Salt-tolerant microbes are divided into three main categories i.e., Mild, Moderate, and High. Salt Tolerant Microbes require levels of sodium chloride above 3% in salt water.¹ Several factors affect the tolerance criteria like growth medium, pH, temperature, and salt concentration. They generally grow up optimally at pH values beyond 9.0, but the growth is inhibited at the pH value that is most closely associated with neutral 6.5.^2,3 The general mechanism followed by Salt Tolerant microbes for surviving in varying saline conditions.

They have minimal dietary needs and a good salt quantity that is high enough for osmotic pressure.⁴ The processes of their halo adaptation (halophilic bacteria can maintain growth and development under salinity conditions) on the internal storage of KCl (potassium chloride) approximately 37% or maintain the equilibrium of sodium ions in the cell plasma and resist the osmotic pressure of the outside surroundings caused by the excessive salinity.

These organisms act on an osmoregulatory mechanism that helps them to grow in acute concentration by balancing ion exchange with the surroundings and their tolerance along with surviving for a long-life span brings the Salt Tolerant Microbes into a new era of development.^5-8

Hypersaline regions offer several possibilities for the production of additional metabolites with industrially relevant bioactivities.^9,10

The secondary metabolites produced by the Salt Tolerant Microbes show properties against drug-resistant bacteria. Using these metabolites with the help of nanotechnology will be used as a powerful tool in pharmaceutical sciences.^11-13

They can produce biological metabolites that have certain actions such as antibacterial, antifungal, antioxidant, and anticancer. The overuse of basically antibiotic drugs has resulted in the development of drug resistance (DR), which reduces or eliminates their efficacy.^14,15 The DR is shown in the human body (Cancer cells and micro-organisms). So, to overcome DR issues advanced technologies have been introduced example drug-resistant strains using biomaterials and metabolites. The challenge is to overcome the difficulties related to drug resistance not only in animals and environmental aspects but also in humans.  Two types of genes are responsible for resistance, where the first is horizontal gene transfer (HGT) and the second is genes that are already encoded in the bacterial genome that can give antibiotic resistance by mutation and activation of mobile elements. The recent drug resistance example is third-generation cephalosporin caused by a mutation in genes encoding penicillin-inactivating enzyme. The invention of new medications is necessary to overcome DR issues for better treatment and the Salt Tolerant Microbes (active metabolites) nanoparticles attracted a lot of attention. Some examples of DR have been observed in clinical strains against various antibiotics, affecting both gram-negative and gram-positive bacteria. Resistance is perceived in Haemophilus influenza to ampicillin, in Helicobacter pylori to clarithromycin and in Staphylococcus aureus shows intermediate resistance to vancomycin. Pseudomonas aeruginosa and Neisseria gonorrhoeae to aminoglycosides and quinolone, Enterobacteriaceae to cephalosporins and carbapenems. Furthermore, Enterococcus faecium exhibits resistance to cephalosporin and vancomycin, whereas Streptococcus pneumoniae discerns resistance to penicillin. Unexpectedly, the quorum-sensing mechanism of Pseudomonas aeruginosa led to the development of fluconazole resistance in Candida albicans. In response to these challenges, there has been a growing interest in utilizing halophilic biomolecules to combat DR bacteria.^16-20

Nano formulation of existing salt tolerant microbes for the targeted diseases
Several factors are required for the biosynthesis and formulation of bioactive metabolites for example uniform size, high purity, and composition for synthesis through selected techniques.^21,22

Various existing nanoformulations of Salt Tolerant Microbes with different targeted delivery like anticancer, antimicrobial, and antioxidant are discussed in Table 1.

Table (1):
Various nano-formulations of Salt Tolerant Microbes

Different methods for preparing nanoparticles with key findings are discussed in Table 2.

Table (2):
Methodology and Key Findings (application) of Biosynthesized Nano-particles

Currently, the nano-formulation of Salt Tolerant Microbes’ active metabolites is considered a scientific tool in the pharmaceutical field. The current approach is focused on treating antibiotic resistance.  The study suggests that the metabolite of Salt Tolerant Microbes produced due to the lack of nutrients, starvation, dehydration, UV-rays, and imbalanced ion concentration makes them deserving candidates for drug discovery. Some examples are also discussed like Anti-cancer activity (Table 3), and anti-oxidant activity (Table 4) in the table we also discuss some tests of anti-oxidant activity like DPPH stands as 2,2-diphenyl-1-picrylhydrazyl is a chemical compound commonly used to measure the antioxidant properties of a substance. The principle behind the DPPH assay is to determine antioxidant properties, through which antioxidant substances will neutralize the free radical of DPPH. ABTS stands for (2,2-casino-bis (3-ethylbenzothiazoline-6-sulfonic acid)), and it measures the ability of antioxidants to scavenge free radicals and prevent oxidation. It observed the reduction of the blue-green color of the solution. The nitric oxide test is used to measure the antioxidant activity of a substance. Nitric oxide is a free radical on which different substances are tested to determine their antioxidant properties by using various methods such as the Griess reagent method.

Table (3):
Anti-cancer activity of a few Active Metabolites of Salt Tolerant Microbes with targeted deliveries

Table (4):
Active metabolites of Halophilic micro-organisms responsible for anti-oxidant activity

Salt Tolerant Microbes	Structure/ metabolite	Antioxidant assay	Free radical cleavage capacity	Reference
Nocardiopsis gilva YIM 90087		DPPH/ ABTS	54.9 ± 2.0% at t 2 mg/ mL in DPPH 68.6 ± 1.0 at 1 mg/mL in ABTS	57
		DPPH / ABTS	14.3 ± 1.5% at 4 mg/mL 28.4 ± 2.7 at 2 mg/mL in ABTS
		DPPH / ABTS	d 47.7 ± 0.9% at 2 mg/mL 78.2 ± 3.7 at 0.5 mg/mL in ABTS
		ABTS	54.6 ± 0.6% at 2 mg/mL
Halophilic Archaea	C50 carotenoids	EPR spectroscopy	43.17 ± 1.79 of microemulsion and 66.08 ± 0.25 of Nanoemulsion (5 min) 82.38 ± 0.13 of microemulsion and 87.98 ± 2.13 of Nanoemulsion (30 min)	57
Haloterrigena turkmenica	Carotenoids (BR, MABR, and BABR)	DPPH / FRAP	66.8% ± 1.2 with DPPH 0.067 ± 0.008 at 0.2 µg with FRAR	57
Halomonas nitroreducens strain WB1	EPS (glucose, mannose, galactose, rhamnose, arabinose)	Hydroxyl radical scavenging activity, DPPH radical scavenging activity	5.0 mg/ml show 83.3%	58
Phialosimplex species	–	DPPH, OH–, b-carotene antioxidant	450.92 ± 6.73 (mg/ml), 390.97 ± 3.97 (mg/ml), 36.59 ± 2.94(mg/ml) respectively	58
Nesterenkonia species	HJ01pe	DPPH, ABTS	37.7 ± 1.7 and 16.2 ± 0.5 respectively	58
Staphylococcus Arlette Bacillus subtilis Bacillus tequilensis Bacillus Hayne	–	ABTS, nitric oxide, phosphomolybdenum, FRAP, and DPPH	86.34 ± 0.007 mM TE/g extract with ABTS 64.79±0.004 μg/ml with nitric oxide 1.69 ± 0.024 mg AAE/g extract with phosphomolybdenum 28.19 ± 0.012 mM Fe (II) E/mg with FRAP 5.48 mg/ml with DPHH	59
Haloarcula species	–	ABTS	95.6 ± 0.1 at 200 004 μg/ml	59
Halorubrum species HRM-150	bacterioruberin (84.12 %), followed by mono anhydrobacterioruberin (15.13 %) and carotenoid extract	2,2-azinobis-3-ethyl-benzothiazole-6-sulfonic acid, 2,2-diphenyl-1-picrylhydrazyl, and hydroxyl radicals.	Bacterioruberin shows better antioxidant activity	59
Aspergillus terreus Tsp22 Aspergillus flavus, Aspergillus gracilis, Aspergillus penicilliosis	Crude extracellular compounds	–	–	60
Halogeometricum limi strain RO1-6 Haloplanus vescus strain RO5-8	–	1,1-diphenyl-2-picrylhydrazyl radical scavenging assay.	–	60

Anti-microbial activity (Table 5) of a few Active Metabolites of Salt Tolerant Microbes with targeted deliveries. The production of carotenoid colors, retinal amino acids, hydrolytic enzymes, and suitable solutes like macromolecule stabilizing agents, biopolymers, and biofertilizers by halophilic microbes is well known. The production of bioplastics, artificial retinas, photoelectric devices, holograms, biological sensors, and other products uses salt-tolerant microbes and extremely halophilic aerobic archaea, also known as haloarchaea, plays a significant role in the industry.^23-28

Table (5):
Salt Tolerant Microbes metabolites examples with antimicrobial activities

No	Salt Tolerant Microbes Organisms	Metabolite	Activity	Ref.
1	Nocardiopsis species		Antibacterial	61
2	Bacillus subtilis		Antibacterial, antifungal	61
3	Aspergillus flocculosus		Antibacterial	61
4	Bacillus subtilis	Glycoprotein	Antibacterial, antifungal	62
5	Norcardiopsosis terrae		Antibacterial and anticancer	62
6	Halomonas salaria	Amylase Protease 8-anilinonaphthalene-1-sulfonic acid  (lipase) (2S,3R,4S,5S,6R)-2-[(2R,3S,4R,5R,6S)-4,5-dihydroxy-2-(hydroxymethyl)-6 [(2R,3S,4R,5R,6R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol  (cellulase) Pectinase DNAase	Antimicrobial	62
7	Actinomyces species		Antimicrobial	62
8	Bacillus subtilis	Carotenoids Polyhydroxy alkanoates	Antibacterial	63
9	Halomonaselongata		Antimicrobial	63
10	Halobacilluskarajiensis	Peptide furanomycin	Antimicrobial	63
11	Vibrio parahaemolyticus B2		Antimicrobial	63
12	Streptomyces species B6921		Antimicrobial	64
13	Actinomadura species M048		Antimicrobial	64
14	Streptomyces nodosus NPS007994		Antimicrobial	64
15	Steptomyces chibaensis species AUBN1/7		Antimicrobial	64
16	Vibriosp. A1SM3-36-8		Antibacterial	65
17	Pseudonocardia endophytica VHK-10		Antimicrobial	66
18	Halobacilluskarajiensis, Alkalibacillus almallahensis	Peptide furanomycin	Antimicrobial	66
19	Steptomonosporaalba		Antibacterial	67
20	Streptomyces species CNQ-418	Marinopyrroles A Marinopyyroles B	Antibacterial	67
21	Marinispora species NPS12745		Antimicrobial	68,69
22	Streptomyces hygroscopicus BDUS 49		Antimicrobial	69

Future perspective
Public health is currently at risk due to the widespread development of antibiotic resistance. Millions of lives have been saved by antibiotics over the years, yet overuse of these drugs has resulted in the development of multi-drug resistant (MDR), which reduces or eliminates their efficacy. Antibiotic resistance has recently reached critical levels, indicating a rise in fatality in the healthy community and a near-term concern for hospitalized patients. In actuality, problems with MDR infections can cause the majority of patient deaths. The exploitation of all organic and environmentally friendly assets, including major environments as an opportunity for new antibiotic discoveries, is being prompted by the urgent need to develop new antimicrobial medicines that are effective and safe. In 1982, Rodriguez-Valeraetal reported the discovery of the first antibacterial substances produced by salt-tolerated microbes. Halocin is the name given to compounds released by numerous Halobacterium species that can lyse and kill the local microbiota. Haloarchaea synthesize peptides and antimicrobial peptides (AMPs) known as halocins. Although some halocins play an ecological and environmental role, less research has been done on how they interact with human infections.⁷⁰

The clinical significance of salt-tolerated microorganisms is rarely described in the race against time, and antimicrobial intervention against the most significant risk category of human pathogens is lacking. Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Enterococcus faecium, and Pseudomonas aeruginosa are still potential pathogens.⁷¹

In the generation of advancement, nanotechnology has been proven as the speedily evolving field that deals with the size of material 1 to 100 nm in diameter.  biomolecules like proteins, nucleic acid, lipids, and polysaccharides are proven to be found in nature and can be used in the development of nanoparticles because they possess their individual properties. To develop distinctive works of art and purpose biomolecules can be engineered with nanoparticles which can result in a Novel Biomolecule Nanoparticle hybrid. So far, there are limited articles available for biomolecule nanoparticles and Salt Tolerant Microbes that can be persuaded for the creation of drug-resistant bacteria to make a variety of antibacterial drugs and anti-cancer drugs. hence, contemporary information on the technology and current trends in an individual field is required. the present review is about the Salt Tolerant Microbes and the metabolites formed by them and integrating them with nanotechnology to form biological nanoparticles which can be considered as new trends in the field of medicine and pharmaceutical field.⁷²