NEW THERAPEUTIC SOLUTIONS FOR ANTIMICROBIAL RESISTANCE??????

INTRODUCTION??

Antimicrobial resistance (AMR) has emerged as one of the principal public health problems of the 21st century, threatening the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses, and fungi no longer susceptible to the common medicines used to treat them. Bacteria causing common or severe infections have developed resistance to each new antibiotic coming to market. The development of bacterial resistance due to the misuse of antibiotics and chemicals can bring dangerous effects to the global population. New, safe biological and antimicrobial solutions are urgently needed. Some of the recent antimicrobial solutions are discussed below:

1.??? Bacteriophages are non-living biological entities consisting of DNA or RNA enclosed within a protein capsid. As naturally occurring bacterial parasites, phages are dependent on a bacterial host for survival. Using bacteriophages, phage therapy is conducted to kill harmful pathogens.

2.??? Bacteriocins are proteinaceous toxins produced by bacteria to inhibit the growth of similar or closely related bacterial strains. They are structurally, functionally, and ecologically diverse.

3.??? Anti-virulence drugs target the virulence factors of pathogens instead of killing or stopping their growth, consequently disarming infectious pathogens. Bactericidal antibiotics may also cause the selective pressure that drives resistance.

4.??? Quorum sensing (QS) is a communication system among microbial cells that relies on small signalling molecules. It facilitates interactions between various microorganisms across different kingdoms, encompassing both Gram-positive and Gram-negative microbes.

5.??? The gut microbiome contributes in various ways to fighting pathogens and signalling the immune system. Our microbiome is a reservoir of drugs, producing ways to kill pathogens even after generations, keeping us strong. Our intestine serves as a ground where host-microbiota interactions occur.

PHAGE THERAPY

Bacteriophages, or phages, are a type of virus that infects and invades bacteria. They are abundant on Earth, corresponding to the population of bacteria. Phages play a vital role in regulating bacterial populations and the evolution of bacteria. The term "bacteriophage" was first coined by Felix d’Herelle and means “bacterium eater” (Gordillo Altamirano, et al., 2019). Phage therapy is a therapeutic method used to invade and kill pathogenic bacteria in humans. It is being investigated as a treatment for challenging infections that are resistant to multiple drugs, often involving biofilms. These infections include chronic and recurring conditions like urinary tract infections (UTIs), rhinosinusitis, skin and soft-tissue infections, as well as drug-resistant respiratory infections. Biofilm-related infections include prosthetic joint infections (PJI), osteomyelitis with implanted devices, infections around cardiac devices, and respiratory issues in individuals with cystic fibrosis (Suh, et al., 2022).

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PRINCIPLE OF PHAGE THERAPY

Phages cause a lytic infection that begins by adsorbing to specific receptors on the surface of the bacterial host. The receptors are present on gram-positive or gram-negative cell walls, polysaccharide capsules, or appendages such as pili and flagella. The extent to which a phage can infect hosts is usually dictated by the compatibility between its structure and bacterial receptors, akin to a lock-and-key mechanism. After the adsorption process, the phage ejects its genetic material into the bacterial host. Next, the virus hijacks the bacterial replication machinery to produce the next generation of phage progeny. This replication process persists until phage-encoded proteins trigger cell lysis, terminating the host and facilitating the release of newly synthesized viruses to restart the cycle. The duration of this intracellular life cycle, known as the lysis time or latent period, varies depending on the phage (Gordillo Altamirano, et al., 2019).

Some examples of phages for phage therapy are

Bacillus virus BCP82 and its host bacteria is Burkhoderia, Escherichia virus EC6 and its host bacteria is Escherichia, Salmonella virus UAB87 and its host bacteria is Salmonella (Sharma, et al., 2017)

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ADVANTAGES

Specificity of Phages

Phages typically exhibit specificity towards both species and strains, which can offer a significant advantage. This is particularly evident when considering the well-documented collateral effects of broad-spectrum antibiotics on the gut microbiota, which often lead to issues like antibiotic-associated diarrhea and Clostridium difficile infection. Additionally, antibiotic disruptions in the gut microbial community can elevate the risk of conditions such as asthma, obesity, and diabetes. While our current understanding of collateral damage from phage therapy is limited, studies suggest that compared to antibiotics, phage therapy causes less disturbance to the gut microbiome while effectively reducing the presence of pathogens like Shigella sonnei and uropathogenic Escherichia coli (Lin, et al., 2017).

Tolerance

Phages are immunologically well tolerated and can effectively engage with the host's immune system. They have evolved mechanisms to interact with hosts, such as the presence of immunoglobulin-like domains in capsid proteins, like those found in the E. coli T4 phage, which interact with mucins and surface glycoproteins on mammalian epithelial cells. Similar domains from the Ig superfamily are present in various phage families, leading to higher phage concentrations in mucosal layers. Consequently, their binding to mucous membranes enhances the susceptibility of certain bacteria to phage-induced lysis.

Auto-Dosage Ability

During infection (in vivo replication), phages demonstrate auto-dosing behaviour, where their numbers fluctuate in relation to bacterial hosts. Essentially, if bacterial populations decrease, phage numbers also diminish. Since bacterial viruses replicate and evolve at a faster rate than bacteria, coupled with the high specificity of phages towards their bacterial hosts and their typically narrow host range, the influence on the physiological microbiome of individual patients during phage therapy remains minimal (Zalewska-Pi?tek, B. 2023).

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DISADVANTAGES

Phage therapy faces several constraints, including a restricted host range, potential for lysogeny, absence of established policies, and insufficient pharmacokinetic data, impacting its clinical implementation. These limitations primarily revolve around three aspects: the inherent characteristics of phages affecting therapy application, the absence of regulatory frameworks, and challenges encountered during clinical use. To advance phage therapy, it's crucial to scrutinize pertinent literature and devise practical strategies to address these hurdles (Lin, et al., 2022).

Governments and public health organizations have strong incentives to allocate substantial resources to fundamental scientific research on phage therapy, particularly in compiling comprehensive databases of bactericidal viruses. This rationale is grounded in the fundamental premise that one of the primary roles of government is to provide essential public goods that are widely needed. These goods encompass efforts to contain the spread of infectious diseases and safeguard the effectiveness of medications used to combat them. It's imperative for governments to fund clinical trials, including 'challenge studies' where patients with untreatable infections receive phage cocktails. Additionally, they should subsidize the creation of reliable diagnostics, which not only enhance patient care but also prolong the effectiveness of current antibiotics. Insights gained from clinical trials will enhance the precision of phage treatment, should it become feasible. More research will help us better understand the advantages and disadvantages of phage therapy as a tool in the fight against pathogenic bacteria and the prevention of antimicrobial resistance (Anomaly, J. 2020).

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BACTERIOCINS

Bacteriocins are peptides synthesized by bacterial species in their natural habitats for self-preservation and competitive edge. The majority of known bacteriocins are produced by Gram-positive bacteria, with relatively few identified among Gram-negative species. These small cationic peptides, usually composed of 30-60 amino acids and featuring amphiphilic helices, differ in their spectrum of activity, mode of action, molecular weight, and biochemical properties. A significant number of Gram-negative bacteriocins resemble eukaryotic antimicrobial peptides like defensins (Meade, et al., 2020). Bacteriocins exhibit activity against species closely related to the bacteriocin-producing bacteria (narrow spectrum) or across different genera (broad spectrum). They inhibit pathogen growth to protect their producers by acting as pore-forming agents or causing membrane disturbances. Additionally, bacteriocins function as signaling peptides. They facilitate bacterial communication through cross talk and quorum sensing within microbial communities or send signals to the host immune system. Bacteriocins can enhance the beneficial effects of probiotics and may even demonstrate antiviral and anticancer activities (Gradisteanu Pircalabioru, G., et al., 2021).

These are some differences between antibiotics and bacteriocins:

1) Antibiotics are synthesized as secondary metabolites, whereas bacteriocins are produced on the bacterial ribosome.

2) Mechanisms of action—unlike antibiotics, which can act primarily at the cell envelope or within the cell, affecting gene expression and protein production, bacteriocins typically function at the membrane level.

3) Stability—bacteriocins are generally less temperature-labile than antibiotics and can withstand extreme pH due to their complex structure, characterized by various post-translational modifications such as nonconventional amino acids, cyclization, and disulfide bridges. However, unlike antibiotics, bacteriocins may be susceptible to proteases because of their peptide backbone. Both bacteriocins and antibiotics can impact processes in the target cell, including cell wall synthesis, membrane integrity, nucleic acid replication and translation, and protein synthesis (Gradisteanu Pircalabioru, G., et al., 2021).

Some examples of bacteriocins are,

Enterocin DD14 produced by Enterococcus faecalis S37, Plantaricin DM5 produced by Lactobacillus plantarum DM5, Bovicin HC5 produced by Streptococcus bovis HC5 (Soltani, et al., 2020).

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ADVANTAGES

Bacteriocins can help in destroying multidrug-resistant bacteria (MDR bacteria). MDR pathogens such as MRSA, VRE, penicillin-resistant Streptococcus pneumoniae, and MDR GNB (e.g., Pseudomonas aeruginosa, E. coli) in particular retain more attention for their potential pathogenicity. The diversity of molecules, specificity of antimicrobial mechanisms, and potential synergy with other drugs are different advantages that make bacteriocins relevant in pharmacology (Simons, et al., 2020). Bacteriocins have demonstrated several advantages over antibiotics. These antimicrobial peptides are considered to offer greater protection without side effects compared to antibiotics. A study investigating the differences between bacteriocins and antibiotics found that oral administration of pediocin PA-1 did not cause any gastrointestinal side effects, whereas antibiotics like penicillin and tetracycline did. Bacteriocins are synthesized ribosomally and are considered primary metabolites, while antibiotics are secondary metabolites. This characteristic enables researchers to design novel bacteriocins with enhanced capabilities using bioengineering techniques based on their synthesis pathways (Darbandi, et al., 2022).

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DISADVANTAGES

Bacteriocins specifically target only certain bacteria, reducing selective pressure on non-targeted species. They generally act quickly, decreasing the likelihood of resistance development when only susceptible cells are present. Bacteriocins interact with cell receptors that are distinct from those used by antibiotics, making cross-resistance between the two types of antimicrobials less likely (Almeida-Santos, et al., 2021). More research on the cytotoxicity, hemolytic activity, distribution, and metabolism of bacteriocins is necessary to fully understand their potential contributions to human health. Due to their unique antibacterial mechanisms compared to conventional antibiotics, bacteriocins hold promise as potential alternatives. Further investigation into the function and mechanisms of action of bacteriocins will facilitate their practical applications in combating infections, treating cancer, and managing inflammation or immunomodulation (Huang, et al., 2021).

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ANTIVIRULENCE DRUGS

Virulence factors are substances produced by bacteria that contribute to disease by causing harm to the host or by evading the host's immune system. Antivirulence strategies aim to disrupt these factors as a means of treating infections, a method that predates the use of antibiotics (Dickey, et al., 2017). Targeting virulence factors is appealing because it does not impact microbial viability, thus avoiding the selective pressure linked to traditional antimicrobials. The aim of antivirulence therapies is to diminish pathogenicity, enabling the host to clear the bacterial infection. This strategy also helps preserve the host's microbiota (Marston, et al., 2016). The bacterial type III secretion system (T3SS) is a virulence factor employed by many pathogenic Gram-negative bacteria to cause infection. It works by injecting virulence proteins, known as effectors, that reprogram host cell machinery and enable evasion of the host immune response. Since the T3SS is absent in commensal bacteria, therapies targeting this system should not affect the beneficial commensal bacteria. The use of antibiotics leads to antimicrobial resistance, and therefore, antivirulence drugs that suppress the T3SS present a promising alternative. Anti-virulence therapies have been proposed as a solution to the drawbacks of antibiotic use. Rather than causing bacterial cell death, these agents target the mechanisms pathogens use to cause infection and evade the host immune response. This approach reduces selective pressure, thereby mitigating resistance formation. Unlike antibiotics, anti-virulence therapies do not harm commensal bacteria, which help protect against secondary infections (Hotinger, et al., 2021).

There are different bacterial pathogenesis mechanisms and stop every particular mechanism there are various antivirulence drugs like,

1.??? Two-component regulatory systems: Artemisinin, Ethoxzolamide.

2.??? Bacterial adherence: Nitazoxanide, Bicyclic 2-pyridone

3.??? Toxins and secretion systems: Toxtazin A, Ebselen (Johnson, & Abramovitch., 2017).

ADVANTAGES

Antivirulence compounds have a wider approach in inhibiting the virulence of species- or even strain-specific pathogens, thereby stopping the virulence of many bacterial species. The landscape of resistance evolution and selection is clearly more complex for antivirulence drugs than for classic antibiotics, where resistance to killing or growth inhibition is always beneficial. The antivirulence approach seeks to inhibit virulence factors without impacting bacterial growth. This strategy has the potential to avoid or minimize the development of resistance, as the selection pressure is expected to be weaker compared to bactericidal or bacteriostatic compounds (Totsika, M., 2016). This approach also has many potential benefits, including expanding the repertoire of bacterial targets and preserving the host's endogenous microbiome (Clatworthy, et al., 2007).

DISADVANTAGES

While there are benefits to anti-virulence strategies, there are also limitations. This approach disrupts pathogen virulence without affecting their growth or viability. The objectives of this approach are to reduce antibiotic use, ultimately decreasing the occurrence of antibiotic resistance, while preserving beneficial flora. Since these agents do not affect bacterial viability, the pathogenic bacteria that have lost their virulence can still affect the non-pathogenic microflora due to competition, which is a natural phenomenon (Maura, et al., 2016). Since many pathogenicity mechanisms in pathogens remain unknown, extensive research on virulence factors and host-pathogen interactions is essential to advance this strategy. Continued and effective collaboration between governments and pharmaceutical companies is crucial to developing innovative treatment strategies (Dehbanipour, R., & Ghalavand, Z., 2022).

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QUORUM SENSING INHIBITORS

Quorum sensing (QS), also known as density sensing, controls various bacterial behaviors. It exists in both Gram-negative and Gram-positive bacteria, each using different signal molecules. Bacteria produce and release self-inducing molecules to influence population behavior. When these molecules reach a threshold concentration, they activate specific genes, regulating population adaptation. QS regulates processes like luminescence, virulence, disinfectant tolerance, spore formation, toxin production, motility, biofilm formation, and drug resistance (Zhao, et al., 2020).

Quorum sensing (QS) molecules encompass N-acyl homoserine lactones (AHLs), furanosyl borate, hydroxyl-palmitic acid methyl ester, and methyl dodecanoic acid. They play a crucial role in preserving the symbiotic relationship between a host and its beneficial microbial flora, while also regulating multiple microbial virulence factors. Furanones, glycosylated chemicals, heavy metals, and nanomaterials are known to act as quorum sensing inhibitors (QSIs), capable of disrupting the microbial quorum sensing (QS) system. The slow development of new antimicrobial agents hampers the treatment of drug-resistant infections. As a result, QSIs are being investigated as potential antimicrobial therapies. These inhibitors are being studied for their ability to target QS-signaling molecules and quorum quenching (QQ) enzymes, thereby reducing microbial activity (Haque, et al., 2021).

Some examples of quorum sensing inhibitors are beticine, floridoside, tumonoic acids and diketopiperazines (Delago, et al., 2016)

MECHANISM OF QUORUM SENSING

Targeting the quorum sensing mechanism involves developing drugs that bind to receptors instead of autoinducers. This strategy aims not to eliminate the microorganism and prevent proliferation directly but rather to disrupt communication. By doing so, group behaviours, such as the development of virulence factors, are inhibited, ultimately rendering the microorganism non-pathogenic.

ADVANTAGES

The use of semi-synthetic compounds derived from natural compounds has gained much importance. These compounds are not biocidal, are non-toxic, and are more effective than the natural parent compounds. This therapeutic approach also shows a variety of novel drug targets, such as biofilm, which can be of great benefit in a clinical setting. This approach has shown that fewer pathogens develop resistance against these quorum sensing inhibitors. Like antivirulence drugs, this method inhibits virulence and doesn’t affect the growth of their population (Tonkin, et al., 2021).

DISADVANTAGES

The application of quorum sensing inhibition to human health requires further research before it can be fully integrated as a commercial practice (Turan, et al., 2017). While beneficial, some quorum sensing inhibitors are toxic and can cause allergies. Additionally, their growth may affect the microflora present in the human gut.

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MICROBIOME OR GUT MICROBIOTA

Our human microbiome consists of various types of bacteriophages, good bacteria, fungi, and protozoa, forming a balanced network that works together for digestion of indigestible components and stimulating immunity. The gut microbiota plays a crucial role in influencing local, innate, and systemic immunity. Recognizing this, scientists and clinicians are now leveraging this knowledge to develop strategies aimed at enhancing the prevention and treatment of infectious diseases. Given the substantial variation in microbiomes and immune responses among individuals, these interventional strategies will need to be personalized. Dietary interventions, which can quickly alter microbiome function and subsequent immune responses, offer a promising avenue for creating customized nutritional plans to impact the progression and treatment success of infectious diseases.

Short-chain fatty acids, the primary fermentation products, have a significant impact on the immune system and can help inhibit the development of infectious diseases. Beyond short-chain fatty acids, prebiotics and dietary fibers can directly prevent infections in the gastrointestinal tract through exclusion mechanisms and antimicrobial activities. Additionally, prebiotics and dietary fibers interact directly with epithelial and immune cells, contributing to infection prevention. Dietary fibers such as beta-glucans and arabinoxylans have been shown to activate C-type lectin receptor dectin-1, which is crucial for inducing trained immunity and enhancing immune responses against secondary infections. Human milk oligosaccharides, arabinoxylans, and pectin also interact with toll-like receptors, leading to improved efficacy of dendritic cells, the induction of tolerogenic dendritic cells via intestinal epithelial cells, protection of the gastrointestinal tract from excessive toll-like receptor signaling, and support for resolving inflammation following gastrointestinal infections (Wiertsema, et al., 2021).

We are only beginning to understand the impact of our diet on disease pathology. Future research should focus on the gut microbiome as a biomarker for dietary intake and disease development, the effects of probiotic supplementation on clinical outcomes, and bacterial therapies for gut health, immunity, and treatment. Emerging technologies that analyze the metabolome pave the way for exploration in this exciting field. The future holds vast potential and promising advancements in this area (Cresci, G. A., & Bawden, E., 2015).

Our microbiome involves the activation of pattern recognition receptor (PRR) pathways, such as toll-like receptors (TLRs), by gut microbiota-derived microbial-associated molecular patterns (MAMPs), which can induce antimicrobial factors like the lectin Regenerating islet-derived protein III gamma (RegIIIγ), combating vancomycin-resistant enterococcus. Additionally, PRRs regulate adaptive immunity, influencing anti-pathogen T- and B-cell responses. For example, C-type lectin receptors interacting with fungal MAMPs coordinate anti-fungal T helper 17 (TH17) cell responses. Gut microbiome-derived metabolites, such as succinate, activate G-protein-coupled receptors, providing type-2 immune protection against worms (Kuziel, et al., 2022).

Our microbiome consists of many genera like Bacteroides, Bifidobacterium, Streptococcus, Enterococcus, Clostridium, Lactobacillus, and Ruminococcus were present in the faeces, reflecting the composition of the luminal community. In contrast, only Clostridium, Lactobacillus, and Enterococcus were identified in the mucus layer and epithelial crypts of the small intestine (Jovel, et al., 2018). Our microbiome also composes of phages like podovirus, myovirus, and siphovirus, and their abundance varies between individuals (Manrique, et al., 2017) along with protozoa like Cryptosporidium species, Giardia intestinalis, Entamoeba histolytica and particularly Blastocystis species can be found in healthy individuals (Chabé, et al., 2017) and even fungi capable of growing in and colonizing the gut are predominantly limited to a small number of species, mostly Candida yeasts and yeasts in the family Dipodascaceae (Galactomyces, Geotrichum, Saprochaete). Malassezia and the filamentous fungus Cladosporium are also potential colonizers. Other fungi commonly detected originate from the diet or environment but either cannot or do not colonize (e.g., Penicillium and Debaryomyces species, which are common on fermented foods but cannot grow at human body temperature). Some fungi like Saccharomyces cerevisiae, a fermentation agent and sometimes probiotic, and Aspergillus species, ubiquitous molds, have dietary or environmental sources but are likely to influence gut ecology (Hallen-Adams & Suhr 2017).

Our microbiome is capable of withstanding antimicrobial resistance and multidrug-resistant bacteria, but the use of antibiotics for 70 years, starting with the invention of the first antibiotic penicillin, along with newer antibiotics, has degraded the potential of the gut microbiota. However, it can be renewed to fight even superbugs. Consumption of prebiotics and probiotics increases the population of good bacteria, and practicing physical activities, exercises, and yoga can keep the gut healthy. Consumption of alcohol and smoking should be prevented, as those toxins inhibit the functions of good bacteria.

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CONCLUSION

antimicrobial resistance (AMR) is a critical global health threat, demanding urgent and innovative solutions. Traditional antibiotics are becoming increasingly ineffective against resistant bacterial strains, highlighting the necessity for alternative approaches. Promising new strategies include the use of bacteriophages, which target and kill specific bacteria, and bacteriocins, natural proteins that inhibit bacterial growth. Anti-virulence drugs offer a way to disarm pathogens without promoting resistance by targeting their virulence factors. Disrupting quorum sensing, the microbial communication system, can prevent coordination among pathogens, reducing their virulence and biofilm formation. Additionally, leveraging the human gut microbiome, which plays a crucial role in fighting pathogens, presents a rich source of potential new treatments. These innovative approaches have the potential to revolutionize infection treatment and effectively combat AMR. Continued research is essential to develop these promising ideas into practical solutions, ultimately safeguarding global health for the future.

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REFERENCES

1.??? Almeida-Santos, A. C., Novais, C., Peixe, L., & Freitas, A. R. (2021). Enterococcus spp. as a producer and target of bacteriocins: a double-edged sword in the antimicrobial resistance crisis context.?Antibiotics,?10(10), 1215.

2.??? Anomaly, J. (2020). The future of phage: Ethical challenges of using phage therapy to treat bacterial infections.?Public Health Ethics,?13(1), 82-88.

3.??? Clatworthy, A. E., Pierson, E., & Hung, D. T. (2007). Targeting virulence: a new paradigm for antimicrobial therapy.?Nature chemical biology,?3(9), 541-548.

4.??? Cresci, G. A., & Bawden, E. (2015). Gut microbiome: what we do and don't know.?Nutrition in Clinical Practice,?30(6), 734-746.

5.??? Darbandi, A., Asadi, A., Mahdizade Ari, M., Ohadi, E., Talebi, M., Halaj Zadeh, M., ... & Kakanj, M. (2022). Bacteriocins: Properties and potential use as antimicrobials.?Journal of Clinical Laboratory Analysis,?36(1), e24093.

6.??? Dehbanipour, R., & Ghalavand, Z. (2022). Anti-virulence therapeutic strategies against bacterial infections: recent advances.?Germs,?12(2), 262.

7.??? Dickey, S. W., Cheung, G. Y., & Otto, M. (2017). Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance.?Nature Reviews Drug Discovery,?16(7), 457-471.

8.??? Gordillo Altamirano, F. L., & Barr, J. J. (2019). Phage therapy in the postantibiotic era.?Clinical microbiology reviews,?32(2), 10-1128.

9.??? Gradisteanu Pircalabioru, G., Popa, L. I., Marutescu, L., Gheorghe, I., Popa, M., Czobor Barbu, I., ... & Chifiriuc, M. C. (2021). Bacteriocins in the era of antibiotic resistance: rising to the challenge.?Pharmaceutics,?13(2), 196.

10. Haque, M., Islam, S., Sheikh, M. A., Dhingra, S., Uwambaye, P., Labricciosa, F. M., ... & Jahan, D. (2021). Quorum sensing: a new prospect for the management of antimicrobial-resistant infectious diseases.?Expert review of anti-infective therapy,?19(5), 571-586.

11. Hotinger, J. A., Morris, S. T., & May, A. E. (2021). The case against antibiotics and for anti-virulence therapeutics.?Microorganisms,?9(10), 2049.

12. Huang, F., Teng, K., Liu, Y., Cao, Y., Wang, T., Ma, C., ... & Zhong, J. (2021). Bacteriocins: potential for human health.?Oxidative medicine and cellular longevity,?2021(1), 5518825.

13. Kuziel, G. A., & Rakoff-Nahoum, S. (2022). The gut microbiome.?Current Biology,?32(6), R257-R264.

14. Lin, D. M., Koskella, B., & Lin, H. C. (2017). Phage therapy: An alternative to antibiotics in the age of multi-drug resistance.?World journal of gastrointestinal pharmacology and therapeutics,?8(3), 162.

15. Lin, J., Du, F., Long, M., & Li, P. (2022). Limitations of phage therapy and corresponding optimization strategies: a review.?Molecules,?27(6), 1857.

16. Marston, H. D., Dixon, D. M., Knisely, J. M., Palmore, T. N., & Fauci, A. S. (2016). Antimicrobial resistance.?Jama,?316(11), 1193-1204.

17. Maura, D., Ballok, A. E., & Rahme, L. G. (2016). Considerations and caveats in anti-virulence drug development.?Current opinion in microbiology,?33, 41-46.

18. Meade, E., Slattery, M. A., & Garvey, M. (2020). Bacteriocins, potent antimicrobial peptides and the fight against multi drug resistant species: resistance is futile?.?Antibiotics,?9(1), 32.

19. Simons, A., Alhanout, K., & Duval, R. E. (2020). Bacteriocins, antimicrobial peptides from bacterial origin: Overview of their biology and their impact against multidrug-resistant bacteria.?Microorganisms,?8(5), 639.

20. Suh, G. A., Lodise, T. P., Tamma, P. D., Knisely, J. M., Alexander, J., Aslam, S., ... & Antibacterial Resistance Leadership Group. (2022). Considerations for the use of phage therapy in clinical practice.?Antimicrobial agents and chemotherapy,?66(3), e02071-21.

21. Tonkin, M., Khan, S., Wani, M. Y., & Ahmad, A. (2021). Quorum sensing-a stratagem for conquering multi-drug resistant pathogens.?Current pharmaceutical design,?27(25), 2835-2847.

22. Totsika, M. (2016). Benefits and challenges of antivirulence antimicrobials at the dawn of the post-antibiotic era.?Drug Delivery Letters,?6(1), 30-37.

23. Turan, N. B., Chormey, D. S., Büyükp?nar, ?., Engin, G. O., & Bakirdere, S. (2017). Quorum sensing: Little talks for an effective bacterial coordination.?TrAC Trends in Analytical Chemistry,?91, 1-11.

24. Wiertsema, S. P., van Bergenhenegouwen, J., Garssen, J., & Knippels, L. M. (2021). The interplay between the gut microbiome and the immune system in the context of infectious diseases throughout life and the role of nutrition in optimizing treatment strategies.?Nutrients,?13(3), 886.

25. Zalewska-Pi?tek, B. (2023). Phage therapy—challenges, opportunities and future prospects.?Pharmaceuticals,?16(12), 1638.

26. Zhao, X., Yu, Z., & Ding, T. (2020). Quorum-sensing regulation of antimicrobial resistance in bacteria.?Microorganisms,?8(3), 425.

27. Johnson, B. K., & Abramovitch, R. B. (2017). Small molecules that sabotage bacterial virulence. Trends in pharmacological sciences, 38(4), 339-362.

28. Soltani, S., Hammami, R., Cotter, P. D., Rebuffat, S., Said, L. B., Gaudreau, H., Bédard, F., Biron, E., Drider, D., & Fliss, I. (2020). Bacteriocins as a new generation of antimicrobials: Toxicity aspects and regulations. FEMS Microbiology Reviews, 45(1).

29. Sharma, S., Chatterjee, S., Datta, S., Prasad, R., Dubey, D., Prasad, R. K., & Vairale, M. G. (2017). Bacteriophages and its applications: an overview. Folia microbiologica, 62, 17-55.

30. Delago, A., Mandabi, A., & Meijler, M. M. (2016). Natural quorum sensing inhibitors–small molecules, big messages. Israel Journal of Chemistry, 56(5), 310-320.

31. Jovel, J., Dieleman, L. A., Kao, D., Mason, A. L., & Wine, E. (2018). The human gut microbiome in health and disease. Metagenomics, 197-213.

32. Manrique, P., Dills, M., & Young, M. J. (2017). The human gut phage community and its implications for health and disease. Viruses, 9(6), 141.

33. Chabé, M., Lokmer, A., & Ségurel, L. (2017). Gut protozoa: friends or foes of the human gut microbiota?. Trends in Parasitology, 33(12), 925-934.

34. Hallen-Adams, H. E., & Suhr, M. J. (2017). Fungi in the healthy human gastrointestinal tract. Virulence, 8(3), 352-358.

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BY: Raghav Shankar