Innovative biotherapeutics for antimicrobial resistance: From monoclonal antibodies to phage therapy

INTRODUCTION

Antimicrobial resistance (AMR) could kill 10 million people every year by 2050 if the current trends are not reversed, which is a major risk to public health as well as the economy.^[1] This rising issue poses a major threat to public health, food safety, and economic stability and is believed to cause chronic infections, increased medical costs, and increased mortality, especially in low- and middle-income countries (LMICs), which cannot fight this problem.^[2] One would believe that it is hard to create new antibiotics because of scientific challenges, money, and regulations, which are largely responsible for the constrictions of the antibiotic pipeline. The emergence of antibiotic resistance increasingly surpasses new therapy development, posing significant threats to infectious disease control.^[3] Monoclonal antibodies (mAbs) are created to bind and neutralize pathogens specifically and to increase immunity to infections. Contemporary research indicates that these antibodies are able to decrease the bacterial burden significantly and ameliorate patient outcomes due to infections caused by resistant strains.^[4] They may be paired with other treatments, including Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated (CRISPR-Cas) systems, so that they can work more efficiently and stop resistance from arising.^[5] New biotherapeutics are promising major ways to address AMR, and mAbs and phage therapy lead the charge. These methods provide targeted solutions to the problems associated with traditional antibiotics, which have become progressively weaker against resistant bacteria. AMR occurs when microorganisms are resistant to infection. It minimizes the treatment options for individuals, animals, and the environment. Phage therapy involves bacteriophages, which are viruses that infect bacteria and introduce a targeted mechanism to kill resistant bacteria without damaging the helpful microbiota.^[6] Recent developments have shown that phages function within the clinic successfully, opening up the potential for their use as a replacement for antibiotics.^[7] Despite their potential, issues related to regulation and requirements for preparation per person create serious challenges for their widespread application.^[8] Phage therapy and mAbs present emerging alternatives for overcoming the dilemma of AMR; however, their reliance may raise issues of new mechanisms of resistance emergence. To remain effective against AMR in the long term, these alternatives need to be subjected to continuous research and redesign. The aim of this review is to critically synthesize evidence on innovative biotherapeutics including mAbs, phage therapy, antimicrobial peptides (AMPs), CRISPR-Cas antimicrobials, endolysins, and microbiome-based therapies as alternatives to conventional antibiotics in combating AMR, while highlighting translational opportunities, regulatory challenges, and One Health strategies for global accessibility.

METHODS

This literature review employed a narrative synthesis approach to evaluate innovative biotherapeutics including mAbs, phage therapy, AMPs, CRISPR-Cas antimicrobials, endolysins, and microbiome-based therapies as alternatives to conventional antibiotics in combating AMR. The review was framed within the One Health perspective, integrating evidence across human, animal, and environmental domains to highlight translational opportunities and systemic barriers. Relevant literature was retrieved from PubMed, Scopus, Web of Science, Google Scholar, and EBSCOhost, supplemented by clinical trial registries and global AMR surveillance reports. Search terms combined “antimicrobial resistance,” “monoclonal antibodies,” “phage therapy,” “biotherapeutics,” “CRISPR-Cas antimicrobials,” “endolysins,” “microbiome therapy,” and “One Health.” Grey literature from the World Health Organization (WHO), Food and Agriculture Organization, World Organization for Animal Health, and United Nations Environment Programme was also reviewed to capture policy frameworks and global initiatives.

The inclusion criteria encompassed peerreviewed articles published between 2000 and 2025, written in English, and addressing biotherapeutics in relation to AMR. Studies were considered if they covered human, animal, or environmental domains relevant to AMR; included policy briefs or gray literature from global health bodies; and presented biological mechanisms, clinical outcomes, or translational applications of biotherapeutics. Exclusion criteria ruled out articles not available in English, studies published before 2000 or lacking relevance to AMR or biotherapeutics, literature focused solely on antibiotic pharmacology without reference to resistance or alternatives, reports without cross-sectoral implications, and editorials or commentaries without empirical data or policy relevance. Reference lists of key articles were manually screened to identify additional sources.

Data extraction focused on evidence describing how biotherapeutics act against resistant pathogens and improve clinical outcomes. Particular emphasis was placed on mAbs, phage therapy, AMPs, CRISPR-Cas systems, endolysins, and microbiome-based interventions. Policy and regulatory frameworks were documented alongside barriers such as manufacturing limitations and restricted access in LMICs. The synthesis integrated scientific, clinical, and systemic insights within the One Health framework.

A thematic synthesis was applied to consolidate findings from biological, clinical, and policy perspectives. Evidence was organized within the One Health conceptual framework, depicting how biotherapeutic functions as ecological, clinical, and systemic interventions across interconnected domains. Four major themes emerged: (i) scientific mechanisms and therapeutic efficacy, (ii) regulatory and manufacturing challenges, (iii) equity and accessibility in LMICs, and (iv) integration into surveillance and stewardship frameworks.

LIMITATIONS OF CONVENTIONAL ANTIBIOTICS

Traditional antibiotics have historically been successful against infectious diseases; nevertheless, they are increasingly encountering challenges that diminish their efficacy over time.^[9] The most significant factor is the emergence of several mechanisms by which bacteria may resist antibiotics. Enzymatic degradation, as shown by β-lactamases, renders antibiotic ineffective by dismantling their molecular structure.^[10] Efflux pumps actively expel pharmaceuticals from bacterial cells, reducing intracellular antibiotic concentrations below therapeutic thresholds.^[11] Target modification, whereby bacteria change the molecular sites to which antibiotics bind, diminishes the efficacy of these medications.^[12] The scarcity of novel antibiotics significantly exacerbates this biological issue. The pharmaceutical pipeline has diminished since the mid-20^th century, when antibiotics were first manufactured.^[13] At present, a limited number of novel pharmaceuticals are used in clinical settings. Scientists, regulators, and the economy are all culpable for this decline. Consequently, physicians are constrained in the use of antiquated therapies that are increasingly ineffective due to resistance. Antibiotics may adversely affect host microbiota and ecosystems in unintended ways.^[14] Broad-spectrum antibiotics disrupt the delicate balance of commensal microorganisms, leading to dysbiosis, opportunistic infections, and reduced immune resistance.^[14,15] The prophylactic use of antibiotics in agriculture may result in environmental contamination and the dissemination of resistant strains across species and geographical boundaries.^[16] These constraints underscore the urgent need for alternative therapeutic strategies. [Table 1] delineates the primary mechanisms by which standard antibiotics fail and develop resistance, emphasizing that there are innovative approaches to infection treatment.^[11,17-22]

mAbs AGAINST RESISTANT PATHOGENS

mAbs have surfaced as possible complements or substitutes for antibiotics in combating resistant pathogens. In contrast to conventional antimicrobials, mAbs provide specific modes of action.^[23,24] They neutralize bacterial toxins, augment host immune responses, and obstruct pathogen attachment to host tissues, thereby averting colonization and disease progression.^[25] Clinical case studies have demonstrated their therapeutic efficacy. Bezlotoxumab, developed for Clostridioides difficile infection, binds to and neutralizes toxin B, thereby decreasing recurrence rates.^[26] Raxibacumab, designed for inhalational anthrax, targets the protective antigen of Bacillus anthracis, obstructing toxin entrance and increasing survival rates.^[27] These instances illustrate the accuracy and effectiveness of mAbs in addressing high-risk illnesses. The benefits of mAbs are significant. Their selectivity reduces off-target effects and maintains the host microbiota.^[25] Moreover, since they do not impose selection pressure on bacterial reproduction, the likelihood of cross-resistance is much lower. mAbs are especially advantageous in contexts where traditional antibiotics are ineffective or where resistance is prevalent.^[23] Nonetheless, obstacles persist. The elevated manufacturing costs and constrained range of activities impede their extensive use.^[28] The majority of mAbs are designed for particular infections or poisons, requiring precise diagnosis and focused application.^[29] Furthermore, their intravenous delivery and cold-chain requirements present logistical challenges in resource-constrained environments. Despite these limitations, the use of mAbs represents a pivotal advancement in the treatment of infectious diseases.^[30] [Table 2] delineates essential mAbs presently used or under development, highlighting their function in augmenting or supplanting conventional antibiotics amidst the challenge of AMR.^[26,31-35]

PHAGE THERAPY AND ENGINEERED PHAGES

Phage therapy, which uses bacteriophages to treat bacterial infections, has become a viable bio-therapeutic technique since AMR is increasing.^[36] Bacteriophages are viruses that infect and kill only bacteria.^[37] This specificity in their activity contrasts with that of broad-spectrum antibiotics, which can disrupt the host microbiota. The ability of phages to multiply at the infection site, infiltrate biofilms, and co-evolve with bacterial hosts renders them very promising for the treatment of multi-drug-resistant (MDR) infections.^[38] Phages can be used as medicine because they connect to bacterial cells, inject their genetic material, and take over the host machinery to produce more phages, which then kill the bacteria.^[39] This procedure not only eliminates the infection but also makes the therapeutic substance stronger in the same place. Recent clinical applications have shown that compassionate use may work, such as treating cystic fibrosis patients with recurrent Pseudomonas aeruginosa infections and post-surgical wounds with MDR Acinetobacter baumannii.^[40] These therapies have shown positive results, such as decreased bacterial load and enhanced clinical recovery, even when standard antibiotics are ineffective. Engineered phages represent a major step forward in this area. Synthetic biology can change phages so that they can infect more types of cells, traverse through biofilms better, and carry antimicrobial drugs such as CRISPR-Cas systems or bacteriocins.^[41] Phage cocktails, which are mixtures of several phages that attack different strains of bacteria or processes, expand the range of treatments and lower the chance of resistance developing.^[42] For example, phages that have been genetically modified to produce depolymerases have been more effective against infections that form biofilms because they break down extracellular polymeric compounds and allow for deeper penetration.^[43] Even with these improvements, there are still a few things that keep people from using them widely. Regulatory frameworks for phage treatment are still not well established, and there is not much agreement among locations.^[44] The need for customized phage formulations adapted to a particular bacterial strain infecting a patient complicates standardization and scalability. In addition, the immune system of the host may neutralize phages before they can do their job; thus, methods are needed to reduce immunogenicity. [Figure 1] illustrates the schematic action of phage therapy against bacterial biofilms, showing adsorption, genome injection, replication, and lysis. It highlights phage specificity, adaptability, and engineered enhancements such as depolymerases for biofilm penetration.

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Figure 1:

Schematic of phage therapy action against bacterial biofilms.

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COMPARATIVE MECHANISMS OF PHAGE THERAPY AND mAbs IN AMR

Phage therapy and mAbs represent two distinct but complementary bio-therapeutic strategies in the fight against AMR. Their mechanisms of action differ fundamentally, offering unique advantages in clinical and translational contexts. Phage therapy employs bacteriophage viruses that infect bacteria by binding to specific bacterial receptors, injecting their genetic material, and hijacking host cellular machinery to replicate. This culminates in bacterial lysis and the release of progeny phages, amplifying the therapeutic effect at the infection site.^[45] Phages are highly specific, self-replicating, and capable of penetrating biofilms, making them particularly effective against MDR pathogens. Recent advances in synthetic biology have enabled engineered phages to evade bacterial resistance mechanisms, incorporate depolymerases for biofilm degradation, and deliver CRISPR-Cas payloads to selectively target resistance genes.^[46] These innovations highlight phages as adaptable “living antimicrobials” with potential across human, veterinary, and environmental domains. mAbs, in contrast, are engineered immune proteins designed to bind bacterial antigens or toxins with high specificity. Their mechanisms include toxin neutralization, blocking bacterial adhesion to host tissues, and opsonization, which marks pathogens for immune clearance. Through Fcmediated effector functions such as antibodydependent cellular phagocytosis and cytotoxicity, mAbs recruit macrophages and neutrophils to engulf and destroy bacteria.^[47] Unlike phages, mAbs do not directly lyse bacteria or replicate at the infection site; instead, they modulate host immunity to eliminate infection while preserving the microbiota. Recent studies emphasize engineered mAbs with enhanced effector functions and bispecific designs, broadening their therapeutic scope against WHO priority pathogens.^[48,49] Together, these modalities underscore complementary strengths: phages act as direct bacteriolytic agents, while mAbs function as precision immunological tools. [Figure 2a] illustrates the lytic cycle of bacteriophages, beginning with attachment to the bacterial cell surface, followed by penetration of phage DNA, biosynthesis of viral components, maturation of new phage particles, and eventual lysis of the host cell, releasing progeny phages.^[50] [Figure 2b] depicts the multifaceted mechanisms of mAbs against bacterial infections. These include neutralization or inhibition of virulence factors (A), blockade of receptormediated adhesion (B), antibody-antibiotic conjugates (C), inhibition or disruption of biofilm formation (D), NETosis and opsonophagocytosis (E), complementdependent cytotoxicity (F), and antibodydependent cellmediated cytotoxicity (G), collectively highlighting the diverse immunological strategies mAbs employ to counteract bacterial pathogens.^[51]

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Figure 2:

(a) Schematic representation of the bacteriophage lytic cycle showing bacterial lysis. (b) Multifaceted mechanisms of monoclonal antibodies against bacterial infections.

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OTHER EMERGING BIOTHERAPEUTICS

AMPs are a family of small-molecule peptides that typically consist of 12–50 amino acid residues. At present, approximately 3100 naturally occurring AMPs have been identified. AMPs are abundant in nature and may be found in fish, birds, insects, microbes, plants, and other species.^[52] They exhibit a wide range of antibiotic properties against bacteria, yeasts, fungi, and viruses as well as cytotoxic effects on cancer cells, alongside anti-inflammatory and immunomodulatory functions.^[53] The CRISPR-Cas system, known as a bacterial adaptive immune system, enables prokaryotes to resist invading genetic elements (basically viruses and plasmids) through foreign DNA/RNA destruction.^[54] This system has emerged as a viable option for the creation of next-generation antibiotics to treat infectious illnesses, particularly those caused by AMR bacteria. Bacteriophage-encoded endolysins (lysins) have become a new class of antibacterial agent to fight the rise in antibiotic resistance. Endolysins are phage-encoded enzymes that lyse host bacterial cells at the end of the lytic cycle to release freshly assembled phages. They target the peptidoglycan layer, the bacterial cell wall’s most stable and conserved structural element, thus preventing resistance.^[55] Colonization by native microbiota is a powerful defense against pathogen invasion of the gut; this is referred to as colonization resistance. Fecal microbiota transplantation (FMT) is an example of a microbiome-based therapy that restores healthy gut bacteria. It is commonly used to treat recurrent C. difficile infection. FMT can also reduce the burden of antibiotic-resistant bacteria in the gut.^[56] [Table 3] provides an overview of emerging biotherapeutics including AMPs, CRISPR-Cas antimicrobials, endolysins, and microbiome therapies. It summarizes their mechanisms, clinical stages, and translational potential as alternatives to antibiotics.^[57-60]

SOCIOECONOMIC AND STRUCTURAL APPROACHES

Biotherapeutics remain largely inaccessible in LMICs owing to excessively high costs, stringent intellectual property rights, and the difficulty and expense of developing biosimilars.^[61] For example, mAbs account for 20% of worldwide revenues, mostly in high-income nations, whereas just 1% come from Africa, which accounts for 17% of the world’s population.^[61] There is a clear contradiction whereby effective medicines exist but are still out of reach for the majority of patients in LMICs owing to limited pooled procurement, weak supply networks, cold-chain constraints, and poor diagnostic and clinical facilities. According to the WHO recommendations on modifications to certified bio-therapeutic items, enhancing regulatory and biomanufacturing capabilities is crucial for the sake of global health. They noted that any modification may have an impact on the performance of the product and that post-approval modifications are unavoidable to maintain regular manufacturing, enhance quality, guarantee safety or efficacy, or update product information. Since “any change to a bio-therapeutic product has a potential impact on the quality, safety, and/or efficacy of that product,” national regulatory authorities are recommended to respond to this change by establishing clear processes commensurate with their resources.^[62] Biotherapeutics have become mainstream in the treatment of many diseases; however, access to biotherapeutics is hindered, particularly in LMICs, by a combination of health system issues, the high cost of these medications, and obstacles to the market introduction of follow-up generic drugs, often known as biosimilars.^[63] [Figure 3] demonstrates the relationship between innovation, cost, and global accessibility of biotherapeutics. It underscores socioeconomic barriers in LMICs, including high prices, biosimilar challenges, and weak supply chains.

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Figure 3:

Relationships among innovation, cost, and global accessibility.

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ONE HEALTH AND INTEGRATED APPROACHES

Integrated surveillance and stewardship frameworks

The role of surveillance and antimicrobial stewardship in addressing AMR and fostering responsible antimicrobial use is inevitable in addressing this global concern.^[64] AMR poses a critical global health threat caused by interactions among humans, animals, and the environment. Despite developments in surveillance, environmental AMR monitoring remains underdeveloped.^[70,71] AMR continues to emerge as one of the most urgent global health crises of the millennium. The call to action is clear, and it aims to operationalize integration, scale innovations, and establish binding commitments that ensure that antimicrobial stewardship remains a shared responsibility across all sectors. The development of interdisciplinary expertise that spans human medicine, veterinary science, and environmental sciences is crucial; for example, harmonizing antimicrobial stewardship programs across the human and animal sectors is vital.^[72] [Figure 4] shows the roadmap for biotherapeutic research and innovation in AMR. It highlights the integration of One Health strategies across human, animal, and environmental domains, emphasizing surveillance, stewardship, and translational research.

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Figure 4:

One health framework for bio-therapeutic deployment.

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CLINICAL AND PUBLIC HEALTH IMPLICATIONS

AMR is a global issue even in underdeveloped communities, and uncontrolled measures and the uncontrolled use of antibiotics in human, animal, and agricultural practices have increased their prevalence in developing countries. Phage therapy is one of the approaches used to combat AMR. There is potential in the use of phage therapy to combat AMR in multiple ways. Hence, the phage approach could not only prevent infectious diseases but also manage AMR.^[73] Phage therapy offers a promising alternative to antibiotics, particularly against MDR pathogens. Moreover, insight into these defenses is essential for augmenting the adoption of phage therapy at scale and advancing bacterial control in clinical settings.^[74] Unlike antibacterials, which usually inhibit essential bacterial functions, mAbs can bind to virulence factors and may be associated with a decreased risk of selecting resistant mutants because mutations in these targets may result in reduced virulence and enhanced clearance by the immune system. On the other hand, the extreme specificity of mAbs makes their spectrum narrow. In addition, mAbs are intrinsically safe, as they are biologics, and little or no toxicity has been reported thus far, unlike small molecules.^[75] Increasing AMR has led to renewed interest in phage therapy as an alternative to traditional antimicrobial agents. Expanded access and compassionate use cases have varied widely. Large knowledge gaps contribute to uneven approaches and a lack of consensus.^[76] mAbs show limited anticancer activity as mono-therapies. An ability to reduce pain side effects has been attempted. To reduce adverse drug reactions, desensitization strategies using an infusion protocol have been shown to reduce hematological side effects, whereas other therapeutic interventions decrease pain.^[77]

CHALLENGES IN RESEARCH AND FUTURE DIRECTIONS

Despite the significant potential of novel biotherapeutics in combating AMR, numerous scientific and practical challenges remain to be addressed. A primary concern is the long-term efficacy of mAbs and phage treatment.^[78] mAbs offer increased specificity and a reduced likelihood of cross-resistance; nevertheless, their narrow spectrum and pathogen-specific formulation limit their efficacy in poly-microbial illnesses.^[79] Moreover, the potential for bacterial evolution to circumvent antibody binding sites constitutes an insufficiently investigated concern, necessitating ongoing surveillance and molecular adaptation techniques. Phage treatment is gaining acceptance through compassionate usage and clinical trials; however, it continues to face challenges with standardization and scalability.^[80] The necessity for tailored phage cocktails targeting specific bacterial strains challenges regulatory approval and mass production.^[81] Moreover, host immune responses may neutralize therapeutic phages through their ability to eliminate bacteria, hence raising concerns over immunogenicity and delivery mechanisms. Engineered phages utilizing CRISPR-Cas systems or depolymerases exhibit superior efficacy; however, they also present biosafety and ethical concerns that necessitate robust evaluative frameworks.^[74] Obstacles to implementation exacerbate the challenges associated with the use of biotherapeutics. Access is challenging due to the intricacies of manufacturing, cold-chain logistics, and elevated production prices, particularly in LMICs.^[82] Regulatory fragmentation among regions complicates the establishment of cohesive approval procedures, hence impeding the implementation of novel medicines in clinical environments.^[83] In several LMICs, inadequate diagnostic infrastructure and restricted clinical capacity hinder the integration of biotherapeutics into standard treatment, despite their potential to mitigate AMR.^[83] A strategic roadmap is essential to overcome these challenges. Investment priorities should shift toward translational research that merges laboratory innovation with practical implementation. This encompasses funding for biomanufacturing systems capable of cultivating decentralized phage libraries and adaptable clinical trial designs. Regulatory agencies should collaborate to establish global standards for the assessment of biotherapeutics, balancing safety and expediency. Capacity enhancement in LMICs by training, infrastructure development, and regional collaboration will be crucial for ensuring equitable access and the sustainability of the program. The future of biotherapeutics in combating AMR relies on interdisciplinary collaboration, innovative policies, and sustained global commitment. Resistance continues to escalate more rapidly than conventional remedies do; hence, these novel methods require enhancement, evaluation, and prompt integration into healthcare systems. [Figure 5] shows the roadmap for biotherapeutic research and innovation in AMR. It highlights the integration of One Health strategies across human, animal, and environmental domains, emphasizing surveillance, stewardship, and translational research. The figure underscores the importance of interdisciplinary collaboration, regulatory harmonization, and equitable access, particularly in LMICs. It serves as a visual framework for guiding innovation, policy, and global solidarity in advancing bio-therapeutic solutions against AMR.

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Figure 5:

Roadmap for bio-therapeutic research and innovation in antimicrobial resistance.

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CONCLUSION

AMR remains one of the most formidable challenges to global health, food security, and economic stability. Conventional antibiotics are increasingly undermined by diverse resistance mechanisms, declining drug discovery pipelines, and ecological consequences, underscoring the urgent need for innovative therapeutic strategies. Biotherapeutics have emerged as promising alternatives, offering pathogen-specific activity and reduced collateral damage to host microbiota compared to broad-spectrum antimicrobials. mAbs exemplify precision biologics capable of neutralizing bacterial toxins, blocking pathogen adhesion, and enhancing immune clearance. Clinical applications such as bezlotoxumab for C. difficile and raxibacumab for anthrax demonstrate their therapeutic potential in resistant infections. Phage therapy, in parallel, employs bacteriophages as direct bacteriolytic agents with the ability to penetrate biofilms, self-replicate at infection sites, and adapt through engineered phages and cocktails. Compassionate clinical use has already shown efficacy against MDR pathogens, highlighting its translational relevance. Other biologics, including AMPs, CRISPR-Cas antimicrobials, endolysins, and microbiome-based therapies, further expand the therapeutic landscape. These modalities are progressing through early-stage trials and illustrate the breadth of biologic innovation available to confront AMR. However, challenges remain in regulatory harmonization, manufacturing scalability, and equitable access, particularly in LMICs. Addressing these barriers will be essential to ensure that biologics can be deployed globally and sustainably. Innovative biotherapeutics, particularly mAbs and phage therapy, represent a critical frontier in AMR control.^{[23-26,36-40]} Their integration into clinical practice will depend on sustained investment, interdisciplinary collaboration, and One Health strategies to ensure equitable access. Future directions should focus on advancing biologic platforms that provide pathogen-specific activity, immune modulation, and precision targeting, thereby strengthening the global capacity to manage AMR with durable and scientifically validated solutions.