barrier against hydrophilic antimicrobial agents and antibiotics such as vancomycin. However, a mutation in the genes related to outer membrane such as porin or even change in their expression level makes them vulnerable to hydrophilic antibiotics (Li et al., 2012).
The antibiotic efflux pumps in bacteria are categorized into five different families: ATP‐binding cassette (ABC), major facilitator superfamily (MFS), resistance–nodulation–division (RND), small multidrug resistance (SMR), and multidrug and toxin extrusion (MATE) (Sun, Deng, & Yan, 2014). Among these, only ABC family proteins use ATP as an energy source for efflux whereas the rest couple the export of their substrate with ion gradients. The acquired determinants of the efflux system are generally located on the plasmids in the pathogenic bacteria such as Tet genes. At least 22 genes have been identified in both Gram‐positive and Gram‐negative bacteria (Roberts, 2005). In pathogenic bacteria, the resistance–nodulation–division (RND) pump systems are operative synergistically with the Tet pump systems. The simple Tet protein effluxes the tetracycline into periplasm where RND captures and exports it outside. This is the plausible reason for increase in the minimum inhibitory concentration of tetracycline against pathogenic bacteria (Lee et al., 2000).
1.5.1.3 Target Modification or Bypass or Protection
The resistant mechanism involving target modification and protection has been also observed in various clinically resistant strains of bacteria. A typical example of target modification is found in methicillin‐resistant Staphylococcus aureus (MRSA) strains. In MRSA strains, the resistance mechanism to β‐lactams is conferred by the exogenous penicillin‐binding protein (PBP) called PBP2a. The acquired PBP2a is devoid of trans‐glycosylase activity; hence, it acts along with