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eISSN: 2576-4519

Applied Bionics and Biomechanics

Review Article Volume 7 Issue 1

Challenges for polyhydroxyalkanoates production: extremophilic bacteria, waste streams, and optimization strategies

Khouloud Hammami,1 Yasmine Souissi,2 Ameur Cherif,1 Mohamed Neifar3

1BVBGR-LR11ES31, Higher Institute of Biotechnology of Sidi Thabet (ISBST), University of Manouba, Tunisia
2Department of Engineering, German University of Technology in Oman, Oman
3APVA-LR16ES20, National School of Engineers of Sfax (ENIS), University of Sfax, Tunisia

Correspondence: Mohamed Neifar, APVA-LR16ES20, National School of Engineers of Sfax (ENIS), University of Sfax, Sfax, Tunisia, Tel 21628762783

Received: June 13, 2023 | Published: July 7, 2023

Citation: Hammami K, Souissi Y, Cherif A, et al. Challenges for polyhydroxyalkanoates production: extremophilic bacteria, waste streams, and optimization strategies. MOJ App Bio Biomech. 2023;7(1):101-107. DOI: 10.15406/mojabb.2023.07.00181

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Polyhydroxyalkanoates (PHA) remain of high interest as a promising alternative to conventional plastics because they are biodegradable and biocompatible and have similar properties to common plastics. Despite their incredible potential, industrialization of PHA is hampered by the high production cost. To address this issue associated with PHA production cost, researchers have been exploring different approaches. In this review, we propose suggestions to overcome these challenges and highlight opportunities for future research such as producing PHA from sustainable waste streams as inexpensive renewable substrates, optimization strategies using experimental design to improve growth conditions. Furthermore, the uses of extremophilic microorganisms have gained significant attention to reduce the overall cost of PHA.


Polyhydroxyalkanoates (PHA) are biopolymers and promising alternative to commonly used petroleum-derived plastics. PHA has gained significant interest as eco-friendly bioplastics due to its biocompatibility and biodegradability (Figure 1).1–3 They can be produced by various microorganisms as a response to unfavorable environmental conditions such as limited nutritional factors like oxygen, nitrogen, phosphorus and excess of carbon substrate and accumulated as intracellular carbon, and energy reserves in form of granules.4–7 Despite the potential benefits of microbial bioplastics over synthetic plastics, production of PHA still faces limitations, including high production cost.8,9 Consequently, industrialization of PHA is limited comparison to synthetic plastics.10 The high production cost can be attributed to several factors such as low conversion efficiency of carbon substrates to PHA, slow growth rates of microorganisms used in the production, challenges associated with downstream separation processes, and high energy demand associated to with complex sterilization processes.11 In this regard, challenges have been addressed for the development of cost-effective PHA production including engineering bacteria for enhanced PHA biosynthesis. Some studies have engineered strains for the robust production.12–14 Furthermore, the optimization of fermentation parameters can further enhance PHA production in a cost-effective way. Optimization of PHA production through Response Surface Methodology (RSM) are required to enhance microbial growth and improve the efficiency of PHA production processes through optimization of different fermentation conditions such as substrate, time required for PHA synthesis, inoculum density.15,16 Another practical strategy to reduce production cost is the use of robust production strains that can thrive in "extreme" environments where the majority of other organisms would not be able to multiply. It is a useful way to lower production cost via simplifying the production process.17 Next-generation industrial biotechnology (NGIB) being the most competitive approach which involves the use of extremophilic bacteria. Overall, NGIB offers a robust and cost-effective approach to industrial biotechnology.11,18 Another approach is exploring inexpensive feedstock from various waste streams are more suitable for increased PHA production.19 Many microorganisms have been reported for the production of PHA using low-cost agricultural feed stock and surplus materials.

Figure 1 Sustainable alternative of petroleum derived plastics.

  1. PHA: structure and properties

PHA are linear polyesters of hydroxyalkanoic acids. According to different monomer compositions, they can be divided into short-chain-length PHA (scl-PHA), consisting of monomers of C2–C5 carbon atoms, and medium-chain-length PHA (mcl-PHA), containing monomers of C6-C14.3,20

The physical and chemical properties of scl- and mcl-PHA vary due to differences in the chemical and structural composition of their monomeric units. Therefore, researchers have been exploring various strategies to optimize PHA synthesis pathways and modulate the composition and structure of these polymers to obtain desirable material properties for different applications.4,21 Scl-PHA, constitute thermoplastic materials, they have characteristics of high hardness and low plasticity, high degree of crystallinity. While mcl-PHA are known as materials with elastomeric and latex-like properties, they have low crystallinity, low tensile strength, low glass transition temperature, and high elongation at break, high viscosity and high plasticity, which broadens the range of applications for mcl-PHA.1,20–23

PHA biopolymers possess distinctive characteristics such as biodegradability, biocompatibility, non-toxicity and similar physicochemical properties to conventional petroleum-based plastics.24,25 PHA can display a range of physicochemical properties, which vary based on the length of their chains and the composition of their monomers which make their material properties highly versatile.21,23,26 Among scl-PHA, PHB and the copolyester poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBHV) are best described.23 The major obstacles that must be overcome before scl-PHA can be widely used are their slow crystallization rates, poor impact resistance. The slow crystallization rates of scl-PHA coupled with their poor impact resistance and rapid aging constitute the key challenges that need to be addressed prior to their widespread use.21 PHB is a highly crystalline and brittle material with strong hardness and water resistance. The addition of 3-hydroxyvalerate (3HV) or 3-hydroxyhexanoate (3HHx) monomer to PHB significantly improve its unfavorable characteristics and shows better overall properties such as lower melting point, lower crystallinity, greater flexibility, and better tensile properties. Higher HV content in PHA also results in better water sensitivity and oxygen permeability. The proportion of HB and HV in PHA affects its final processing and mechanical properties, and by regulating the monomer composition of PHA, we can synthesize PHA with different processing requirements.3,27,28

  1. Applications

The inherent properties make PHA an important material having diverse applications in numerous fields including medical and therapeutic applications, packaging, agriculture, food industry.5,8,29 PHA is utilized as a packaging material in food industry to enhance the shelf life and quality of food products. Also, PHA are highly suitable for medical applications such as tissue engineering applications and even in drug delivery for biomedical and therapeutic purposes due their biodegradability, biocompatibility, and non-toxic nature.29–32 PHA copolymers, such as P(3HB-HV) and P(3HB-4HB), have been used for implants and microspheres that can release antibiotics and hemoembolizing agents. PHB can be used as a supplement in various applications, including the development of artificial bones.31

Numerous companies are involved in industrial scale production of PHA in Germany, Brazil, China, Japan, USA. PHBV was firstly commercialized by Imperial Chemical Industries (ICI) and PHB by Industrial Brazil and Mitsubishi Gas Chemical Company.33–35

  1. Biosynthesis pathways

Biosynthesis of PHA is highly dependent on the use of carbon source and the expression of the relevant genes involved in the biosynthetic pathways. Synthesis of scl-and mcl-PHA occurs via different metabolic pathways (Figure 2). Indeed, fatty acid oxidation, de novo fatty acid synthesis pathway, and glycolysis biosynthesis pathways are involved in the PHA precursors synthesis which is further polymerized into PHA polymer. The formation of PHA biopolymer involves a series of specific enzymatic reactions within the metabolic pathways. For scl-PHA biosynthesis, the enzyme β-ketoacyl CoA thiolase (PhaA) catalyzes the condensation of two acetyl-CoA molecules, obtained by glycolysis, to form acetoacetyl-CoA. Then, the reduction of acetoacetyl-CoA into 3-hydroxybutyryl-CoA takes place by the enzymatic activity of acetoacetyl-CoA reductase (PhaB). Afterwards, PHA synthase (PhaC) polymerize the 3 hydroxybutyryl-CoA to form PHB or PHBV.24,30 On the other hand, the metabolic pathways involved in mcl-PHA biosynthesis are β-oxidation when using fatty acid carbon source or de novo synthesis pathway when using sugars as substrate. β-oxidation pathway generates intermediates such as trans-enoyl-CoA, (S)-3- hydroxyacyl-CoA, and 3-ketoacyl-CoA in which further converted into (R)- hydroxyacyl-CoA by the action of (R)-enoyl-CoA hydratase, 3-hydroxyacyl-CoA epimerase and ketoacyl-CoA reductase, respectively. 3-hydroacyl-CoA is polymerized by PHA synthase into mcl-PHA. Another pathway involved in mcl-PHA is de novo synthesis pathway. Indeed, 3-hydroxyacyl-Acyl (ACP), derived from the synthesis of fatty acids from sugars, converted to 3-hydroxyacyl by 3-hydroxyacyl-ACP-CoA transferase, followed by mcl-PHA synthesis by PHA synthase.30,36

Figure 2 Putative metabolic pathways for scl-PHA and mcl-PHA biosynthesis.

PHA synthases can be classified into four classes depending on their in vivo substrate specificities, subunit composition, and primary amino acid sequences. PhaC I, PhaC III and PhaC IV use precursors to produce scl-PHA and PhaC II use alkane precursors to produce mcl-PHA.37–39

  1. PHA Production: challenges and prospects

PHA are synthesized by numerous microorganisms particularly Gram-negative bacteria. Capabilities of bacteria to produce different types of PHA can vary due to their differential sensitivities towards production factors.30,35 Several microorganisms are responsible for producing PHA as bioplastics, including Ralstonia eutropha, Halomonas sp., Bacillus sp, and Pseudomonas sp.40–43

However, due to the relatively high production cost in comparison to petrochemical plastics, large-scale production and commercial applications of PHA is limited. In order to reduce the overall expense of PHA, there are various attempts. This includes enhancing microbial strains, optimizing cultivation parameters, use of renewable biomass as well as use of extremophilic bacterium (Figure 3). Genetic engineering strategies have been used to enhance PHA production.44 The overexpression of related genes can further increase the conversion efficiency of substrates to PHA. The successful knockout of Halomonas TD01 resulted in a significant enhancement of the conversion rate of propionic acid into the 3HV fraction within the copolymer which leading to a reduction in the substrate cost.45 Also, an engineered strain of Cupriavidus necator has been shown to accumulate PHA.46 Furthermore, developing approaches that permit the recovery of PHA by a simple, efficient and less polluting process participate in reducing the cost of downstream processes.17

Figure 3 Factors affecting PHA production cost.

  1. Inexpensive feedstocks

The primary factor related to the high production cost is the use of a simple and pure carbon source. In which, carbon source accounts around 40-50% of the total production cost of PHA. The use of waste and renewable biomass contributes to the reduction of high production cost of PHA for large-scale PHA synthesis and also helps in reducing of organic waste in landfills associated with waste disposal.10,15,42,47–50 Research endeavors are being carried out to use inexpensive feedstocks as suitable substrate for cost-effective production of PHA (Table 1), Among such inexpensive feedstocks, non-edible biomass, by-products, and agro-waste generated from various industrial processes, was already investigated for PHA production such as lignocellulosic biomass,42 fruit pomace,51 rice mill effluent,52 waste frying oils (WFO) from fast food industries51,53,54 PHA can also be synthesized using plastics waste.55–58 By using these wastes as carbon sources, PHA production becomes more cost-efficient and resolves waste management challenges and addresses waste management issues.16,59 A recent study exploits the use of discarded fish scale waste for PHA production by Bacillus megaterium NCDC0679 with a maximum PHA yield of 6.33 g/L.60 Moreover, Allegue et al.61 42% of PHA using urban organic waste.




Polymer type


Pseudomonas putida CA-3

Oil styrene from polystyrene pyrolysis




Bacillus siamensis PD- A10

Orange peel




Bacillus subtilis JCM 1465

Orange peel




Halomonas taeanenisis YLGW01

Crude glycerol




Microbial mixed culture

Olive Oil Mill Waste water




Pseudomonas resinovorans

Spent coffee grounds




Zobellellae tiwanensis DD5

Banana peels




Pandoraea sp.

Crude glycerol






Ralstonia eutropha and Bacillus megaterium

Carob pods




Bacillus cereus VK92

Bacillus cereus VK98

Rice straw





Acinetobacter junii BP25

Rice mill effluent




Pseudomonas resinovorans

Fruit pomace




Pseudomonas aeruginosa CWS2020

Poultry (chicken feather) waste




Lysinibacillus sp. RGS

Sugarcane bagasse




Bacillus siamensis PD-A10

Orange peel




Paraburkholeria sacchari IPT 101

Wood hydrolysate





Bacillus cereus 64-INS

Raw potato starch




Pseudomonas putida GO1

PET derived terephtalic acid




Ideonella sakaiensis 201-F6 





Table 1 PHA production by a diverse range of microbial strains involves using various renewable resources

  1. Extremophilic microorganisms

Another approach has been addressed to reduce cost of biotechnological PHA production process is the use of extremophilic bacteria.11,18,62 Indeed, microorganisms that are able to thrive in extreme environmental conditions, such as high temperatures, salinity, heavy metal exposure, or acidic/alkaline pH values, are becoming more prominent as potential candidates for PHA biosynthesis in which they reduce the risk of microbial contamination.39,63 Extremophiles microorganisms capable of producing PHA in an open and unsterile fermentation process, which eliminates the need for sterilization procedures, results in energy savings and enables the use of low-cost materials.17,18 For instance, a study by Kouřilová et al.64 has investigated PHA accumulation by two thermophilic species, Rubrobacter xylanophilus and Rubrobacter spartanus. Furthermore, a halophilic Haloferax mediterranei is capable of synthesizing PHA from various inexpensive substrates.65–67 Halophiles, which are currently considered as potential candidates and best studied cases, possess the remarkable capability to accumulate PHA.68 Their adaptation to extreme conditions provides them with unique advantages, including reduced extraction cost, lower contamination risks, and the ability to produce PHA using unconventional carbon sources such as food waste, agricultural residues, or industrial by-products.69 The majority of halophilic microorganisms exhibit characteristics of both alkaliphilic and halophilic properties, which provide dual barriers to effectively prevent microbial contamination.18 Haloalkalophilic microorganisms offers several advantages in in the production of PHA, easy recovery, and lower cost compared to other extremophiles.39 For instance, the production of PHB was carried out using an alkaliphilic strain, Bacillus marmarensis DSM 21297,70 and an acidophilic bacterium was used in another study.71 Halophiles PHA-producer such as Haloferax mediterannei72 and halophilic marine bacteria Vibrio proteolyticus73 were operated in unsterilized conditions. Among halophiles microorganisms, Halomonas species has been widely studied. Halomonas TD01, a potential PHA producer, exhibits contamination-free growth under unsterile and continuous processes at high pH and high salt concentration. It has been successfully developed as a cost-effective platform for the unsterile and continuous production of chemicals.12,74 Additionally, H. campaniensis LS21 was reported to produce PHA under open and continuous conditions.75

  1. Optimisation strategies

Optimization strategies play a crucial role in enhancing the yield of PHA and improving the cost-effectiveness. Therefore, various mathematical models and statistical tools, such as Response Surface Methodology (RSM), Central Composite Design (CCD), and Plackett-Burman Design (PBD) have been used to optimize growth conditions and maximize PHA production. Indeed, optimizing fermentation parameters enables the identification of optimal conditions for the growth of PHA-producing microorganisms, leading to increased PHA yield and reduced cost of production.76 RSM is a statistical optimization approach that has emerged as a widely employed experimental design method for describing and optimizing the response.77 Many microorganisms have reported the effectiveness of RSM in enhancing the biosynthesis of PHA.78 A study by Ray et al.79 carried out the optimization of PHA production by Pannonibacter phragmitetus ERC8 using glycerol waste, also a genetically modified strain C. necator was investigated to produce P(3HB-co-3HHx) copolymers under statistical optimized conditions.77 Furthermore, Experimental designs carried out to select the best conditions for obtaining PHA by H. boliviensis.69 Studies have used Box-Behnken design (BBD) for optimization of process parameters for higher PHA yield from microorganisms such as Acinetobacter junii BP 25 using rice mill effluent,52 Burkholderia sp. ISTR5,80 marine Pichia kudriavzevii VIT-NN02 using banana peels and chicken feather hydrolysate,81 Halomonas sp. YLGW01 using volatile fatty acids.82 A Plackett Burman Design (PBD) was also used for RSM analysis for screening the significant parameters on PHA production. Priestia megaterium POD1 produce 1.431 ± 0.06 g/L PHA employing PBD,78 the halophilic bacterium H. boliviensis employ PBD for optimize variables, agitation, temperature, pH, initial concentration of glucose, nitrogen and KH2PO4.69 Bacillus endophyticus is capable of accumulating a maximum yield of 46.57% PHA under optimized conditions.83 A large number of optimization studies have been conducted, and it has been observed that the optimization is generally done on the various factors such as nutrient composition, inoculum size, and incubation time.84–91


(PHA), a biodegradable and biocompatible polymer that is a used in various applications due to their functionality, physico-chemical properties. The high cost of production is still an issue which poses a significant constraint on large-scale PHA production. Future research should prioritize the use of sustainable waste streams as cost-effective carbon substrates, optimize fermentation conditions, and focus on engineering microbes for efficient substrate utilization to enhance PHA production potential. Additionally, the emphasis should be placed on engineering PHA-producing microorganisms, particularly extremophiles that are resistant to contamination, and developing specialized engineering techniques for these extremophiles.





Conflicts of interest

The authors declare that they have no competing interests.


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