5. Additives and Other Active Ingredients

Additive products provide long-term physical stability, inhibit germination, and influence sensory perception. Recently, the cosmetic industry has been strongly criticized for the addition of chemicals such as formaldehyde, dioxane, parabens, and phthalates. Controversies regarding the human health impact of those synthetic molecules and their analogs have encouraged the research of new additives from natural sources. 

According to relevant studies,cistanche is a common herb that is known as "the miracle herb that prolongs life". Its main component is cistanoside, which has various effects such as antioxidant, anti-inflammatory, and immune function promotion. The mechanism between cistanche and skin whitening lies in the antioxidant effect of cistanche glycosides. Melanin in human skin is produced by the oxidation of tyrosine catalyzed by tyrosinase, and the oxidation reaction requires the participation of oxygen, so the oxygen-free radicals in the body become an important factor affecting melanin production. Cistanche contains cistanoside, which is an antioxidant and can reduce the generation of free radicals in the body, thus inhibiting melanin production.

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5.1. Antimicrobial Agents

One of the most widely used antimicrobial agents against bacteria, viruses, and fungi contamination in cosmetics is chitosan (18) (Figure 5). This polysaccharide is composed mostly of glucosamine and a variable number of N-acetylglucosamine residues. Although chitosan is present in large amounts in the exoskeleton of crustaceans, insects, crabs, and shrimps, its production is limited due to factors such as seasonality, production sustainability, and processing cost. To face these difficulties, chitosan can be produced by alternative and more effective sources of microbial origin since 22–44% of the cell wall of fungi is composed of chitosan [2]. An optimal production was found in Rhizopus oryzae (0.5 g/L), R. japonica (0.6 g/L), and Mucor indicus (0.75 g/L) (Table 1) [63], while A. niger, isolated from the lichen Roccella Montagne, showed a higher yield of 1.3 g/L, which was further increased to 1.93 g/L when glucose was added [65]. In addition to its antimicrobial activity, chitosan is known for its emulsifying and delivering properties. This compound has a better water-binding capacity than methyl-cellulose, which is commonly used in cosmetics [2]. Consequently, chitosan and its derivatives, like the copolymer chitin-glucan, can present potential candidates for cosmetic and cosmeceutical formulations. Other examples of anti-aging activity that also combine with antimicrobial activity are presented in Table 1.

5.2. Moisturizers and Biosurfactants

Rhamnolipids are commonly used in cosmetics as moisturizers and biosurfactants [108]. Rhamnolipids, primarily crystalline acids, are composed of a β-hydroxy fatty acid attached by the carboxyl end to a rhamnose sugar molecule and are classified as mono and di-rhamnolipids [157]. Compared to chemical surfactants, biosurfactants have several advantages, because of their better compatibility, lower toxicity, and higher biodegradability [158]. Rhamnolipids are mainly produced by Pseudomonas aeruginosa as well as by other Pseudomonas sp. They are also used in the pharmaceutical industry for their antiviral and antimicrobial properties [159,160] and for other targets related to skin regeneration such as wound healing with reduced fibrosis, cure of burn shock, and treatment of wrinkles [161]. 

5.3. Pigments

Microorganisms produce several compounds that can be used as natural pigments. A lot of synthetic dyes have been commercialized, but few of them are eligible for cosmetics. Natural pigments are more stable and less allergenic compared to synthetics [162]. Pigments commonly biosynthesized by fungi include aromatic polyketides such as quinones, anthraquinones, naphthoquinones, melanins, flavins, and ankaflavins. Purpurogenone (20) and mitorubrin (21) are two characteristic examples, produced by the fungus Penicillium purpurogenum [95] (Figure 5) (Table 1). Recently, the potential use of terrestrial fungi as a source of natural pigments has been considerably investigated [163–165].

Cyanobacteria are an interesting source of pigments, that can produce phycobiliproteins, which are brilliantly colored fluorescent proteins. Among phycobiliproteins, phycocyanins are already used in diagnostic assays such as fellow cytometry, fluorescence-activated cell sorting, histochemistry, etc. Their intense blue color allows their use in cosmetics as natural dyes [166]. Phycocyanins are mainly produced by the photoautotrophic cyanobacterium Arthrospira platensis (3.2 g/L) [167]. However, the unicellular rhodophyte Galdieria sulphuraria showed excellent results; this red alga, growing usually in acidic springs, produced c-phycocyanin with a yield of 2.9 g/L [168] (Table 1).

5.4. Flavoring and Fragrances

Many flavoring and fragrance compounds on the market are still produced through plant and animal sources. However, a rapid and sustainable alternative is given as such high-value compounds can be also produced by microorganisms [169]. Numerous yeasts and terrestrial fungal and bacterial strains can synthesize potentially valuable fragrance compounds, including alcohols, aldehydes, esters, fatty acids, ketones, lactones, aromatic compounds, and pyrazines [170]. In support, several articles and reviews have been published and offer sufficient information regarding the use of microbial cultures or enzyme preparations for the production of flavor compounds valuable for the cosmetic industry [171–174]. Vanillin (22) is a very good example of a natural fragrance where the increasing demand and value have led to the development of alternative strategies for its production [175] (Figure 5). Strains including Pseudomonas putida, Aspergillus niger, Corynebacterium glutamicum, Corynebacterium sp., Arthrobacter globiformis, and Serratia marcescens were successfully introduced for its production by converting eugenol or isoeugenol to vanillin [170].

Benzaldehyde (23) is among the most commonly used flavoring agent, with strong cherry and almond-like aroma. An E. coli strain was successfully engineered to produce this aromatic [100,176], while the fungus Ashbya gossypii has been tested for its ability to synthesize the rose flavor 2-phenyl ethanol (24) [104]. Among terpenes, limonene (25) is one of the most widely used terpenes due to its unique citrus scent [169]. Optimization of the expression pathway in E. coli led to a yield of 435 mg/L with 1% of glucose as a carbon source [177]. When the impact of a different carbon source has been explored, the fermentation using glycerol led to titers of 2.7 g/L [106] (Figure 5) (Table 1).

6. Other Targets of Skin-Protecting Interest 

Elastase and collagenase inhibitors of microbial origin are promising cosmeceutical agents that worth to be further exploring. Elastase, a member of the chymotrypsin family of serine proteases, is responsible primarily for the breakdown of elastin, which is an important protein found within the extracellular matrix of the skin, whose damage has a signifificant impact on skin aging. Nostopeptins A and B isolated from the freshwater cyanobacterium Nostoc minutum are the only reported inhibitors of elastase (IC50: 1.3 and 11.0 µg/mL) [178]. On the other hand, collagen, the major constituent of the skin (80% of skin dry weight), is responsible for tensile strength. The metalloproteinases named collagenases are capable of cleaving collagen and elastin. To the best of our knowledge, terrestrial microorganisms, apart from the aforementioned example of nostopeptins A and B, have not been investigated thoroughly yet for their ability to produce metabolites with elastase and collagenase inhibitory effects although large screening programs on terrestrial microorganisms and endophytes have been recently presented [179,180].

7. Targets for Future Developments

Concomitantly, natural compounds that activate the PN have also been reported to possess anti-aging properties in either cell-based or in vivo models [7,11,182]; likewise, natural products significantly delay the appearance of the aged skin hallmarks. To the best of our knowledge, only a few molecules of microbial origin were reported to activate proteostatic modules. Betulinic acid was recently isolated from the endophytic fungi Phomopsis sp. and it preferentially activated the chymotrypsin-like proteasomal activity with no or minimal effects on trypsin-like and caspase-like activities [184,185]. The second case of a microbial natural product, that is well known for its anti-aging proprieties is rapamycin. This molecule isolated from Streptomyces hygroscopicus, delays cellular senescence through (among others) the inhibition of the TOR pathway and the downstream-induced alterations to both autophagy and the rate of protein synthesis [7]. 

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