Revolutionizing orthopedic healthcare: a systematic review unveiling recombinant antimicrobial peptides

Abstract

The increasing demand for orthopedic surgeries, including joint replacements, is driven by an aging population and improved diagnosis of joint conditions. Orthopedic surgeries carry a risk of infection, especially in patients with comorbidities. The rise of antibiotic resistance exacerbates this issue, necessitating alternatives like in vitro bioengineered antimicrobial peptides (AMPs), offering broad-spectrum activity and multiple action mechanisms. This review aimed to assess the prevalence of antimicrobial potential and the yield after purification among recombinant AMP families. The antimicrobial potential was evaluated using the Minimum Inhibitory Concentration (MIC) values against the most common bacteria involved in clinical infections. This systematic review adhered to PRISMA guidelines, focusing on in vitro studies of recombinant AMPs. The search strategy was run on PubMed, Scopus and Embase up to 30^th March 2023. The Population, Exposure and Outcome model was used to extract the data from studies and ToxRTool for the risk of bias analysis. This review included studies providing peptide production yield data and MIC values against pathogenic bacteria. Non-English texts, reviews, conference abstracts, books, studies focusing solely on chemical synthesis, those reporting incomplete data sets, using non-standard MIC assessment methods, or presenting MIC values as ranges rather than precise concentrations, were excluded. From 370 publications, 34 studies on AMPs were analyzed. These covered 46 AMPs across 18 families, with Defensins and Hepcidins being most common. Yields varied from 0.5 to 2,700 mg/L. AMPs were tested against 23 bacterial genera, with MIC values ranging from 0.125 to >1,152 μg/mL. Arenicins showed the highest antimicrobial activity, particularly against common orthopedic infection pathogens. However, AMP production yields varied and some AMPs demonstrated limited effectiveness against certain bacterial strains. This systematic review emphasizes the critical role of bioengineered AMPs to cope infections and antibiotic resistance. It meticulously evaluates recombinant AMPs, focusing on their antimicrobial efficacy and production yields. The review highlights that, despite the variability in AMP yields and effectiveness, Arenicins and Defensins are promising candidates for future research and clinical applications in treating antibiotic-resistant orthopedic infections. This study contributes significantly to the understanding of AMPs in healthcare, underscoring their potential in addressing the growing challenge of antibiotic resistance. Systematic review registration:https://osf.io/2uq4c/.

Keywords: antibiotic resistance; minimum inhibitory concentration; orthopedic infections; recombinant antimicrobial peptides; yield.

Figure 1

Schematic flow chart of the systematic review. The figure presents a detailed flow chart outlining the methodology from the data search to extraction. Outcomes include the selected studies highlighting the range values of yield and MIC. The figure also depicts the results, quantified by the number of selected studies, of the predominant AMP families against the three primary bacteria genera responsible for orthopedic infections. Created with BioRender.com.

Figure 2

This figure illustrates the meticulous process undertaken to select studies for inclusion in our review, emphasizing our commitment to transparency and rigor. The PRISMA flow began with a comprehensive search and meticulous screening of a vast literature. After removing non-compliant studies, the data from 34 publications were extracted for the further steps of this review.

Figure 3

A classification of the AMP families described in the selected literature is represented, which serves as a demonstration of the diversity and complexity of these molecules. AMP families are ranked based on the total number of MIC values reported. The corresponding genus of the bacteria tested is also represented and the alluvial chart shows the connection between AMP families and microbe genus. This general categorization was used to select the most represented AMP families and targeted microorganisms.

Figure 4

The alluvial chart visually describes the Hepcidins family by tracing their journey from production yield to their microbial targets and effectiveness. Starting from the left, the chart records the yield of each Hepcidin in mg/L, illustrating the diversity in production efficiency among the family members. This flows into the central section, which outlines the various bacterial genera targeted by these peptides, highlighting the broad spectrum of their antimicrobial activity. On the right, the minimum inhibitory concentration (MIC) range in μg/mL is reported, describing the antimicrobial activity of Hepcidins against these bacterial targets. A unique color is assigned to each AMP, thereby enabling readers to follow the story of each peptide across the chart. This figure provides a comprehensive overview of the Hepcidins’ antimicrobial capabilities and emphasizes the potential of these peptides in developing new antibacterial therapies.

Figure 5

The alluvial chart visually describes the Arenicins family by tracing their journey from production yield through to their microbial targets and effectiveness. Starting from the left, the chart records the yield of each Arenicin in mg/L, illustrating the diversity in production efficiency among the family members. This flows into the central section, which outlines the various bacterial genera targeted by these peptides, highlighting the broad spectrum of their antimicrobial activity. On the right, the minimum inhibitory concentration (MIC) range in μg/mL is reported, describing the antimicrobial activity of Arenicins against these bacterial targets. A unique color is assessed to each AMP, thereby enabling readers to follow the story of each peptide across the chart. This figure provides a comprehensive overview of the Arenicins’ antimicrobial capabilities and emphasizes the potential of these peptides in developing new antibacterial therapies.

Figure 6

The alluvial chart visually describes the Defensins family by tracing their journey from production yield through to their microbial targets and effectiveness. Starting from the left, the chart records the yield of each Defensin in mg/L, illustrating the diversity in production efficiency among the family members. This flows into the central section, which outlines the various bacterial genera targeted by these peptides, highlighting the broad spectrum of their antimicrobial activity. On the right, the minimum inhibitory concentration (MIC) range in μg/mL is reported, describing the antimicrobial activity of Defensins against these bacterial targets. A unique color is assessed to each AMP, thereby enabling readers to follow the story of each peptide across the chart. This figure provides a comprehensive overview of the Defensins’ antimicrobial capabilities and emphasizes the potential of these peptides in developing new antibacterial therapies.

Figure 7

The alluvial chart visually describes the ALFs family by tracing their journey from production yield through to their microbial targets and effectiveness. Starting from the left, the chart records the yield of each ALF in mg/L, illustrating the diversity in production efficiency among the family members. This flows into the central section, which outlines the various bacterial genera targeted by these peptides, highlighting the broad spectrum of their antimicrobial activity. On the right, the minimum inhibitory concentration (MIC) range in μg/mL is reported, describing the antimicrobial activity of ALFs against these bacterial targets. A unique color is assessed to each AMP, thereby enabling readers to follow the story of each peptide across the chart. This figure provides a comprehensive overview of the ALFs’ antimicrobial capabilities and emphasizes the potential of these peptides in developing new antibacterial therapies.

Figure 8

In orthopedic infections, three bacteria genera are the most represented (Staphylococcus, Pseudomonas and Escherichia). The alluvial chart illustrates the efficacy of various AMP families (on the left side: Arenicins, Defensins, ALFs, and Hepcidins) in inhibiting these bacteria genera. On the right side of the chart, minimum inhibitory concentration (MIC) values are categorized as either greater than (>) or less than or equal to (≤) the 75^th percentile, with the following thresholds: Arenicins at 10 μg/mL, Defensins at 65.6 μg/mL, ALFs at 318 μg/mL, and Hepcidins at 436.5 μg/mL. The legend at the bottom shows each AMP considered in the chart.