Human antibodies as emerging drugs for antimicrobial resistance.

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Published before final editing as: Trends Immunol. 2026 May 27:S1471-4906(26)00096-7. doi: 10.1016/j.it.2026.04.003 Human antibodies as emerging drugs for Antimicrobial Resistance Matteo Ridelfi 1, § , Vittoria Zucconi Galli Fonseca 2, § , Claudia Sala 3 , Rino Rappuoli 3 Author information Copyright and License information 1 Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA 2 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. 3 Fondazione Biotecnopolo di Siena, Siena, Italy ✉ Corresponding author: Rino Rappuoli, rino.rappuoli@biotecnopolo.it § these authors contributed equally PMC Copyright notice PMCID: PMC13225620  NIHMSID: NIHMS2167401  PMID: 42203543 The publisher's version of this article is available at Trends Immunol Abstract Antimicrobial resistance (AMR) is one of today’s most worrisome health emergencies. Bacteria once easily treatable with antibiotics have acquired resistance to many or all available drugs. In 2019, 1.27 million infection-related deaths were directly caused by AMR. By 2050, AMR could put 10 million lives per year at risk, particularly in low- and middle-income countries. This review focuses on monoclonal antibodies (mAbs) as a novel class of antimicrobials that can bypass classical resistance mechanisms and exert prophylactic and therapeutic effects. Advantages and limitations of mAbs are discussed, along with the need for rapid diagnostics for personalized use. The risk of selecting resistant strains is also addressed, as well as strategies to reduce production costs, expand global access, and improve equity. Keywords: antimicrobial resistance, monoclonal antibodies, superbugs, precision medicine The fight against infectious diseases: from antibiotics to monoclonal antibodies Prior to the 20th century, infectious diseases were a leading cause of mortality worldwide, contributing to a life expectancy usually lower than 50 years [ 1 - 3 ]. In the last two centuries, improved hygiene and the advent of antibiotics and vaccines increased life expectancy by more than 30 years in high-income countries [ 4 ]. While vaccination on the large scale allowed the control of several major infections, such as poliomyelitis, yellow fever and rabies, and even led to complete eradication of the disease in the case of smallpox [ 5 ], the discovery of penicillin in 1928 marked the beginning of the antibiotic revolution [ 6 ] which drastically reduced morbidity and mortality rates associated with bacterial infections [ 1 ]. Antibiotics target essential bacterial components or metabolic pathways that are different or non-existent in eukaryotic cells, making most drugs non-toxic for the host. On the other hand, broadspectrum antibiotics can reduce the diversity of the host gut microbiota by eradicating beneficial microbes while killing bacterial pathogens [ 7 ]. Antibiotic use is intrinsically linked with bacterial capacity to rapidly evolve and develop resistance. Indeed, the first cases of penicillin resistance were reported as early as in the 1940s [ 8 ], and since then over 150 compounds have been discovered, with resistance emerging quickly to the majority of them [ 9 ]. Moreover, the rise and spread of multidrug-resistant (MDR) “superbugs” [ 4 ] across the globe is further exacerbating the problem [ 10 ]. Well-characterized examples include Klebsiella pneumoniae intraspecies clone shifting [ 11 ], such as the recent global expansion of the KL64 capsule-bearing lineage, which is associated with enhanced virulence [ 12 ], as well as specific Salmonella Typhi strains [ 13 ]. These dominant clones become responsible for often unrecognized MDR epidemics, displacing antibiotic sensitive isolates, and transforming the global population structure of pathogens [ 14 ]. Complex MDR elements on transmissible plasmids or within chromosomal integration sites act as hydrophore pumps which continuously capture and integrate new resistance and new virulence factors in the bacterial genomes generating “monster” strains ( Fig. 1 ) that make infections more severe and difficult to treat [ 9 ]. Today, antimicrobial resistance (AMR) is globally recognized as a major public health concern with profound clinical and economic implications. The ‘silent pandemic’ caused by resistance to antibiotics is deeply intertwined with other global health threats: it interacts with climate change, extreme poverty and socioeconomic challenges, as well as with non-communicable diseases and other infectious diseases. The combination of these factors creates a global syndemic (see Glossary) that disproportionately affects the most vulnerable populations [ 15 ]. Figure 1. Bacterial evolution and generation of hypervirulent pan-resistant strains. Open in a new tab The figure illustrates how bacteria can evolve from non-virulent commensals to antibiotic-resistant pathogens by acquiring determinants of virulence and antimicrobial resistance through natural transformation, conjugation with transfer of plasmids and transduction mediated by bacteriophages. Multiple steps can be involved and lead to the final generation of extremely dangerous clones that show extensively drug-resistant (XDR), pan-resistant and hypervirulent phenotypes. Plasmids carrying genes that confer antibiotic resistance or encode virulence factors are indicated by closed circles/ovals, phage particles are shown with the yellow and blue head, bacterial conjugation is also schematically displayed. In this scenario, there is increasing interest in finding effective alternative solutions that can fight and prevent the emergence of new superbugs. In the last decades, monoclonal antibodies (mAbs) have been widely used in medicine and more than one hundred have been approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA), mostly for the treatment of cancer and inflammatory diseases. Recently, they have been also explored as an alternative approach to treat bacterial infections, although their application against pathogenic bacteria remains limited [ 16 ]. From the pioneering polyclonal horse sera of Emil von Behring in the 1890s and the hybridoma technology of Köhler and Milstein in the 1970s, the field of immunotherapies has continued to evolve immensely. In the last decades, technological advances such as phage display [ 17 ], high-throughput single cell sorting [ 18 ], and immunoglobulin isolation and expression [ 19 ], have accelerated the discovery and development of mAb-based therapies for infectious diseases. However, despite the advances in technology, only three mAbs have been approved by the Food and Drug Administration (FDA) for use against AMR bacterial pathogens. Specifically, Bezlotoxumab [ 20 ] has obtained approval for the prevention of recurrent Clostridioides difficile infections, while Raxibacumab and Obiltoxaximab can be used for prophylaxis of inhalational anthrax due to Bacillus anthracis [ 21 , 22 ]. In addition to these, several mAbs against high-risk bacterial pathogens are undergoing preclinical studies ( Table 1 ). Some examples include mAbs targeting Staphylococcus aureus [ 23 ], Neisseria gonorrhoeae [ 24 ], Shigella sonnei [ 25 ], K. pneumoniae [ 26 , 27 ]. Table 1. Available monoclonal antibodies and targeted bacterial pathogens. Bacteria Antibiotic Resistance mAbs under development Priority 1: Critical Acinetobacter baumannii Carbapenems Murine anti-capsular mAbs – preclinical [ 93 ] Enterobacteriaceae Carbapenems, 3rd-generation cephalosporins Anti-O-Antigen and anti-capsule mAbs – preclinical [ 26 , 94 ] Secretory IgA vs. enterotoxigenic E. coli – preclinical [ 95 ] Priority 2: High Salmonella spp. Fluoroquinolones Murine anti-outer membrane protein mAb Sal-06 – preclinical [ 96 ] Anti-Type 3 Secretion System mAb – preclinical [ 45 ] Anti-LPS Sal4 IgA – preclinical [ 97 ] Shigella spp. Fluoroquinolones Anti-Type 3 Secretion System mAb, Anti-O-Antigen mAb - preclinical [ 25 , 45 ] Enterococcus faecium Vancomycin Murine anti-capsular and anti-secreted antigen A mAbs-preclinical [ 98 ] Pseudomonas aeruginosa Carbapenems WVDC-5244 – preclinical [ 99 ] Anti-PcrV mAb – preclinical [ 44 ] MEDI3902 - phase 2 [ 79 , 81 ] Anti-SpuE mAb – preclinical [ 100 ] Neisseria gonorrhoeae 3rd-generation cephalosporins, fluoroquinolones 2C7 (anti-lipooligosaccharide mAb) – preclinical [ 24 ] Staphylococcus aureus Methicillin, vancomycin intermediate and resistant MEDI4893 - phase 2 [ 80 ] Priority 3: Medium Haemophilus influenzae Ampicillin Anti-Type 4 pilus mAb- preclinical [ 101 ] Streptococcus pneumoniae Penicillin non-susceptible Anti-capsular mAbs- preclinical Group A Streptococci Macrolides Bivalent dual-Fab Anti-M protein- preclinical [ 102 ] Group B Streptococci Penicillin NA Open in a new tab This review examines the current landscape of antibacterial mAbs, highlighting their advantages and limitations compared to traditional antibiotics. We describe their mechanisms of action and the most recent technological advances that allow antibody engineering. Finally, we discuss the potential of mAbs in precision medicine and diagnostics, as well as the challenge of developing scalable manufacturing platforms to ensure global accessibility. Monoclonal antibodies: advantages and disadvantages Technological progress in high-throughput antibody discovery and development is substantially shortening the timelines. Methods such as rapid assembly, transfection, and production of immunoglobulins (RATP-Ig) [ 28 ] allow for high-throughput cloning, expression, and functional screening of mAbs directly from single human B cells. In parallel, antigen-agnostic approaches [ 26 ] are expanding the identification of conserved and synergistic bacterial targets without prior antigen selection. Even though mAbs are not frequently used to treat bacterial infections, their intrinsic characteristics offer many benefits, especially when compared to antibiotics. Firstly, their high target specificity results in a narrow-spectrum functionality against the pathogen causative of the infection, thus reducing or abrogating collateral damage on the host microbiome [ 29 ]. This is an important advantage in contrast with broadspectrum antibiotics, which, by disrupting the equilibrium of the microbiota, can cause short- and long-term consequences such as diabetes and obesity, as well as susceptibility to other bacterial infections and malnutrition [ 30 ]. Indeed, as illustrated in Fig. 2 , the main targets of antibacterial mAbs and antibiotics are different. Antibodies target mostly surface or secreted antigens such as toxins, membrane proteins, oligo or polysaccharides, and organelles like pili or secretion systems. On the other hand antibiotics focus on membrane integrity or on intracellular pathways involved in nucleic acid replication, on ribosomes involved in translation, or on enzymes involved in cell wall synthesis. Figure 2. mAb and antibiotic targets. Open in a new tab The figure illustrates the most frequent bacterial targets for mAbs (on the left) and for antibiotics (on the right). Among mAb targets, there are surface-exposed polysaccharides constituting the capsule and/or the O-Antigen, which confer serotype specificity, protein targets such as secretion systems, toxins, pili/fimbriae and membrane proteins, notoriously more conserved across multiple serotypes. On the other hand, standard antibiotics usually inhibit essential intracellular functions like DNA replication, transcription, translation, cell wall synthesis and bacterial metabolism. Prolonged antibiotic treatments and their injudicious use is also contributing to the selection of multi-drug resistant strains, and mAb therapy is a powerful tool for treating MDR infections [ 31 ], as mAb targets are usually different from those of standard antibiotics thus bypassing bacterial mechanisms of resistance [ 29 ]. Importantly, while resistance to antibiotics is expected, resistance to mAbs has not been reported or fully investigated yet. Still, since mAb targets are mostly vaccine antigens, and resistance to vaccines has not been described, it is generally believed that mAb therapy will be associated with reduced risk of generating resistance. However, an example of possible mechanism leading to the generation of resistant clones has been documented in Streptococcus pneumoniae , where the introduction of multivalent pneumococcal conjugate vaccines substantially reduced vaccine-type invasive lineages but imposed selective pressure that led to serotype replacement by non-vaccine clonotypes [ 32 ]. Early prediction and detection of mAb resistant clones is therefore crucial: experimental in vitro evolution (i.e. exposure of bacteria to increasing mAb concentrations to select resistant mutants), whole-genome sequencing of bacteria recovered from animal studies, identification of the mAb epitope to allow precise mapping of potential resistant mutations, AI-driven approaches should be implemented to thoroughly characterize the candidate mAb. Binding to structurally well-defined and species-specific antigens allows mAbs to be fine-tuned against pathogenic species and to be employed safely in immunocompromised patients. Nevertheless, the same high specificity that makes mAbs so advantageous and safe also represents a major limitation, especially when dealing with highly variable targets such as bacterial polysaccharidic structures like capsules and O-Antigens [ 26 , 31 ] (see Outstanding Questions Box ). While potent antibacterial mAbs can neutralize bacterial infections and limit the emergence of MDR, their narrow spectrum applicability contrasts with the broader one of antibiotics, raising concerns about clear clinical benefits [ 33 ]. Consequently, current strategies are focusing on mAbs cocktails [ 34 ] or on generating antibodies against protein antigen conserved across different pathogenic species [ 35 ], or combination approaches with antibiotics [ 36 ]. Moreover, the isolation of patient-derived mAbs, combined with antibody-antigen structural studies and AI, can be used to implement vaccine design through Reverse Vaccinology [ 29 , 37 ]. OUTSTANDING QUESTIONS BOX. 1. Antibody design and mechanisms of protection How can the narrow specificity of mAbs be mitigated to ensure efficacy against highly heterogeneous bacterial pathogens without compromising precision? Which Fc-mediated effector functions and antibody isotypes are required for protection in different anatomical sites and infection contexts? Which functional features and immune signatures best define measurable mechanistic correlates of protection for antibacterial mAbs across different pathogens? How predictive are current in vitro and animal models for identifying mechanisms of protection, and how can their relevance be enhanced for antibacterial mAbs? 2. Translational models and assays How can existing models be upgraded to bridge the gap between in vitro efficacy, in vivo validation, and clinical success of mAbs? Can organoids and organ-on-chip systems be standardized and validated as physiologically relevant platforms for antibacterial mAbs development? How can functional assays for antibody activity be standardized to enable comparison across studies? 3. Clinical implementation and future tools How can the most appropriate patient cohorts for antibacterial mAb therapy be identified? At which stage of infection—prophylaxis, early disease—are mAbs most effective against bacterial pathogens? Can mAbs be exploited as adjunctive therapy? Which factors limit the clinical translation of mAbs against bacterial pathogens, despite their successful use as anti-toxin therapies and their broad clinical application in oncology and autoimmune diseases? Do mAb–based interventions exert selective pressure on bacterial populations, and what is the risk of antigen escape or resistance evolution? How can AI be further integrated across discovery, optimization, and clinical development to accelerate the translation of antibacterial mAbs from bench to bedside? Discovering anti-bacterial mAbs: assays and model systems Antibodies can mediate a wide range of immune mechanisms, including blocking bacterial adhesion to, or invasion of, host cells, neutralizing toxins, promoting agglutination, activating complement-mediated killing, enhancing opsonophagocytosis, and preventing biofilm formation ( Fig.3 ). Early-stage mAb characterization relies on a combination of binding and functional assays that determine not only if a mAb recognizes its antigen, but also whether this interaction results in meaningful antibacterial effects. These assays ( Table 2 ) are essential for selecting the most promising candidates before advancing to more complex ex vivo and in vivo models. Figure 3. mAb mechanisms of action. Open in a new tab The figure shows how mAbs exert their antibacterial functions. Antibodies can inhibit interaction and adhesion of bacteria with epithelial cells or block toxins secreted by bacteria; they can promote complement deposition with formation of the membrane attack complex and subsequent lysis of the pathogen. mAbs can also favor phagocytosis by macrophages and neutrophils in a process called opsonophagocytosis and can interfere with biofilm formation or disrupt existing biofilms. Table 2. Functional assays for the assessment of mAb activity in vitro . Assay Readout Measure References Axenic cultures Complement-mediated killing Luminescence/Fluorescence Luminescence or fluorescence intensity as a proxy of bacterial viability [ 38 ] Complement deposition Flow cytometry analysis of C3b staining [ 103 ] Imaging Imaging of Membrane Attack Complex (MAC) formation [ 104 ] Biofilm formation Colony Forming Units (CFU)/Crystal violet staining Evaluation of planktonic bacteria and of the amount of biofilm formed [ 39 ] Imaging Biofilm biomass [ 105 ] Bacterial agglutination Flow cytometry analysis Bacterial clusters [ 40 ] Imaging Number and size of bacterial clusters [ 40 ] Imaging Bacterial chains [ 25 , 26 , 41 ] Eukaryotic cells-based assays Opsonophagocytic assay (OPA) CFU Internalized bacteria released upon cell permeabilization [ 38 ] Flow cytometry analysis Phagocytic cells containing fluorescent bacteria [ 42 ] Imaging Phagocytic cells containing fluorescent bacteria [ 24 , 43 ] Adhesion/Invasion assay (AIA) CFU Infecting bacteria released upon cell permeabilization [ 45 ] Imaging Epithelial cells infected by fluorescent bacteria [ 45 ] Fluorescence Fluorescence intensity upon metabolism of resazurin to resorufin by live bacteria released upon cell lysis [ 25 ] Quantitative Polymerase Chain Reaction (qPCR) Amplification of bacterial genes present in the cell lysate [ 40 ] Epithelial cells killing Fluorescence Fluorescence intensity upon metabolism of resazurin to resorufin by live cells survived bacterial infection [ 44 ] Hemolysis assays Optical Density (OD) 540 nm Heme release [ 46 ] Toxin neutralization Imaging Chinese Hamster Ovary (CHO) cell clusters due to the toxic effect of the pertussis toxin [ 106 ] Open in a new tab mAb efficacy in axenic cultures Upon binding to their target antigen, mAbs can initiate the complement cascade through hexamer formation on the bacterial surface, leading to complement-dependent cytotoxicity (CDC) and bacterial lysis. The serum bactericidal assay (SBA), whether based on colony forming units (CFU) counts, or luminescence- or fluorescence-based detection, is a reliable method to measure bactericidal activity in the presence of an exogenous complement source [ 38 ]. Antibodies can impact biofilm formation by targeting proteins involved in its development or by inducing bacterial agglutination. The gold-standard assay for evaluating anti-biofilm activity relies on crystal violet staining as demonstrated for Omp38-specific mAbs inhibiting biofilm formation by Acinetobacter baumannii [ 39 ]. Preventing biofilm formation or disrupting existing biofilms can substantially enhance bacterial susceptibility to antibiotics. Bacterial agglutination is another protective mechanism mediated by mAbs. Using flow cytometry and microscopy, anti-Mfa1 mAbs were recently shown to induce aggregation of Porphyromonas gingivalis [ 40 ]. A related mechanism, known as enchained growth, was recently described as an effective antibody-dependent means of accelerating bacterial clearance, as proved for anti- Salmonella IgA [ 41 ] and later observed for anti- K. pneumoniae capsule IgG [ 26 ] and anti- S. sonnei LPS IgG [ 25 ]. Unlike classical agglutination, this mechanism depends on bacterial replication rather than density, underscoring its potential relevance in controlling early-stage infections. mAbs in host-pathogen interaction studies The ability of antibodies to mediate bacterial uptake and killing by phagocytic cells is evaluated by opsonophagocytosis assays (OPA) using either primary neutrophils or monocyte-derived macrophages or cell lines such as HL-60 or THP-1. These provide essential information on Fc-dependent effector functions, as phagocytes recognize opsonized bacteria through Fcγ receptors (FcγR) and complement receptors (CR1, CR3), ultimately leading to internalization and pathogen clearance. In a typical assay, bacteria are first opsonized with antibodies (and, when required, complement) and then incubated with phagocytes. Internalization and killing can be quantified through CFU counts. Flow cytometry has been used to measure S. aureus uptake by human neutrophils [ 42 ], while confocal microscopy has been applied to visualize phagocytosis of N. gonorrhoeae by differentiated THP-1 cells [ 24 , 43 ], as well as anti-LPS antibodies mediated S. sonnei uptake [ 25 ]. Adhesion to host cells represents a critical early step in bacterial colonization and infection. Antibodies directed against adhesins or surface-associated protein complexes can interfere in the interaction between host and pathogen and thereby limit downstream pathogenic events. For instance, a human alveolar epithelial cell line (A549 cells)-based killing assay has been developed to identify potent neutralizing mAbs against PcrV, the needle-tip protein of the Pseudomonas aeruginosa Type 3 Secretion System (T3SS). In this model, the protective efficacy of mAbs is determined by measuring the metabolic viability of A549 cells using a resazurin-based fluorescence assay following exposure to P. aeruginosa . Specifically, the assay evaluates the ability of mAbs to neutralize the PcrV protein, thereby blocking the T3SS and preventing bacteria-induced cell death [ 44 ]. Finally, hemolysis assays, which detect heme release, are commonly used to screen for mAbs that neutralize the T3SS of bacterial pathogens as demonstrated with P. aeruginosa, Salmonella , and Shigella [ 44 - 46 ]. Innovative and more complex systems for mAb discovery and validation are represented by organoids and organs-on-chip . These novel technologies are currently under development and optimization but show great promise being at the interface between in vitro and in vivo models . mAbs for toxin neutralization Toxin secretion is a major virulence mechanism of many bacterial pathogens and mAbs can directly neutralize these factors, preventing their interaction with host cells and thereby blocking downstream cytotoxic effects. Of note, the three FDA-approved mAbs are directed against toxins produced by Clostridioides difficile and Bacillus anthracis , respectively. Other examples are represented by a humanized mAb targeting the S1 subunit of the pertussis toxin which was shown to block receptor binding and protect chicken erythrocytes from hemagglutination [ 47 ] and by MEDI4893, a human mAb that targets the S. aureus α-toxin thus preventing binding to cell receptors [ 48 ]. More recently, mAbs that block the activity of the Type 3 Secretion System, and therefore the injection of toxic effectors into the host cell, have been described for P. aeruginosa [ 44 , 49 , 50 ]. Assessing mAb activity in vivo: strengths, weaknesses, flaws Among human bacterial diseases, shigellosis is one of the most challenging to model in animals, primarily because Shigella spp. display strict human tropism and fail to induce the full spectrum of symptoms in most species. Consequently, both vaccines and mAbs have been evaluated using intranasal mouse infection models [ 51 ] which, despite their limitations, permit assessment of bacterial colonization, dissemination, and animal survival following passive or active immunization. A mouse intraperitoneal (IP) challenge model has also been employed to evaluate mAb efficacy against Shigella [ 25 ], providing a means to measure protection against systemic infection. A similar IP challenge approach has been applied to assess the protective activity of mAbs against K. pneumoniae [ 26 ]. In this case, the model is considered more physiologically relevant, as the pathogen frequently causes bloodstream infections, making systemic challenge a meaningful proxy for severe human disease. A pneumonia mouse model has also been used to validate the in vitro efficacy of anti– P. aeruginosa mAbs, demonstrating substantial in vivo protection comparable to that achieved with standard-of-care antibiotics [ 44 ]. Recently, a lower genital tract mouse model of N. gonorrhoeae infection enabled evaluation of an anti-PorB mAb [ 24 ]. Finally, toxin-targeting mAbs were evaluated in vivo . For instance, female SPF KM mice have been used to assess the ability of mAbs to neutralize C. botulinum neurotoxin, both in therapeutic and prophylactic settings [ 52 ]. Another example is the S. aureus –induced dermonecrosis mouse model, which was used to demonstrate the in vivo efficacy of three mRNA-encoded anti–alpha-toxin mAbs [ 53 ]. Animal models remain indispensable for establishing protective activity, pharmacokinetics and safety of novel candidate medications, including mAbs. However, several important limitations must be acknowledged. Species-specific differences in immune receptor expression, immune cell repertoire, and toxin susceptibility can markedly influence mAb performance and may not accurately predict human responses. Moreover, as mentioned before, certain pathogens exhibit strict human tropism, making it difficult for animal models to reproduce key features of the disease, such as epithelial invasion or the full inflammatory phenotype. Finally, ethical considerations and regulatory constraints may restrict the scope and duration of animal studies. Monoclonal antibodies as tools for novel applications Antibody engineering Antibody–drug conjugates (ADCs) combine the high specificity of mAbs with the potency of antibacterial payloads thus enabling targeted delivery of antimicrobial agents to bacterial pathogens. This strategy increases the local drug concentration while minimizing off-target effects and systemic toxicity [ 54 ]. A successful ADC in the viral field is the conjugation of a small molecule neuraminidase inhibitor to the human antibody Fc domain which provides very long half-life and protection from influenza [ 55 ]. A representative example of antibody-mediated drug delivery in bacteria is provided by Tvilum and colleagues, who demonstrated that antibodies can be used to deliver antibacterial agents directly to S. aureus , thereby overcoming the limitations of non-targeted antibiotics, which are not active within bacterial biofilm [ 56 ]. A complementary strategy, proposed to treat intracellular P. aeruginosa , is the development of ADC incorporating host-cleavable linkers. In this case, the antibody binds extracellular bacteria, while host enzymes trigger cleavage of the linker and release of the bactericidal payload within the cell, once the bacterium has been opsonophagocytosed [ 57 ]. A distinct approach is presented by Johnson et al. , who reported the development of an antibody fused directly to an antimicrobial peptide (AMP) targeting P. aeruginosa . The antibody confers specificity toward the target bacterium, while the AMP exerts rapid, membrane-disruptive antibacterial activity upon binding [ 58 ]. In addition to the above-described strategies, mAb engineering includes structural modifications to improve CDC, Fc engineering to enhance engagement of immune effector cells, and approaches to optimize in vivo performance. Sequence-level engineering, including targeted amino acid substitutions designed to promote antibody hexamerization or extend serum half-life, further expands the functional potential of antibacterial mAbs [ 59 ]. These strategies will not be discussed in this article; we refer to a recently published comprehensive review [ 60 ]. Delivering mAbs as mRNA molecules The recent validation of the mRNA technology by the anti-COVID vaccines has prompted the exploitation of mRNA for the delivery of therapeutics as well. In the field of mAb development, there are increasing efforts for the optimization of lipid nanoparticle (LNP) composition for improving stability, pharmacokinetic properties and targeted release of the cargo mRNA [ 61 ]. No antibacterial mAb has been proposed as mRNA-encoded yet, however LNP-encapsulated mRNA that encode anti-viral mAbs have been developed with promising results in preclinical studies, including human immunodeficiency virus (HIV), Rabies virus, Influenza virus, Zika virus, Respiratory syncytial virus (RSV) and Chikungunya virus (CHIKV) [ 62 - 64 ]. The delivery of mAbs as mRNA molecules offers several advantages over the conventional recombinant antibody including rapid antibody expression in vivo , a simple and fast cell-free synthesis protocol that avoids the complexities associated with mammalian cell culture and protein purification. On the other hand, mRNA suffers from the notorious transient stability and short half-life, and administration routes should be optimized to favor maximum efficacy and specific targeting of the infection sites. mRNA could represent a game-changing approach for the delivery of IgA mAbs, which can be relevant in the protection at mucosal interfaces but are characterized by complex and time-consuming manufacturing procedures [ 65 ]. Recently, Moderna demonstrated the efficacy of LNP-encapsulated mRNA encoding dimeric IgA against S. enterica serovar Typhimurium and P. aeruginosa [ 66 ]. Artificial intelligence for mAb research and development Recent advances in artificial intelligence (AI) and machine learning (ML) are reshaping the fields of antibody discovery and development. Computational modeling approaches, including molecular dynamics and homology modeling, have long supported antibody engineering and antigen binding proprieties by describing antibody structure and flexibility [ 67 ], while recent structure-prediction tools such as AlphaFold3 can predict antibody-antigen complexes with an atomic level accuracy [ 68 ]. Moreover, de novo design of antibody scaffolds and binding interfaces has been made possible by generative models such as RoseTTAFold and RFDiffusion [ 69 , 70 ]. AI has enabled antigen-agnostic identification of broadly neutralizing antibodies, as shown for poxvirus antibodies targeting OPG153 [ 37 ]. Finally, machine learning supports antibody affinity optimization by predicting beneficial mutations and guiding in silico maturation, often in combination with deep mutational scanning and display technologies [ 71 ]. In parallel, AI-driven softwares that analyze open-source data have improved early detection of infectious disease outbreaks, enabling faster public health responses. Tools such as EPIWATCH have demonstrated the ability to identify epidemic signals earlier than traditional surveillance systems, highlighting the potential of AI to support outbreak prevention and preparedness [ 72 ]. Maximizing benefits from mAb therapy and promoting broad accessibility Precision medicine, diagnosis and clinical settings Given their high specificity for the pathogen they target, mAbs and ADCs represent a significant step toward precision medicine. By expanding the therapeutic toolbox beyond traditional antibiotics, these strategies offer new opportunities for selectively targeting AMR bacterial pathogens and may play an important role in the future treatment and prevention of bacterial infections without harming beneficial microbiota. Moreover, their specificity can be exploited also for precise diagnosis of the infectious species. Today the most frequently used diagnostic methods include Polymerase Chain Reaction (PCR), culture tests, serological assays that detect the presence of antibodies against the bacterium of interest, or Matrix-Assisted Laser Desorption/Ionization - Time-Of-Flight (MALDI-TOF) for advanced bacterial identification through a protein fingerprint [ 73 ]. While these methodologies promise accurate results, some of them are time-consuming, others could be hardly applicable to fastidious bacteria or difficult to implement as point-of-care tests. Lateral flow assays [ 74 ], based on mAbs, can circumvent these issues by providing a simple tool that can diagnose infections in body fluids with no need for special equipment or laboratory settings thus making them broadly applicable. An example of lateral flow test based on mAbs is PneumoResp, which was developed for the detection of Streptococcus pneumoniae in respiratory samples from pediatric patients. The assay is based on an immunochromatographic approach using antibodies that recognize pneumococcal cell wall polysaccharide antigens. When compared with PCR-based methods, the test showed a sensitivity greater than 98% and a high negative predictive value, supporting its reliability for the rapid detection of pneumococcal infection [ 75 ]. Antibodies are also widely used as biorecognition elements in biosensor-based diagnostic platforms. For instance, antibody-functionalized electrochemical nanobiosensors have been developed for the rapid detection of Escherichia coli , where antibodies immobilized on membrane-coated electrodes selectively capture bacterial cells and generate a measurable electrochemical signal upon antigen–antibody interaction [ 76 ]. Similarly, disposable amperometric immunosensors employing antibody-functionalized magnetic beads have been designed for the rapid selective detection of S. pneumoniae serotype 37. Notably, this approach allows a total analysis time of approximately 3.5 hours from sampling to measurement, highlighting its potential for timely clinical diagnosis [ 77 ]. More recently, amine-functionalized thermoplastic electrodes have been used to immobilize E. coli -specific antibodies for label-free detection, achieving a low limit of detection (27 CFU/mL) and demonstrating high specificity and recoveries in urine samples [ 78 ]. Collectively, these examples illustrate the versatility of antibody-based diagnostic tests for rapid, sensitive, and selective detection of pathogenic bacteria in clinical settings.The increasing number of anti-bacterial mAbs discovered will contribute to expanding the number of infection diseases that can be easily identified thereby supporting targeted application of mAbs as novel therapeutics in the context of personalized medicine. Beyond the general challenges of narrow specificity and the need for rapid diagnostics, it is important to consider the different clinical contexts in which mAbs against AMR bacteria could be deployed, as each carries different requirements and endpoint evaluation. The first is the use of mAbs for prophylaxis in well-defined high-risk cohorts, such as ventilated patients at high risk of nosocomial pneumonia, a context in which eligibility can be based on colonization status rather than active infection, as demonstrated in the EVADE and SAATELLITE trials [ 79 , 80 ]. MEDI3902 (gremubamab) was evaluated in a prophylactic setting in P. aeruginosa -colonized mechanically ventilated patients, with incidence of nosocomial pneumonia at 21 days as the primary endpoint which, unfortunately, was not met [ 79 ]. On the other hand, the subsequent GREAT-2 study in non-cystic fibrosis patients with bronchiectasis (where P. aeruginosa infections are prevalent) reported reduced exacerbations of symptoms and sputum markers of inflammation [ 81 ]. SAATELLITE was a phase 2 study for ASN100 against S. aureus pneumonia which was halted because it was unlikely to meet the efficacy endpoint [ 82 ]. A different scenario is evaluating antibacterial mAbs in adjunctive therapy. For example, AR-301 (tosatoxumab), targeting S. aureus alpha-toxin, was tested as an addition to standard-of-care antibiotics in ICU patients with microbiologically confirmed severe S. aureus ventilator-associated pneumonia, with primary endpoints including clinical cure [ 83 , 84 ]. Finally, standalone mAb therapy is the most relevant scenario for pandrug-resistant infections where no antibiotics can be used effectively [ 26 ], but no clinical trials have been conducted yet. In this case, trials must be designed to demonstrate direct microbiological and clinical efficacy, and early diagnosis is critical. It is worth noting that the failure of many trials to meet their primary endpoints may reflect heterogeneous antigen expression in vivo , limited antigen accessibility, not choosing the right patient cohort, and late initiation of therapy, rather than biological failure, and it highlights once more the need for effective diagnostics for a timely and targeted response. The scarcity of clinical trials and clinical data reflects both the difficulty of enrolling the right patient cohorts and the commercial challenges of developing therapeutics with such a narrow spectrum of activity. Low-cost and scalable platforms for mAb production Despite their therapeutic potential, the widespread use of mAbs for treating bacterial infections is limited by the high manufacturing costs, raising critical concerns regarding equity and global accessibility. Addressing this challenge requires advances in alternative expression platforms, including fungal and plant systems, and cell-free protein synthesis, which have demonstrated cost-efficiency and scalability for recombinant proteins and vaccines [ 85 ]. Careful attention to post-translational modifications like glycosylation should be paid to ensure stability, effector function, pharmacokinetics, and immunogenicity. For example, a genetically engineered Thermothelomyces heterothallica C1 strain (DNL155) was used to produce the anti-SARS-CoV-2 HuMab 87G7 which was found to be as potent as the counterpart obtained in mammalian cells, despite distinct glycosylation profiles [ 86 ]. Of note, glycosylation patterns can be modified through genetic introduction of human glycosylation pathways in the fungal cell line [ 87 ]. Aspergillus oryzae has been used to obtain full-length adalimumab , which demonstrated TNFα binding and neutralization comparable to CHO-derived antibody, although FcγRIIIa binding was not detected, highlighting the platform’s potential for low-cost mAb production with some limitations in Fc effector functions [ 88 ]. Nicotiana benthamiana was used to manufacture the anti-SARS-CoV-2 mAb J08-MUT, which showed human-like glycosylation and was functionality comparable to CHO-derived antibodies, although with low yields [ 89 ]. Finally, cell-free protein production systems were exploited for the synthesis of the VirG protein vaccine against Shigella spp. [ 90 ] and VAX-A1, a low-cost conjugate vaccine for Group A Streptococcus (GAS) [ 91 ]. Concluding remarks At the end of this journey throughout anti-bacterial mAbs as novel anti-infectives, a few key points should be emphasized. The first relates to the enormous potential of these molecules, which represent versatile and highly specific tools in the fight against bacterial infections, acting through a plethora of immune-mediated mechanisms different from the mode of action of conventional antibiotics. While mAbs are being deeply exploited in oncology and against autoimmune diseases, their application to AMR is still in its infancy but potentially vast as it spans from passive immunization to therapy, from diagnosis to engineering of new products including bispecific antibodies, ADCs and mRNA-based therapies. Also, monoclonals can be instrumental in standardizing immune-serological assays as described in Text Box 1 . TEXT BOX 1: Antibodies as standards in immuno-serological assays. It is common for different laboratories to use different immunoassay formats (e.g. ELISA, bactericidal assays) and reporting units which make comparison of data across clinical studies very difficult and hinder progress and recommendation of potentially promising vaccines. Standardizing immunoassays is therefore important for interpretation of clinical trial data. mAbs can play a role in this matter since they can represent an everlasting source of well-defined reference material that bypasses the intrinsic variability of human polyclonal serum which is being used nowadays [ 92 ]. On the other hand, correlates of protection are measurable biomarkers that allow prediction of vaccine efficacy. A mechanistic correlate of protection that measures a functional response (e.g. neutralization, opsonization, bactericidal activity) associated to protection is ideal. Alternatively, the amount of antigen-binding serum immunoglobulin G (IgG) can be used as a surrogate. Recent research work revealed that multi-functional mAbs, capable of killing the pathogen in vitro , promoting bacterial enchainment and phagocytosis, protect animals from challenge [ 25 , 26 ], thereby suggesting that studying mAb functionalities can help identify those features associated to protection from bacterial infection. The second point concerns the identification of antibodies with meaningful antibacterial activity. This is crucial before advancing candidates to more complex and costly development and requires the optimization of the most appropriate and informative screening procedures and high-throughput assays that recapitulate bacterial physiology. For these reasons, intense, cooperative, and long-lasting efforts and investments are needed. As discussed in the above paragraphs, the importance of careful patient cohort selection, appropriate endpoint definition, and timing of prophylaxis are critical for translating promising preclinical observations into effective therapies. Finally, ensuring global accessibility will be critical for significant impact: the implementation of low-cost and scalable production platforms is essential to make antibacterial mAbs broadly available. Together, addressing these points and several remaining challenges in the field (see Outstanding Questions ) can position mAbs not simply as alternatives to antibiotics, but as a multifunctional platform capable of transforming prevention, treatment, and research, providing a path forward to combat the silent pandemic of AMR. HIGHLIGHTS. Monoclonal antibodies (mAbs) enable precision medicine approaches by allowing highly specific diagnosis and treatment of bacterial infections, supporting targeted therapies against antimicrobial-resistant (AMR) pathogens while preserving the host microbiota. Bispecific mAbs, combination therapy with antibiotics, and antibody-drug conjugates can improve efficacy against multi-drug-resistant (MDR) infections. mAb discovery against bacteria is more complex than against viruses due to their larger genomes, antigenic diversity, pathogen heterogeneity, and the presence of masking capsules. Artificial intelligence (AI) and machine learning are increasingly applied to accelerate discovery, optimize binding specificity, and enhance Fragment Crystallizable (Fc)-mediated activities of mAbs. Robust, high-throughput functional assays remain critical for screening and selecting functional anti-bacterial mAbs. Beyond therapy and diagnostics, mAbs can be used to identify correlates of protection, supporting vaccine design and clinical and research applications. Significance. Human monoclonal antibodies (mAbs) represent a promising class of medications that can help address the global challenge of antimicrobial resistance and the quest for novel antibacterials. mAbs can bypass antibiotic resistance mechanisms and exert their antibacterial effect by leveraging the immune responses. ACKNOWLEDGEMENTS We thank Giorgio Corsi for artwork. Glossary Adalimumab human monoclonal antibody targeting Tumor Necrosis Factor Alpha (TNF-α) thus reducing inflammation. It is used to treat autoimmune diseases. Hybridoma technology method developed in the 1970s and used for producing monoclonal antibodies by fusing antibody-producing B cells, usually from mice, with immortal myeloma cells. Polyclonal horse serum Emil von Behring in the 1890s demonstrated that serum from horses immunized with diphtheria toxin could protect children from diphtheria. This serum was polyclonal, meaning it contained several antibodies originating from different B cells. von Behring’s pioneering work marked the beginning of passive immunization. Opsonophagocytosis process where pathogens, like bacteria, are coated with antibodies to facilitate their uptake by macrophages and neutrophils. Reverse Vaccinology vaccine discovery approach that exploits the genome sequence of the pathogen of interest to identify possible antigens and therefore rationally design vaccines. Reverse Vaccinology has accelerated the development of vaccines for fastidious pathogens that were previously considered impossible to target. An example is represented by the vaccine against serogroup B Neisseria meningitidis . Syndemic the term derives from the combination of synergy and epidemics and indicates the clustering of two or more disease conditions, frequently associated with socio-economic issues. Footnotes COMPETING INTERESTS R.R. holds shares in the GSK group of companies and declares no other financial or non-financial relationships and activities. V.Z.G.F. and C.S. are listed as inventors on patent “Antibodies against multidrug-resistant Klebsiella pneumoniae: WO2024157135” and declare no competing financial interests. The other authors declare no competing interests. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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