Novel Strategies to Combat Antimicrobial Resistance: History
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Contributor:
Yosra A. Helmy
,
Khaled Taha-Abdelaziz
,
Hanan Abd El-Halim Hawwas
,
Soumya Ghosh
,
Samar Sami AlKafaas
,
Mohamed M. M. Moawad
,
Essa M. Saied
,
Issmat I. Kassem
,
Asmaa M. M. Mawad

Antimicrobial resistance (AMR) is one of the most important global public health problems. The imprudent use of antibiotics in humans and animals has resulted in the emergence of antibiotic-resistant bacteria. The dissemination of these strains and their resistant determinants could endanger antibiotic efficacy. Therefore, there is an urgent need to identify and develop novel strategies to combat antibiotic resistance. 

  • antimicrobial resistance
  • antibiotics alternatives
  • quorum sensing
  • prebiotics
  • probiotics

1. Small Molecules (SMs)

SMs are non-peptide organic molecules that are synthetic or obtained from natural product extracts. They have drug-like properties that can interact with biological molecules, including protein and nucleic acids, and can alter their normal functions. The low molecular weight (~200–500 Da) and high hydrophilicity of these molecules allow their effective absorption by both host and pathogen barriers [1][2]. SMs can be modified to enhance the qualities desired for specific applications, such as stability and solubility under adverse environmental conditions. These properties can be exploited to enhance the SMs’ antimicrobial efficacy and their mass applicability. High-throughput screening (HTS) of SM libraries is commonly used for the development of antibacterial drugs and identification of SM candidates that inhibit either bacterial growth in whole-cell assays or the activity of a main bacterial enzyme or protein [3]. Indeed, a cost-effective, cell-based HTS expedient approach has been recently developed to enhance anti-bacterial molecule discovery [4][5]. SM antimicrobials targeting bacterial membranes are highly desired because they have low potential for resistance development by pathogens, can potentiate the activity of many antibiotics, are effective against slow-growing bacteria and biofilms, and have high stability in serum and good tissue penetration [6]. They have been reported to be effective against several MDR bacteria, such as E. coli, P. aeruginosa, Enterococcus faecium, methicillin resistant S. aureus (MRSA), Klebsiella pneumoniae, Acinetobacter baumannii, and Enterobacter species [7][8][9]. Recently, SMs were used for the treatment of plant pathogens such as Xanthomonas spp., Erwinia tracheiphila, Acidovorax citrulli and Salmonella infection [10][11][12][13], as well as for the potentiation of antibiotics, which can help in reducing the resistance of the treated bacteria [14].

2. Quorum-Sensing/Antivirulence Inhibitors

Bacterial cells adapt to their surrounding environment and regulate their density and behavior via a cell-to-cell communication process named quorum sensing (QS). This process is mediated by bacterial secretion of extracellular signaling molecules called autoinducers (AIs) [15]. The bacteria produce and release AIs to coordinate their gene expression for survival as multicellular organisms. Additionally, AIs are also key regulators of biofilm formation, stress adaptation, secondary metabolite production, swarming motility, enzyme production, and virulence factor production [16][17]. Active transport or diffusion is used to release autoinducers into the environment to achieve efficient communication between bacterial cells [18]. As the bacterial population density rises, AIs build up in the environment, and, after this reaches a certain threshold, bacteria use them as extracellular signaling molecules to adjust their density and coordinate their gene expression [19].
QS systems are based on three fundamental concepts. (1) One is the bacterial cells’ density: at a high cell density, the cumulative generation of AIs results in local accumulation at a high concentration, which facilitates detection and response. However, at a low cell density, the AIs diffuse away, as they are present at concentrations below the detection threshold [20]. (2) Receptors generated in the cytoplasm or on the membrane are used to identify AIs. (3) The recognition of AIs leads to increased bacterial synthesis of AIs in addition to stimulation of gene expression required for cooperative behaviors [21].
Generally, the bacterial QS systems are classified into three types: (1) LuxI/LuxR–type QS, which is found in Gram-negative bacteria and uses acyl-homoserine lactones (AHL) as signaling molecules [22], (2) oligopeptide-two-component-type QS, which is found in Gram-positive bacteria and utilizes oligopeptides as signaling molecules, and (3) luxS-encoded autoinducer-2 (AI-2) QS, a general system, which is found in both Gram-negative and Gram-positive bacteria and uses AI-2 as signaling molecules [16]. The AIs are categorized into acylated homoserine lactones (AHLs), utilized by Gram-negative bacteria, oligopeptides, utilized by Gram-positive bacteria, and furanosyl borate diester, utilized by Gram-negative and Gram-positive bacteria. In addition, there are other signaling molecules of the QS system called autoinducer-3 (AI-3), which are utilized by P. aeruginosa and do not belong to any of the previous classes. This complex network of signals allows the bacterial community to react and adapt to different environments [23].
Interrupting the connection system between bacterial cells results in a reduction in bacterial biofilm formation and pathogenicity [23][24]. Therefore, many strategies have been developed to hinder this connection and control the QS-dependent bacterial infections [25]. The inactivation, blocking, or degradation of QS signal molecules refers to QS inhibition or quorum quenching (QQ) [26]. The perfect QS inhibitors (QSIs) are low-mass compounds with a great selectivity for the QS regulator and no deleterious side effects on the bacterium or a potential eukaryotic host. They must also be chemically stable and extremely efficient [23]. QSIs may be natural or artificial molecules. In fact, many anti-QS compounds are isolated from plants and microbes. 

3. Probiotics

Probiotics are microorganisms that live in a symbiotic relationship with the host. They provide health benefits and perform several biological functions when provided in adequate amounts. Probiotics were discovered and selected based on certain criteria, which ensure safety and effectiveness requirements [27]. The FAO/WHO have specified several parameters that should be assessed in vitro when selecting probiotics, such as safety, efficacy, cost effectiveness, function, and technological and physiological applications. The selected probiotics can be characterized by a lack of pathogenicity, tolerance to changes in the human gastrointestinal microenvironment, capacity for adherence to and colonization of the intestinal epithelium, antimicrobial activity, genetic and phenotypic stability, and immunomodulatory capabilities [28]. Several in vitro tests can be used to evaluate the efficacy of probiotics before starting the clinical trials, such as the agar spot test [29], the agar well diffusion assay [30], microdilution [31], antibiofilm analysis [32], 3D cell cultures, and use of human tissues and animal models [33][34][35].
Additionally, probiotics have been found to help with a variety of pathological conditions, including constipation, diarrhea, polycystic ovarian syndrome, ulcerative colitis, stress and anxiety, inflammatory bowel disease, breast cancer, and diabetes [36]. Probiotics are classified into four categories: (1) viable and active probiotics, (2) viable/non-active probiotics, in the forms of spores or vegetative cells, (3) dead/nonviable probiotics [37], and (4) next-generation probiotics [38]. The biological properties of probiotics have been extensively investigated, but only a few studies focused on their antimicrobial properties as novel antibiotic alternatives

4. Prebiotics

Prebiotics are defined as “non-digestible food materials that beneficially impact the host by selectively enhancing the growth and/or metabolism of bacterial species inhabiting the GIT, and thus improve the host health” [39]. Prebiotics are also defined as “any substrate preferentially consumed by host microorganisms that result in increasing the health benefit” [39]. Evidence indicates that prebiotics are promising alternatives in the medicinal and food industries. Prebiotics are characterized by (1) the ability to withstand the acidic environment during passage through the digestive tract (GIT) [40], (2) resistance to digestive enzymes but susceptibility to probiotic-hydrolyzing enzymes [41][42], (3) non-direct absorbance [43], (4) maintenance of gut microbial ecology [41], and (5) the ability to stimulate the host immune response [40]. Prebiotics are non-digestible oligosaccharides (fructans, inulins, xylans, galactans, and mannan), fibers (pectin, non-starch polysaccharides (such as β-glucan), xylooligosaccharides, andisomaltooligosaccharide), and seeds containing gums [44][45]. Human milk oligosaccharide is considered an endogenous source of prebiotics that increases the population of Bifidobacterium spp. in breastfeeding newborns, thereby enhancing their immunity [46]. To use prebiotics as alternatives to antibiotics, specific criteria must be met. Prebiotics should have a well-identified source chemical composition and structure, be a pure product, be at a suitable dose, and have been assessed in animal models or 3D cells to confirm their safety and beneficial health impact on the microflora [45]. When used as feed additives for livestock and poultry, prebiotics have shown an ability to improve host health and productivity via selective stimulation of proliferation and metabolism of the gut microbiota, such as Akkermansia spp., Christensenella spp., Propionibacterium spp., Faecalibacterium spp. and Roseburia spp., Lactobacillus spp., and Bifidobacterium spp. [47]. In the context of their benefits for human health, fermentation of the prebiotics konjac glucomannan hydrolysate and inulin in a batch culture of human feces has been associated with the production of short-chain fatty acids and proliferation of the genera Bifdobacterium, Lactobacillus and Enterococcus [48]. A meta-analysis of 64 studies reported that addition of dietary fibers stimulated Bifidobacterium spp. and Lactobacillus spp. resulting in an increase in the concentration of fecal short-chain fatty acids (SCFAs) in healthy adults [49]. Moreover, other studies have revealed that these bacteria play a key role in maintaining the composition of GIT microflora, enhancing the food and mineral absorption, and promoting the host defense system [50].
Prebiotics have also shown potential to eliminate harmful bacteria, such as Salmonella, Campylobacter, Clostridium and E. coli [51][52]; however, their mechanism of action remains to be elucidated. Fermentation of prebiotics by the gut’s resident microbiota and the subsequent production of SCFAs results in a reduction in the gut pH, which, in turn, make the condition unfavorable for the growth and colonization of invading pathogens [53]. It was reported that the activity of probiotic Bifidobacterium strains against C. difficile was significantly stimulated in the presence of five prebiotics (oligosaccharides) [54]. Similarly, the activity of Pediococcus acidilactici was enhanced against E. coli, Salmonella, E. fecalis and S. aureus in the presence of garlic and basil (natural prebiotics) [55]. Moreover, the use of the prebiotics mannan-oligosaccharides and fructooligosaccharides, as poultry feed supplements, reduced the colonization of Campylobacter and Salmonella in the GIT of poultry [52]. Supplementation of weaning pigs with prebiotic oligofructose resulted in a significant increase in the number of Bifidobacteria and Lactobacilli and a significant reduction in the number of clostridia, enterobacteria, and enterococci [56]. A reduction in disease severity was observed following treatment of patients with C. difficile-associated diarrhea with inulin and oligofructose [57].

5. Antimicrobial Peptides (AMPs)

AMPs are naturally produced by various immune cells and play a vital role in the innate immune systems of various animals, plants, and microorganisms [58]. AMPs, have a wide spectrum of antimicrobial activity against bacteria, fungi, viruses, and parasites [59]. In addition to their antimicrobial activities, AMPs possess biological functions, such as immune modulation, angiogenesis, antitumor activity, and wound healing [60][61]. AMPs are considered promising alternatives to antibiotics, due to many advantages; (1) they act on multiple target sites on the intracellular targets and plasma membranes of pathogenic bacteria, (2) they have potent killing activity against drug-resistant bacteria [59][62], (3) they are a component of the innate immune system, (4) their natural production by the host cells saves time and energy compared to antibody synthesis via acquired immunity, and (5) they reach the target sites faster than immunoglobulin [58]. AMPs are classified into several subgroups based on their amino acid sequences (10–100), the net charge of the peptide (+2 to +9), and their protein structure and sources [63]. These subgroups include (1) anionic AMPs, which consist of 5–70 amino acid residues and have a net charge range of −1 to −8 [64]. Their structural characteristics include α-helical peptides and cyclic cystine knots [64]. They use the negatively charged content of the microbial membrane to form salt bridges, leading to disruption of the microbial membrane [65]. (2) Cationic α-helical AMPs are ≤40 amino acids in length (50% hydrophobic in nature) and have a charge of +2 to +9 and the C-terminus amidated [66]. The structure of cationic α-helical AMPs is disordered in aqueous solutions [67]. They are capable of forming amphiphilic structures when interacting with target cells [68]. (3) Cationic AMPs, where the peptides consist of 2–8 cysteine residues forming 1–4 pairs of intramolecular disulfide bonds. These disulfide bonds play a crucial role in β-sheet AMP stabilization and biological functions [69]. (4) Extended cationic AMPs containing amino acids including tryptophan, arginine, proline, histidine and glycine and lacks the regular secondary structures [68]. (5) Fragments from antimicrobial proteins that have a broad-spectrum bactericidal effect, such as lysozyme [70]. The helix–loop–helix (HLH) region in the human and chicken lysozyme has a strong effect on the growth of pathogenic bacteria and fungi [71].
Many antimicrobial peptides, isolated from different sources, have shown activity against a wide variety of pathogenic bacteria. For example, magainin-2 (α-helix (TFE)) was originally isolated from frogs and has been shown to be active against P. gingivalis, F. nucleatum, P. intermedia, E. coli, and S. aureus [72]. Cecropin and cecropin P1 (α-helix structure) were isolated from silk moth and pig, respectively. These peptides inhibited the growth of E. coli ML-35p [73], S. aureus, B. subtilis, M. luteus, P. aeruginosa, S. Typhimurium, S. marcescens and E. coli [74]. In addition, apo-lactoferrin (α-helix structure), discovered in bovine and human PDB code (1BOL), inhibited the growth of E. coli O157:H7 [75]. Melittin (α-helix structure), extracted from bee, was active against S. salivarius, S. mitis, S. mutans, S. sanguinis, S. sobrinus, L. casei, and E. faecalis [76]. Temporin A and temporin L, extracted from frog, were active against MRSA [77], B. megaterium Bm11, S. aureus Cowan I, and E.coli D21 [78]. Moreover, buforin II and clavanin A (α-helix structure), discovered in extended toad and Styela clava, respectively, possess inhibitory activity against B. subtilis, S. aureus, E. coli, S. Typhimurium [79], E. coli ML35p and L. monocytogenes [80]. Furthermore, protegrin-1 (β-sheet structure), isolated from human and porcine, has demonstrated antagonistic activity against MRSA and P. aeruginosa [81]. Tachyplesin-I (β-sheet structure), discovered in horseshoe crab, was shown to inhibit the growth of S. Typhimurium [82]. Furthermore, hepcidin (β-structure), extracted from humans, has demonstrated capabilities to inhibit E. coli, S. aureus, and S. epidermidis [83]. Daptomycin (cyclic lipopeptide membrane), isolated from Streptomyces roseosporus, can kill MRSA [84] and nisin (lantibiotic), isolated from L. lactis, was shown to kill MRSA, S. pneumoniae, Enterococci and C. difficile [85]. NPSRQERR [P1], PDENK [P2], and VHTAPK [P3]), derived from L. rhamnosus GG, showed inhibitory activity against APEC in chicken [86].

6. Bacteriophages

Phages or bacterial viruses are obligate parasites that infect bacteria and archaea. Phages are classified according to their size, shape, type of nucleic acid and mechanism of action in the host bacterial cell [87]. The genomic sequences of phages range from a few thousand base pairs to 498 kilobase pairs in phage G, the biggest phage ever sequenced [88]. Some phages have wide host ranges; however, the majority of them have high host specificity [89]. Based on the last classification, bacteriophages are classified as virulent (e.g., lysis of the bacterial cells to release new phages) or temperate (e.g., incorporation of its genetic material in the host genome and the host changes its genetic characters) bacteriophages [87]. In vitro trials showed that phages have many advantages over antibiotics, including (1) high host specificity (phages can target one strain of bacteria without perturbing the human or animal gut microbiota, while antibiotics do not distinguish between pathogenic and beneficial bacteria); (2) cost effectiveness and time saving [90]; (3) inhibition of multi-drug-resistant bacteria while antibiotics increase them; (4) ease of delivery to the target site and ability to penetrate the blood–brain barrier [91]; (5) no antagonistic effect detected between phages when given as a cocktail (mixture of different phages); (6) that phages could prevent biofilm formation [92]; and (7) phages might be used as an alternative in antibiotic-allergic patients; however, very few reports discussed this [93]. Several studies have reported that phage therapy development might be a potential solution to bacterial antibiotic resistance as well as the treatment of numerous bacterial infectious illnesses [94]. As the poultry gut is considered the main reservoir of Campylobacter, most Campylobacter phages have been isolated from avian GIT. Many studies have demonstrated that administration of individual phages resulted in a significant decrease in the number of Campylobacter without altering the GIT microbiota [95]. The most multi-drug-resistant bacterial strains, such as E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter spp, have been reported to cause serious human diseases. 

7. Nanoparticles (NPs)

NPs are considered one of the potential alternative candidates of antibiotics for controlling multi-drug-resistant microorganisms [96]. They have demonstrated therapeutic potential due to their unique chemical and physical characteristics [97]. NPs have a tiny size (1–100 nm) with a large surface area to interact with target organisms [98]. They can be chemically or naturally synthesized from different sources with variable chemical structures that allow different chemical functionalities [99]. NPs exhibit antimicrobial activities through targeting critical active sites in pathogens, leading to partial or complete inhibition [99]. Organic or inorganic (metal and metal oxide) NPs can be synthesized from different sources. Inorganic NPs possess bactericidal activity against bacteria using multiple mechanisms and, therefore, they are denominated “nanobactericides”. The nanobactericides activity of inorganic NPs is attributed to (1) their tiny size [99], (2) formation of weak and nonspecific interactions with bacterial surfaces [100], (3) Van der Waals forces (distance-dependent interactions between atoms or molecules) [101], and (4) attachment through specific receptor–ligand bonds [102]. Therefore, the bacterial cells’ susceptibility to NPs depends on their structural components as well as their growth rate [103]. Gram-positive bacteria are more susceptible to NPs than Gram-negative bacteria. Gram-positive bacteria have a permeable and negatively charged cell wall, making them an easy target for NP penetration, while the non-porous cell walls of Gram-negative bacteria serve as penetration barriers against the NPs [104]. Moreover, bacteria with slow growth rates are more sensitive to NPs than those with rapid growth rates. This is due to different stress-response genes’ expressions in fast-growing bacteria [103].

8. Organic Acids (OAs)

Organic acids are widely used as antimicrobials in food processing and many industries [105]. Bacteria, fungi, and yeast play a critical role in the synthesis of organic acids during their lifecycle with high yields that can be achieved using cost-effective substrates. The bioproduction of OAs depends on many factors, such as the species of microorganism, inoculum size, substrate or carbon source, and environmental conditions (aeration, temperature, pH and agitation) [106]. Increasing the acidity by adding an acidulant or integrating natural fermentation is one of the commonly used methods to minimize and/or inhibit microbial growth. Using organic acids as an alternative to antibiotics depends on several factors, such as chemical formula structure, molecular weight, the value of the dissociation constant (pKa), minimum inhibitory concentration (MIC), nature of the microorganism, and exposure time to the food [107], where the pKa is an important criterion because of the undissociated part of the acid that is responsible for the antimicrobial effect.
Common OAs that are microbially produced and commercially used for microbial inhibition and food processing include (1) acetic acid, which is produced after fermentation of many substrates, such as glucose, lactose, and sucrose. This has the European code E260 and is used in the production of vinegar, stabilizer, flavor enhancer, and firming agent [106]. (2) Adipic acid is a crucial intermediate in the pathways of cyclic alkanes, long-chain aliphatic dicarboxylic acids and cyclic alcohols [108]. It is commonly used in the synthesis of polymers, plasticizers, nylon, clothing, automobile parts, and lubricant [109]. (3) Butyric acid is used in the fuel, plastic pharmaceutical, and textile industries. (4) Citric acid is used as a pH regulator, flavor enhancer, pharmaceutical reagent, and firming agent, in addition to its antimicrobial properties [110]. It is also used in soft candies, baked goods, gelatins, snacks, dairy products, and cheese warps as an antimicrobial and in the fuel industry. (5) Lactic acid is used in dairy products, biochemical processes, and the leather, pharmaceutical, textile, and biodegradable biopolymer industries [111]. (6) Malic acid, which is an intermediate compound in the tricarboxylic acid cycle, is naturally found in fruits including apricot, blackberry, cherry, mango, peach, and plum. It has been used in the food, water treatment, textile, metals, and pharmaceutical industries [112]. (7) Phenyl lactic acid naturally exists in honey and has an effective and broad microbial activity against bacteria, fungi, and yeast [113]. (8) Propionic acid naturally presents in apples, strawberries, grains, and cheese [114]. Adding propionic acid to chick diets was found to improve their growth, exert an antimicrobial effect in the intestine, and reduce the yellowness of the meat [115]. (9) Succinic acid is used in food preservation, perfume intermediates, herbicide production, and the plastics and textiles industries [116].

9. Essential Oils (EOs)

Essential oils are volatile, aromatic, and oily liquids extracted from plant parts, such as seeds, leaves, buds, twigs, flowers, bark, herbs, wood, fruits, and roots [117]. Plants generate EOs as a natural defense against pathogens and herbivore feeding by reducing the appetite of herbivores. As a result, the Department of Health and Human Services has designated EOs as safe antibacterial additives [118]. To date, about 3000 EOs have been recorded, 300 of which are economically valued in the pharmaceutical, agronomic, food, sanitary, cosmetics and perfume industries [119]. EOs are complex natural mixes that contain anywhere from 20 to 60 distinct components in various proportions. The antibacterial effects of EOs are dictated by their primary ingredients (85%), which include terpenes, terpenoids, and aromatic and aliphatic groups from different natural sources [120]. These groups are characterized by low molecular weights, which are limonene (31%) and α-phellandrene (36%) in Anethum graveolens leaf oil, d-limonene (over 80%) in citrus peel oils, α/β-thujone (57%) and camphor (24%) in Artemisia herba-alba oil, carvacrol (30%) and thymol (27%) in Origanum compactum oil, α-phellandrene (36%) and limonene (31%) in Anethum graveolens leaf oil, menthol (59%) and menthone (19%) in Mentha piperita oil, and carvone (58%) and d-limonene (37%) in Anethum graveolens seed oil [121].
Menthol, pulegone, linalool, thymol and camphor, extracted from Salvia lavandulifolia Lavandulaangustifolia, Mentha piperita, Mentha pulegium, and Satureja montana, respectively, have shown antagonistic effects against P. aeruginosa, S. pyogenes, S. mutans, S. sanguis, S. salivarius, and E. feacalis [122]. Thymol and carvacrol, extracted from many sources, such as Origanum compactum, Lavandula latifolia, Lavandula angustifolia, Rosmarinus officinalis, Origanum vulgare, Thymus vulgaris, and Thymus zygis chemotype thymol, have shown activity against S. aureus, C. hystoliticum, C. perfringens, E. coli O157:H7, S. Typhimurium, S. Enteritidis, and L. monocytogenes [122][123]. Linalool, linalyl acetate α-terpineol, β-caryophyllene and nerol, produced by Mentha citrata Ehrh, have shown inhibitory effects against P. aeruginosa, K. pneumoniae, E. coli (DH5α), E. coli (MTCC 723) and S. Typhimurium, S. aureus, S. epidermidis and S. mutans [124]. Additionally, E-anethole, linalool, 1,8-cineole, α-pinene, camphor, camphene, menthol, menthone, and limonene, produced by Ocimum basilicum, Rosmarinus officinalis, O. majorana, Mentha piperita, Thymus vulgaris, and Pimpinella anisum, have shown activity against C. perfringens [125]. Epilobium parviflorum, Salvia desoleana, S. sclarea, and Allium sativum were reported to produce palmitic acid, linoleic acid and α-linolenic acid, which have shown an ability to inhibit E. faecalis, S. aureus, P. aeruginosa, S. epidermidis, and E. coli [126]. Moreover, cinnamomum was reported to produce cinnamaldehyde, which was shown to inhibit E. coli, S. aureus, and S. Typhimurium [127]. Dipterocarpus gracilis was reported to produce elemicin and geranyl acetate, which were shown to suppress B. cereus and Proteus mirabilis [128].

10. Fecal Microbial Transplant (FMT)

FMT is a process of transferring processed fecal material from the intestine of a healthy donor to the intestine of a recipient patient [129]. Processed fecal matter can be administered to the recipient through several methods, such as a nasoduodenal tube [130], nasojejunal tube [131], colonoscopy, or retention enema [132]. Colonoscopy administration of fresh or frozen and thawed fecal matter from stool banks into the cecum and colon of C. difficile-infected children in Maryland resulted in complete resolution of CDI in recipients as well as reductions in both AMR and multidrug resistance genes. Moreover, FMT resulted in sustained elevations in alpha diversity post-FMT as well as significant changes in beta diversity, in addition to improving the biosynthetic pathways [132]. In another study performed in mice, when a combination of FMT and lytic phages was used for treatment of S. Typhimurium, a complete clearance of Salmonella, a reduction in inflammatory cytokines, and restoration of the intestinal microbial diversity was observed [133]. Additionally, patients with MRSA enteritis who were treated with FMT through nasointestinal tube, jejunostomy fistula tube or gastrostomy fistula tube had negative stool cultures for MRSA, and gut microbiota analysis also revealed that all recipients developed donor-related bacterial diversity [134]. FMT has also shown satisfactory results when given to patients infected with beta-lactamase-producing Enterobacteriaceae. Four weeks after the first FMT dose through nasoduodenal tube, decolonization was detected in 20% of the recipients, with recipients’ microbial composition showing a shift toward the donors’ microbial diversity [135]. Administration of fresh fecal matter using nasojejuneal tube into K. pneumoniae-infected patients stopped sepsis and resulted in elimination of K. pneumoniae, as demonstrated in the blood cultures and general improvement of the health status. Moreover, a restoration of microbial diversity was observed after 6 weeks of treatment [131]. Administration of fresh fecal matter using nasoduodenal gastroscope into the third part of the duodenum of chronically infected hepatitis B patients (CHB) also resulted in suppression of the hepatitis B virus as well as clearance of the HBeAg [130]. In addition to its use in the treatment of microbial infections, FMT has also shown potential to improve non-infectious GIT conditions, such as ulcerative colitis, where it resulted in a lowered pediatric ulcerative colitis activity index (PUCAI) following completion of the FMT treatment course [136]. Similar observations were made for other inflammatory bowel diseases [137]. Moreover, several experiments were undertaken to assess the safety and efficacy of FMT in treating other extra-intestinal disorders, such as obesity and metabolic disorders [138] and psoriatic arthritis [139].

11. Vaccines

Vaccines are preparations used to stimulate the body’s immune response against diseases by exploiting the ability of the human immune system to respond to, and remember, the antigens of pathogens. Several vaccines have been developed to make a revolutionary change in the world, such as fowl (avian) cholera, anthrax, polio, norovirus, rift valley fever, and rabies vaccines [140][141][142]. Vaccines play a pivotal role in reducing the need for antibiotics and controlling the emergence of AMR bacterial strains [143]. Vaccines reduce the burden of antimicrobial resistance through disease prevention and thus reducing the use of antibiotics [144][145]. This occurs as a vaccine curbing the ability of the pathogen to establish a foothold in the host, by conferring immunity against these pathogens, thus minimizing the chances of some bacterial mutations and the development and spread of resistant genes to other bacteria [146][147]. For instance, a 67% reduction in the circulation of penicillin-resistant invasive pneumococcal strains was demonstrated in a group of children that received pneumococcal conjugate vaccine 9 (PCV9) compared to controls in South Africa [148]. Conjugate vaccines combine weak antigens with strong antigens (which serve as the carriers) to increase the response of the body to the weaker antigen. In this context, the typhoid conjugate vaccine (TCV) has been introduced in children in order to protect them extensively from drug-resistant S. Typhi [149]. It has been observed that TCV can avert 44% of typhoid cases, of which 35% are resistant to antibiotics [150]. Salmonellosis, caused by Salmonella spp., is one of the most common zoonotic diseases associated with consumption of dairy and beef [151]. S. enterica serotype Dublin, which infects cattle and can be shed in milk, colostrum, and feces, also poses a threat to public health. S. Dublin causes bloodstream infections in humans, with a relatively high case fatality [152]. Data from the CDC (Centers for Disease Control and Prevention) showed that Salmonella Dublin infections caused more hospitalization during 1996–2004. Additionally, a higher percentage of Salmonella isolates were resistant to more than seven classes of antimicrobial drugs during 2005–2013 (50.8%) compared to only 2.4% during the period 1996–2004. Resistant S. enterica causes at least 100,000 foodborne human infections annually [153]. A commercial modified-live Salmonella Dublin vaccine (EnterVene-d) is approved by the USDA for use in calves, but vaccination does not reduce the likelihood of contamination or the risk to public health; it only improves clinical outcome [154]. C. perfringens enterotoxin (CPE) and Shiga-toxin-producing E. coli (STEC) are also common causes of food poisoning. Research has been conducted on possible development of a vaccine for CPE and STEC in the form of a bivalent food poisoning vaccine. The bivalent vaccine uses a fused protein (Stx2B-C-CPE) consisting of the B subunit of E. coli Shiga toxin 2 fused to CPE to enhance its antigenicity [155]. Two other extremely important bacteria, C. jejuni and C. perfringens, have been the subject of many vaccine studies in poultry [156][157][158][159]. The efficacy and commercial potential of these vaccines has been described and reviewed in detail elsewhere [160]. It is worth mentioning that the conserved N-glycan heptasaccharide conjugated to GlycoTag, or fused to the E. coli lipopolysaccharide core, has shown tremendous potential to reduce C. jejuni colonization in the gastrointestinal tract of chickens by up to 10 log10 [161]. Despite the demonstrated efficacy of this vaccine, its commercialization remains murky.
Vaccination can cause indirect effects on infections. While resistance is a predictable outcome of antibiotic use, resistance to vaccines is very rare [162]. Vaccines are administered prophylactically, whereas antibiotics are administered only once symptoms have begun to show. Thus, by the time antibiotics are administered, there are possibly already millions of copies of the pathogen, raising the probability of mutation occurring. Vaccines prevent the pathogen from gaining a foothold and multiplying in the first place. In many cases, the use of vaccines has globally eradicated some diseases, while decreases of 95% in the incidence of diseases like diphtheria, tetanus, and pertussis have been observed [163]. Much progress has been made in bacterial vaccine development. Bacterial vaccines can and should help address the global AMR problem. It is reasonable to believe that reductions in MDR infections as well as the prevention thereof can be achieved using bacterial vaccines. Attention should also be paid to the role of veterinary bacterial vaccines to reduce antibiotic use in animals, especially food-producing animals. The role of bacterial vaccines is set to expand dramatically in response to the crisis of AMR and MDR [164]. Although vaccines against major AMR pathogens are still missing, predictions of the impact of vaccines against AMR hint that vaccines could have a significant impact in controlling resistance [165].

12. Antibodies

Antibodies, also known as immunoglobulins, are the most diverse set of proteins [166]. They have two major functions: antigen binding and effector functions [167]. Most of these effector functions are induced via the constant Fc (fragment crystallizable region, the tail region of an antibody) of the antibody, which can interact with complementary proteins and specialized Fc-receptors. This can activate or inhibit pathways, depending on the type of receptor [168]. Therapeutic antibacterial monoclonal antibodies (mAbs) are gaining traction as an alternative in treating infectious diseases [145]. Monoclonal antibodies could offer more effective ways of addressing antibiotic resistance and bacterial infections due to their superb specificity, by which they target conserved pathways. This allows for fewer off-target effects and less selective pressure for cross-resistance to other mAbs or antibiotics. Monoclonal antibodies also do not harm the beneficial microbiome [169][170] In 1879, Amil von Behring and Shibasaburo Kitasato were the first to develop antibodies called antitoxins that target specific toxins. Blood-serum-containing antitoxin was directly injected to convey immunity to diphtheria in humans [171][172]. The toxin/antitoxin approach provided a steady treatment against numerous pathogens, such as Haemophilus influenzae, Neisseria meningitides, Corynebacterium diphtheria, Clostridium tetani, S. pneumonia, and Group A Streptococcus. However, the antitoxin approach exhibits heterogeneity between lots, allergic reactions, and a limited spectrum, eventually leading to its replacement by antibiotics in 1930 [173]. Antibiotic production peaked for the next 80 years because of their safe application and their ease of formulation and manufacture [174]. However, due to the development of the hybridoma technology and recent advances in mAb engineering, awareness has shifted back to antibacterial mAbs [175].

13. Conclusions and Future Perspectives

The alarming rise in the emergence and spread of AMR and the associated global impact necessitate an urgent intervention of alternatives to combat the growing threat of antibiotic-resistant bacteria. Beside their potential adverse events, the inappropriate prescription or dispensing of antibiotics for humans and their irrational use in animal agriculture are among the factors contributing to the growing incidence of AMR in humans. As such, averting AMR could be achieved by focusing on two aspects: one is to implement antimicrobial stewardship programs through promoting prudent use of antibiotics in healthcare and agricultural settings, and the other is to develop effective antimicrobial alternatives to substitute antibiotics in animal food production. In fact, developed countries, including Europe and North America, have taken steps to ban the use of sub-therapeutic doses of antibiotics as growth promoters in livestock and poultry production; however, such steps have yet to be implemented in developing countries. Thus, a global solution is crucial to tackle AMR, as the world has become increasingly interconnected. Research efforts have been made to limit AMR in both humans and animals by exploring various interventions, including SMs, QSIs, probiotics, prebiotics, phage therapy, nanoparticles, EOs, AMPs, OAs, FMT, vaccines, and immune-based strategies, as potential replacements for antibiotics. Despite the promising role of most of these strategies in promoting host immunity and in antagonizing a range of human and animal pathogens, their variable effects, combined with their limited spectrum, safety concerns, and poor efficacy, are among the potential limitations to their use. Nonetheless, the exuberant development of molecular technologies may improve the efficacy of existing strategies and reduce their limitations. For instance, the recent breakthroughs in CRISPR-Cas9-based genome editing offer a revolutionary platform for designing safe and effective vaccines. Likewise, computational molecular biology has directed vaccine development towards genome-based reverse vaccinology approaches, a process of analyzing the whole genome sequence for identification of novel target antigens. The processes of 16S rRNA next-generation sequencing and bioinformatics analysis have enabled the identification of bacterial strains at species level. This technology can be utilized to not only identify novel probiotic species, but also to develop a consortium of beneficial microbes, which may offer a safer and acceptable alternative to FMT. With millions of people travelling around the world and the uncontrollable spread of AMR, holistic AMR control requires global solidarity to expand and implement robust antimicrobial stewardship programs in both medical and veterinary practices.

This entry is adapted from the peer-reviewed paper 10.3390/antibiotics12020274

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