Antimicrobial Peptides Demonstrate Activity against Resistant Bacterial Pathogens

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Mary Garvey	--	3373	2023-08-22 13:49:44	\|
2	format change	Peter Tang	Meta information modification	3373	2023-08-23 02:52:38	\|

This entry is adapted from the peer-reviewed paper 10.3390/idr15040046

The antimicrobial resistance crisis is an ongoing major threat to public health safety. Low- and middle-income countries are particularly susceptible to higher fatality rates and the economic impact of antimicrobial resistance (AMR). As an increasing number of pathogens emerge with multi- and pan-drug resistance to last-resort antibiotics, there is an urgent need to provide alternative antibacterial options to mitigate disease transmission, morbidity, and mortality. As identified by the World Health Organization (WHO), critically important pathogens such as Klebsiella and Pseudomonas species are becoming resistant to last-resort antibiotics including colistin while being frequently isolated from clinical cases of infection. Antimicrobial peptides are potent amino acid sequences produced by many life forms from prokaryotic, fungal, plant, to animal species. These peptides have many advantages, including their multi-hit mode of action, potency, and rapid onset of action with low levels of resistance being evident. These innate defense mechanisms also have an immune-stimulating action among other activities in vivo, thus making them ideal therapeutic options. Large-scale production and formulation issues (pharmacokinetics, pharmacodynamics), high cost, and protease instability hinder their mass production and limit their clinical application.

antimicrobial peptide potent therapeutic resistance infectious disease

1. Introduction

Antimicrobial peptides (AMPs) are peptide sequences produced by bacteria, archaea, protozoal, fungal, amphibians, birds, fish, plant, and animal species. In animal and plant species, AMPs are a component of innate immunity to infectious agents ^[1] as listed in the Antimicrobial Peptide Database (APD). Additionally, there are numerous synthetically synthesized AMPs ^[2]. AMPs possess potent broad-spectrum activity against bacteria, fungi and viral species ^[3] and play important roles in immune regulation via agonizing cell receptors ^[4], healing and possess antitumor activity ^[5]. Certain animal AMPs have a chemotactic action on leukocytes, regulate cell proliferation, epithelialization, angiogenesis, wound healing, and adaptive immunity ^[2]. As a component of the innate immune system, AMPs offer a more rapid rate of production and antimicrobial action than the acquired immune response utilizing immunoglobulins ^[5]. AMPs contain between 10 and 60 amino acids and typically average ca. 33 amino acids in length ^[6]. Specific genes code for AMPs, which are induced by external factors leading to gene expression and amino acid production ^[3]. The mode of action of AMPs relates to osmotic lysis due to interaction with the bacterial membrane. Research also demonstrates that AMPs result in membrane damage, inhibit macromolecular synthesis, damage cellular organelle and DNA, inhibit enzymes and regulate host immunity ^[7] (Figure 1). Inhibiting essential cellular process such as DNA replication, nucleic acid synthesis, protein synthesis, liposaccharide (LPS) and cell wall formation is possible with AMPs that cross the cytoplasmic membrane ^[8]. The presence of a cationic rich moiety and hydrophobic aminos acids is typical in AMPs, leading to a cationic arrangement with amphiphilic (hydrophilic and hydrophobic) characteristics ^[3]. The overall positive charge of AMPs promotes binding to the bacterial cell membrane via electrostatic interactions with the negatively charged phospholipid components (phosphatidylglycerol, cardiolipin, or phosphatidylserine) ^[9]. This allows for specificity to prokaryotic membranes because mammalian cells have a net-neutral charge due to the presence of zwitterionic phospholipids, e.g., phosphatidylethanolamine, phosphatidylcholine, or sphingomyelin ^[10]. Nisin, for example, is a ribosomal-synthesized bacteriocin produced by Lactococcus lactis having antibacterial activity against Gram-positive species including Staphylococci, Streptococci, Listeria, Bacilli and Enterococci species ^[11]. Indolicidin, for example, is a bovine cathelicidin AMP that has activity by disrupting the bacterial cell membrane and by inhibition of DNA topoisomerase synthesis ^[12]. AMPs can be classified based on their activity, structural characteristics, amino acid-rich species, and source host ^[6].

Figure 1. Mode of action of AMPS against bacterial pathogens.

Currently, AMPs are classified into five major families based on their structural compositions and amino sequence: defensins, cathelicidins, hepcidins, histone-rich peptides (Table 1), and the fish-specific piscidins ^[13]. Mammals possess two classes of AMPs, the cathelicidins and defensins, with a third family termed the histatins also found in humans ^[1]. Defensins are furthered categorized as α-, β-, and θ-defensins depending on the position of disulphide bonds ^[9]. Human β-defensins are expressed by epithelial cells, monocytes, macrophages, and dendritic cells where they actively regulate the microbiome and dysbiosis ^[14]. The fish-specific AMP piscidin1 has broad-spectrum antimicrobial activity and regulate inflammatory and immune responses ^[15]. In animals, the AMPs are stored in the granules of granulocytes, e.g., neutrophils and macrophages ^[16]. Defensins and cathelicidins are also present in animal milk (breast milk in humans) with the concentrations of each varying in colostrum versus mature milk ^[17]. As such, the provision of breast milk to newborns offers protection against neonatal infection, e.g., necrotizing enterocolitis, infection of the gastrointestinal tract (GIT), and respiratory infections ^[17]. Plants possess numerous AMPs isolated from the stems, seeds, and leaf subsequently categorized into thionins, defensins, and snakins ^[6]. Insect AMPs (e.g., cecropin) are produced in cells and fat bodies and have demonstrated antimicrobial, anti-inflammatory activity and in some cases anticancer activity ^[18]. Hepcidin, a cysteine-rich AMP, has an important role in iron regulation and antimicrobial, anticancer, antiparasitic, and immunomodulatory activity ^[19]. As a peptide hormone, hepcidin is produced and secreted by liver hepatocytes and Kupffer’s cells ^[20]. Human hepcidin displays moderate antimicrobial activity ^[4]. Bacteriocins are antimicrobial peptides produced by bacterial species, which are cationic and smaller than 10 kDa (excluding class III bacteriocins) ^[11]. The small size and cationic nature of bacteriocins allows for adherence and penetration of bacterial phospholipid membranes resulting in cell death ^[21]. Bacteriocins exhibit multiple modes of action by forming pores in membranes, inhibiting cell wall biosynthesis, and affecting cellular respiration ^[11].

Currently, there is a pandemic of antimicrobial-resistant (AMR) and extensively drug-resistant (XDR) bacterial pathogens, where AMR species are predicted to cause increased mortality rates yearly. The widespread application of antibiotics in clinical settings, animal husbandry, and food production (agriculture and aquaculture) has proliferated the emergence and re-emergence of AMR pathogens. Species including vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) and the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) as well as AMR fungal species are commonly identified in difficult-to-treat cases of infectious disease ^[22]. Small colony variants of S. aureus are associated with persistent difficult-to-treat skin infections ^[14], while S. aureus bacteremia is estimated to be fatal in approximately 30% of patients. The application of AMPs in the treatment of infectious disease and as biocontrol agents in food production may offer solutions to mitigating the threat of AMR pathogens. Replacing antibiotics and antimicrobial pesticides has become important in the pharmaceutical, agricultural, veterinary, and food industries given the focus on green technologies aligned with the Sustainability Development Goals (SDGs) ^[23]. Importantly, antibacterial peptides currently applied therapeutically include gramicidin (for topical and eye application) and colistin (polymyxin E) ^[24].

Table 1. Examples of antimicrobial peptides from varying sources in terms of their antibacterial action and relevant additional information.

Family	AMP	Action	Additional Info
Defensin	Alpha- and beta-defensins Human neutrophil peptides (HNPs) ^[25] Human enteric defensins	Directly kill phagocytosed microbes. Can enhance the production of inflammatory cytokines, e.g., interleukin-1 ^[25]	Produced by neutrophils, lymphocytes, and epithelial cells of the skin and mucous membranes ^[1]. Stored in the azurophilic granules of human neutrophils. Secreted by paneth cells in the small intestinal
Cathelicidins	Bactenecins Human cathelicidin LL-37 ^[9]	Immunomodulatory activity, impacts quorum sensing mechanisms in P. aeruginosa biofilm formation ^[25], apoptosis induction, inflammasome activation, and phagocytosis ^[13] LL-37 inhibits Aspergillus fumigatus infection and reduces inflammation ^[9], LL37 analogue peptides (AC-1, AC-2, LL37-1, and D) effetive against C. albicans yeasts ^[3]	The bactenecin ChBac3.4 appears more active against bacterial membranes and tumor cells compared to normal cells ^[26] LL-37 effective against various Gram-positive and Gram-negative bacteria, and AMR species ^[9]
Hepcidins	Human liver-expressed antimicrobial peptide (LEAP) Fish hepcidins HAMP1 and HAMP2	Antibacterial Iron regulatory mode of action ^[19]	Type II acute phase protein Results in a reduction in ferroportin expression
Histone- histidine-rich peptides	Histatins—cationic peptides secreted into human saliva by salivary glands	Antifungal action, antibacterial ^[27]	High biocompatibility, effective against azole-resistant fungi ^[27]
Piscidins	Present mainly in the tissues of gills, muscle, head kidney, skin, and intestine ^[15]	Potent and broad-spectrum ^[15], antibacterial, antifungal, and antiviral properties	Efficacy toward MDR MRSA, vancomycin-resistant Enterococci, piscidin has antitumor activity against cancer-derived cell lines ^[15]

HNPs—human neutrophil peptides, AMR—antimicrobial resistance, MDR—multidrug resistant, LEAP—human liver-expressed AMP, MRSA—methicillin-resistant S. aureus.

2. Clinical Bacterial Infectious Disease

The application of antimicrobial agents and vaccination programs have provided excellent disease prevention and control strategies for decades. The emergence and proliferation of antimicrobial resistance, however, have greatly hindered this approach, where pan-drug-resistant bacteria are often isolated from cases of infectious disease ^[28]. Morbidity rates resultant from infectious disease are increasing globally, particularly in developing countries. Factors including demographic location, emergence, and re-emergence of pathogenic microbes, AMR, population growth, climate change, and globalization are contributing to disease transmission. Importantly, AMR promotes biocidal resistance with many clinical pathogens displaying intrinsic and acquired resistance to many antimicrobial chemicals and antibiotic therapeutics. Extended-spectrum beta-lactamase (ESBLs) producing Enterobacterales including K. pneumoniae and Escherichia coli are now frequently isolated from clinical infections in tertiary care facilities including intensive care units (ICUs) ^[29]. Importantly, pneumonia caused by MDR Gram-negative bacteria is associated with morbidity and high mortality rates, particularly in ICU patients ^[30]. Enterobacterales are Gram-negative facultative anaerobes associated with severe clinical infections including septicemia, community-acquired infections, urinary tract infections (UTIs), and intra-abdominal infections ^[28]. Gram-negative bacteria including Acinetobacter sp., P. aeruginosa, E. coli, and Klebsiella sp. are frequent causative agents of UTIs, with S. aureus, coagulase negative staphylococci, and Enterococcus species being common Gram-positive agents of infection with resistance species resulting in high mortality rates annually ^[31]. Bloodstream infections (BSIs) resultant from infections of the lungs, abdominal cavity, and genitourinary track are associated with high mortality in North America and Europe ^[32]. Approximately 60% of bacteria detected in BSIs display resistance to third-generation cephalosporins, including ceftriaxone and ceftazidime with ≥50% of E. coli isolates displaying resistance to fluoroquinolones ^[33]. Additionally, carbapenem resistance is also emerging in Enterobacterales species, with an increasing prevalence in K. pneumoniae and E. coli where there is increased risk of morbidity ^[34]. K. pneumoniae is responsible for approximately 30% of Gram-negative nosocomial and community-acquired infections globally ^[35]. Bacterial pathogens were the second-leading cause of mortality in 2019 and were associated with one in eight deaths globally. A study published in 2022 identified five pathogens that were associated with 750,000 or 50% of these bacterial deaths, namely S. aureus, E. coli, Streptococcus pneumoniae, K. pneumoniae, and P. aeruginosa ^[36]. S. aureus was the most frequent causative agent of deaths, totaling 1.1 million mortalities with E. coli resulting in 950,000 deaths, S. pneumoniae in 829,000, K. pneumoniae in 790,000, and P. aeruginosa resulting in 559,000 deaths ^[36]. The antibiotic colistin has been the drug of choice for Gram-negative bacterial infections of species such as P. aeruginosa, A. baumannii, Klebsiella sp., E. coli, and other Enterobacterales due to its action on the liposaccharide (LPS) of the outer membrane ^[35]. MDR species of K. pneumoniae displaying ESBL, carbapenem, cephalosporin, fluoroquinolone, and aminoglycoside resistance are currently treated with the antibiotics tigecycline and colistin ^[31]. Colistin-resistant K. pneumoniae have now emerged due to the overuse and misuse of colistin both in clinical and veterinary settings ^[28]. Furthermore, colistin has biocompatibility issues due to its nephrotoxic and neurotoxic adverse side effects due to permeabilization and lysis of eukaryotic membranes ^[35]. Biocompatibility can be improved via administration as the prodrug colistin methanesulfonate, which produces colistin after enzymatic hydrolysis ^[37]. The selectivity of AMPs to bacterial pathogens over animal cells relates to the cell membrane with Gram-positive bacteria having varying levels of peptidoglycan, phosphatidylglycerol, and phosphatidylethanolamine, and Gram-negative bacteria having lipoteichoic acids and lipopolysaccharides on the cell surface ^[38]. The presence of biocompatibility issues raises concerns in for AMP formulation.

There is an urgent need for alternative therapeutic options in the treatment of bacterial infectious disease as stand-alone or combination modalities as well as optimal disinfection agents and protocols. Combination therapy may also allow for the treatment of numerous infectious agents in one treatment protocol ^[28]. The mitigation of infectious disease and the control of infectious agents fall under SDG 3, “ensure healthy lives and promote wellbeing for all ages”, and are of paramount importance to curb epidemic and pandemic disease outbreaks. The application of AMPs as a method of disease prevention has shown efficacy in the treatment of bacterial pathogens associated with clinical disease as demonstrated by colistin.

3. Issues Preventing the Application of AMPs as Broad-Spectrum Antimicrobials

Currently, AMPs are not broadly implemented in the treatment of infectious disease with the exception of colistin and gramicidin. Their biocompatibility and cytotoxicity in vivo greatly hinder their application parenterally, with nephrotoxicity and hepatoxicity being evident in some cases ^[39]^[40]. Indeed, the AMPs currently in use are considered last-resort antibiotic agents ^[6]^[41]. Issues with large-scale production and drug formulation to meet the needs of large populations are also present, where the mass production of antibiotic agents is a well optimized and a more efficient system is required to produce the quantities needed at global level. The sporicidal ^[11], antibiofilm ^[25]^[41]^[42] and potent activity against AMR species means that AMPs warrant extensive research to overcome such issues.

3.1. Future Direction of AMP Production and Formulation to Overcome Current Issues

The AMP database gives a list of the current natural and synthetic peptides that have been identified. Defensins and bacteriocins are the groups that show highest antimicrobial potential for application as human therapeutics ^[43]. The large-scale production and clinical application of AMPs are areas of much research with in vitro studies, showing the promising potential of these potent peptides. The production of sufficient quantities of suitable purity remains a challenge to clinical application, with isolation from natural sources providing low AMP yield ^[44]. The use of solid-phase peptide synthesis allows for AMP synthesis of peptides of small to medium size (50 amino acids) ^[45] but scale up is not feasible and its suitability for producing long chain peptides is limited and results in sequence errors ^[44]. Natural AMPs are prone to protease degradation due to the L-amino acid content and results in poor bioavailability when administered therapeutically. The genetic engineering of AMPs using recombinant DNA technology and expressions systems grown in bioreactors including bacterial, yeast, plant, or animal cells may allow for large-scale production. Bioreactors allow for critical parameter control such as temperature, pH, and dissolved oxygen (DO) to obtain optimal cell density and protein yield ^[44]. Currently, synthesis methods have resulted in low yield and downstream processing issues with poor quality AMP production limiting the number of AMP reaching clinical trials and market ^[46]. The bacterial species E. coli and B. subtilis and yeast Pichia pastoris and Saccharomyces cerevisiae have been utilized for the production of biologics and AMPs due to their fast growth rate, cheap media requirements, and high yields ^[47]. These yeast expression systems are used to produce AMPs, including cathelicidin, enterocin, pediocin, plantaricin, and α-sarcin, while E. coli and B. subtilis have been used to produce defensin, hepcidin, histonin, and lactoferrin among others ^[48]. Yeast expression systems are particularly beneficial as they are robust, readily agreeable to genetic engineering/modification (GM), cost-effective, and able to carry out post-translational modifications (PTMs), with no endotoxin production that may contaminate the production process, as seen with bacterial systems ^[49]. Endotoxin contamination, which can occur with bacterial expression systems, may result in fatal septic shock in treated patients ^[50].

Post-translational modification, which is the alteration of the peptide via the addition of a chemical group such as a carbohydrate (glycosylation) or peptide (ubiquitylation), is key to the functioning of biologics in vivo ^[49]. C-terminal amidation appears important for antimicrobial activity because it raises the net charge of a peptide through neutralization of the C-terminal carboxylate and the helicity of the peptide ^[45]. Studies show that amidated AMPs repeatedly have the lowest MIC values ^[51]. Lantibiotics, which are ribosomal-synthesized peptides, are post-translationally modified via glycosylation ^[52], while class II bacteriocins do not have large PTM needs ^[43]. The toxicity of AMPs to host microbial expression systems is an issue with bacterial and yeast-based production systems ^[50]. Plant chloroplasts such as AMP expression systems in bioreactors show potential due to their high yield because each plant cell has numerous chloroplasts. The expression of AMPs in plants has many benefits, including cheaper cost, high yield, ease of scale up, reduced purification and processing steps, low contamination issues, increased biocompatibility of the product, and ability to conduct PTMs ^[48]. Smaller peptides (<65 amino acids) produced in plant chloroplasts, however, are prone to protease degradation ^[46]. Research shows reduced protease activity by constructing protein fusions that produced larger AMPs that were not recognized by plant protease enzymes by linking or fusion smaller AMPs together ^[53]. Producing fusion AMPs aids in production, purification, and reduces proteolysis by expression systems because it increases the overall size of the AMP ^[44]. Cleavage of the fusion tag can then be achieved via enzymatic or chemical means prior to formulation ^[44]. The human-derived cathelicidin antimicrobial peptide (hCAP18/LL-37) has been expressed in the Chinese cabbage plant and LL-37 in Hordeum vulgare L. (Barley) ^[46]. The AMP Protegrin-1 has been expressed in a tobacco plant showing efficacy against K. pneumoniae, S. aureus, E. coli, and C. albicans ^[48]. Long AMP sequences tend to have high production costs, issues with enzymatic degradation, and induce immunogenic reactions in vivo, and trimming unnecessary amino acid sequences or regions may shorten the AMP and reduce this production limitation ^[54]. The use of edible plants as expression systems may double as an oral mode of delivery and thus eliminate the need for downstream processing, gastrointestinal degradation, and risk of septic shock in the patient ^[50]. Research studies successfully produced a cecropin-like insect AMP (MIC of 0.8 µM for E. coli) using a cell line derived from an insect (armyworm moth) in a continuous process, with the isolated product having efficacy against E. coli ^[51]. Recombinant AMP production has a reduced cost and lower environmental impact ^[48] but is more complex, often requiring cleavage of fusion tags at purification, and is more labor intensive than chemical synthesis ^[45]. Synthetic peptides can also be produced by ring opening polymerization (ROP) of N-carboxyanhydrides derived from a-amino acids (NCAs); an excellent review of this process is provided by Rasines Mazo et al., (2020) ^[55].

3.2. Pharmacokinetics and Pharmacodynamic Considerations

The use of AMPs therapeutically is susceptible to formulation limitations due to their pharmacodynamic and pharmacokinetic profiles in vivo, which impacts their route of administration. Orally delivered AMPs are prone to protease degradation in the GIT, chemical instability, and adsorption issues limiting their bioavailability, while some are pH sensitive ^[54]. Parenterally administered formulations avoid GIT degradation but may be exposed to proteases present in the bloodstream and binding to circulating serum albumin ^[43].

Furthermore, AMPs have reduced antibacterial activity in vivo due to physiological salt impacting on the electrostatic interactions with cell membranes ^[9]. This instability of AMPs greatly affects their pharmaceutical development, formulation, and clinical use. To allow for oral delivery and improved bioavailability of AMPs, the use of drug delivery systems can be employed. Nisin is readily degraded in the GIT and so has been encapsulated in pectin-based compression coated tablet, giving a controlled-release delivery system ^[9]. Encapsulation within delivery systems composed of synthetic polymers, polysaccharides, proteins, liposomes, or inorganic materials improves the immunogenicity, biocompatibility, and stability of peptide therapeutics ^[56]. Using biocompatible polymers as delivery systems for AMPs can improve in vivo stability, half-life, and reduce cytotoxicity ^[39]. Encapsulation in nanoparticle delivery systems may improve the targeting of intracellular pathogens such as clinically relevant M. tuberculosis, S. enterica, and L. monocytogenes ^[45]. The failure of the macrolide murepavadin to pass phase III clinical trials as an IV administered antibiotic due to renal toxicity prompted its phase I investigation for inhaled treatment of P. aeruginosa lung infection. Murepavadin demonstrated a good pharmacokinetic and safety profile in healthy volunteers at up to 300 mg, with further testing to follow at phase II ^[57].

The formulation of AMPs as prodrugs may improve the bioavailability of orally delivered peptides. Prodrugs are inactive formulations that are activated in vivo biochemically/chemically to allow for targeted drug delivery. An AMP prodrug may be constructed via linking the peptides to a promoiety such as an amino acid that is cleaved via protease activity in the GIT or via the pathogen itself ^[45]. Biocompatibility issues relating to destruction of the host cell membrane such as erythrocyte cells leading to hemolysis ^[58] and cell death by AMPs have been observed in vivo ^[59], which prohibits systemic application clinically. Genetically engineering the AMPs to alter peptide amino acid sequences to increase antibacterial activity and selectivity to protect host cells may help overcome such issues ^[59]. Similarly, genetically modifying AMPs by altering amino acid sequences to be less susceptible to proteolytic degradation in vivo may improve bioavailability ^[43]. At present, there is a sparsity of human in vivo studies detailing the biocompatibility profile of AMPs with studies currently limited to cytotoxicity and hemocompatibility. In accordance with the FDA and International Standards Organization (ISO), testing guidelines testing the sensitization, pyrogenicity, genotoxicity, reproductive toxicity, and more is required to achieve FDA approval ^[39].

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