AMR has emerged as a significant threat to global health. Bacteria have become stronger at resisting the medications that are supposed to kill them. The WHO estimates that antibiotic resistance is highest in the South-East Asian and Eastern Mediterranean regions, where 1 in 3 reported infections were resistant. In the African region, 1 in 5 infections was resistant. Resistance is also more common and worsening in places where health systems lack the capacity to diagnose or treat bacterial pathogens. Bacterial AMR contributed to an estimated 4.95 million fatalities in 2019, with a concerning 1.27 million of the fatalities being directly caused by infections that were resistant to treatment [8]. The burden is not evenly shared; low- and middle-income countries (LMICs) suffer the brunt of the impact as their health systems have been less effective, their diagnostic tools are limited, and they have more risk factors, including lack of good nutrition and immunocompromised patients. Many factors contribute to AMR, such as the overuse and misuse of antibiotics in human medicine and veterinary and agricultural settings, poor infection prevention and control (IPC) practices, inadequate diagnostics and surveillance, and the spread of resistant organisms beyond borders via travel, trade, and the environment [9]. Clinically, the outcome is extended hospitalizations and heightened morbidity and mortality, especially for children, the elderly, and the immunocompromised. If AMR is not effectively addressed, it may necessitate substantial economic investment [10-12]. Some studies say that LMICs could lose more than 5% of their GDP by 2050, and the world could lose up to $100 trillion. Clinically, this leads to longer hospital admissions and higher rates of illness and death, especially in children, the elderly, and people with weak immune systems [13]. If we do not take quick, coordinated action involving better stewardship, global surveillance, more money for diagnostics, and the creation of novel therapies, the stealthy spread of resistance may undo decades of progress in treating infectious diseases and render the health system more susceptible overall [14].

Drug repurposing, also known as drug repositioning, is a good alternative for (or addition to) conventional de novo drug development, with the aim of finding newer applications outside the scope of the original medical indication for existing drugs that are currently on the market or have already received approval [15]. Repurposing makes extensive use of pre-existing safety and clinical data [16]. The benefits of employing this specific approach include cost-effectiveness and less time needed for the drug discovery process. The drug repurposing approach is especially attractive in the context of AMR [17]. A combination of repurposed drugs and conventional antibiotics can be used to fight resistant bacteria such as S. aureus, K. pneumoniae, P. aeruginosa, and Escherichia coli (Figure 1). However, issues like serious off-target effects, toxicity, and intellectual property and regulatory issues [18] pose serious challenges. Because repurposed medications already have the manufacturing and shipping infrastructure, pharmacokinetic and toxicological data, and established safety profiles, they may be a quicker and less expensive option.

In the realm of antimicrobial therapeutics, repurposed drugs may operate as direct bactericidal or bacteriostatic agents, function as adjuvants that augment the effectiveness of current antibiotics (for instance, efflux pump inhibitors or β-lactamase inhibitors), or engage in host-directed mechanisms that alleviate infection or the development of resistance [19]. The approach is promising, but it has some problems, such as less effective potency in new indications, complicated dosing and pharmacology, and possible unintended effects on resistance dynamics [20]. Therefore, repurposing serves as a strategic complement to conventional antibiotic discovery rather than a substitute. From a mechanistic standpoint, repurposing may yield (i) direct antibacterial activity from non-traditional compounds (e.g., non-antibiotic drugs exhibiting off-target antimicrobial effects); (ii) adjuvant effects when used alongside existing antibiotics to restore or enhance efficacy (e.g., efflux-pump inhibitors, quorum-sensing inhibitors, or agents disrupting biofilms); and (iii) host-directed therapies modulating host immunity or pathophysiology rather than directly targeting bacterial viability [21].

This review comprehensively focusses on drug repurposing as an emerging strategy to overcome AMR. The scope includes the study of resistance trends across bacterial pathogens, surveillance data, molecular mechanisms [22], trends and gaps in antibiotic research and development (R&D), drug repurposing strategies, computational platforms, preclinical and clinical investigations, and regulatory considerations. Incorporation of precision medicine approaches, phenotypic screening, combination therapy, and synergistic drug repurposing.

Comparatively simple screening of soil-derived microorganisms and abundant natural-product reservoirs drove the early decades of antibiotic discovery. However, the scientific community established what is now referred to as an antibiotic discovery “void” when these easily accessible sources ran out. As a consequence of growing scientific and translational challenges, the approval of new antibiotic classes has drastically decreased since the 1970s. Establishing compounds that may penetrate bacterial envelopes, especially the impermeable outer membrane of Gram-negative pathogens, minimizing intrinsic resistance determinants, obtaining acceptable pharmacokinetic and safety profiles, and sustaining activity in the face of rapidly evolving resistance are major challenges [31].

Significant financial and regulatory disincentives exacerbate scientific barriers. In comparison with other medications for chronic illnesses, antibiotics have a significantly lower potential for profit because they are usually prescribed for brief periods of time and are increasingly reserved as last-line treatments. Many pharmaceutical companies have withdrawn from antibacterial research and development as a result of this limited market viability. Because of this, there is a growing gap between clinical need and therapeutic availability as antimicrobial resistance continues to rise globally, and the antibiotic innovation pipeline is severely underpowered.

Some repurposed drugs show direct antimicrobial activity, some show adjuvant effects, and some exhibit host‐directed therapies, indirectly reducing infection burden. Repurposing is a vital alternative to traditional antibiotic development, as it is an efficient mode of therapy while the R&D of novel antibiotics are still in the pipeline [32].

The primary benefits stem from leveraging the extensive R&D already completed for the original drug, leading to a faster, cheaper, and lower-risk path to new therapies [32] (Table 1).

The microorganisms that develop antimicrobial resistance are referred to as “superbugs”. These may be bacteria, fungi, virus, or protozoa. The resistant bacterial species of resistant Gram-negative bacteria that are pathogenic include Salmonella, Helicobacter pylori, Campylobacter jejuni; Shigella dysenteriae, Shigella flexneri, and Shigella sonnei. Gram-negative bacteria are found to show intrinsic resistance to multiple drugs. Some Gram-positive bacteria have also been found to be multi-drug resistant and include Enterococcus faecalis, Staphylococcus aureus, Methicillin-resistant Staphylococcus epidermidis (MRSE), and MDR S. epidermidis. The genera of fungi that are found to be resistant include Aspergillus, Candida, and Pneumocystis [34–40]. The organisms and their resistance to certain antibiotics are mentioned in Table 2.

The formation of biofilms on the outer membranes of bacteria is one of the major hinderances for the effectiveness of certain antibiotics. A biofilm allows microbes to resist host immune responses and the effect of antibiotics. Both Gram-positive and Gram-negative bacteria can form biofilms, leading to an ongoing battle on various surfaces.

The infection that is caused due to antimicrobial resistance developed through biofilms is termed “biofouling.” It is a polysaccharide-encased multicellular bacterial aggregation adhering to various surfaces. Biofilm infection is recognized to be responsible for more than 65% of infections, posing a huge threat to public health. Biofilm-forming microorganisms possess different characteristics like collective cooperation, resistance to antimicrobials, and source capturing [41–48, 51, 52].

Repurposing strategies are also referred to as repositioning or reprofiling of drugs. The resistance mechanisms in microorganisms have helped to create new formulations for antibiotics that were not able to prevent microbial proliferation during the occurrence of a disease. The process of repurposing is found to be safe during human clinical trials and quite effective.

The repurposing of drugs involves a ubiquitin-proteasome degrading system (UPS). UPS is a major cytosolic protein degradation system. Ubiquitin is an evolutionary conserved protein which can be degraded at 19 S proteasome (bounded ATP dependant cytosolic protease) in resistant bacteria. The process targets 19 S proteasome components-deubiquitinases POH1 and USP14/UCHL5 (D’Arcy et al, 2011) and ubiquitin-binding receptor RPN13 that causes ATP hydrolysis. Also, the repositioning of drugs is done to inactivate ubiquitin activating enzyme (UEA1) by TAK-243 or inhibition of p97/VCP segregase upstream by proteasome CB5083. Both these compounds target the resistance mechanisms, thereby improving the antibiotic entry into the microorganisms. The unfolded proteins along with the drugs are actively translocated into proteolytic chambers in the proteases (Figure 2). It is found that these molecular targets have shown to overcome resistance with bortezomib/carfilzomib antibiotics in resistant microbes [49, 50, 53–66].

Antibiotic resistance is caused by the inappropriate use of antibiotics and is considered a major global issue, causing significant deaths all over the world. Moreover, with increasing medical expenses and decreasing numbers of approved antimicrobial agents [67], alternative strategies to combat antibiotic resistance is the need of the hour. One such strategy is repurposing non-antibiotic drugs. Drugs that are originally designed for disease mitigation that subsequently possess antimicrobial properties are classified under drug repurposing as “non-antibiotics” [68]. Since COVID-19, therapies using drug repurposing approaches have accelerated and the antimicrobial activity of drugs belonging to different categories like antidepressants, antihypertensives, anti-inflammatories, antineoplastics, and hypoglycaemic agents have been explored thoroughly. In this particular section of the review, current trends in the repurposing of anticancer, antidepressants, antipsychotics, anti-inflammatory, antifungals, and immunomodulatory agents, as well as existing antibiotics for AMR, are discussed.

Repurposing non-antibiotic drugs may pose clinical implications like disrupting immune regulation or gut microbiome imbalance. Since the fundamental design and development of the anti-cancer drugs is to target cell proliferation, these agents pose the risk of impeding immune responses, resulting in secondary infections and many other complications. Therefore, preventing over-suppression and further complications for patients should be considered.

Bacteria reduce antimicrobial drug accumulation through certain specific mechanisms, such as the over expression of bacterial efflux pumps. These bacterial efflux pumps can be inhibited with antidepressants and antipsychotics, which act as efflux pump inhibitors (EPIs) [77]. Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic antidepressants (TCAs), and phenothiazine-type antipsychotics are considered as EPIs as they exhibit efflux pump-modulating activity (Table 4). However, persistent use of antidepressant drugs can disrupt the gut bacteria, leading to potent adverse effects. Further, these drugs are required in slightly higher concentrations for antimicrobial effects than the therapeutic concentrations required for psychiatric conditions, raising serious toxicity concerns.

Antimicrobial resistance in microorganisms occurs through several mechanisms: the presence of ß-lactamase enzymes, which disrupt the molecular structure of antibiotics and inactivate them; and the development of efflux pumps, which expel antibiotics to decrease their concentration within the cells. The molecular structure of the target site of antibiotics may be modified through microbial genetic mutations. These mutations also cause altered ribosomal structure, leading to damage in intrinsic enzymatic synthesis that causes reduction in the binding affinity of antibiotics and makes them ineffective [79–85].

Based on the above mechanisms, certain antibiotic adjuvants can play an important role in inhibiting these pathways and contribute to the prevention of antibiotic resistance in microorganisms. Antibiotic adjuvants are the agents or substances that are co-administered with antibiotics that increase the activity of antibiotics. These substances function by improving their effects on a suitable target, resulting in an increase in the antimicrobial effects. They are also involved in the pathways associated with antimicrobial resistance and modulate the host immune response for an overall increase in the therapeutic effects. It was shown that treatment with an antibiotic adjuvant along with an antibiotic has more potential effectiveness in treatment than an antibiotic alone against the infections caused by drug-resistant microorganisms [antibiotic + adjuvant (chemical agent)] [86–89].

The adjuvants lower the minimum inhibitory concentration of the antibiotics and enhance the concentration of already-existing antibiotics (Melander and Melander [90]).

Class IA (active resistance inhibitors) can be combined with ß-lactam antibiotics including penicillin, cephalosporins, carbapenems, and monobactams. These antibiotics consist of a ß-lactam ring that is antimicrobial in nature. When these antibiotics are administered alone, the ß-lactamase enzyme within the microbes degrade this ring by opening its molecular structure, thereby making it ineffective against the microorganism. When combined with an inhibitor, it causes an irreversible inhibition of ß-lactamase enzyme, thereby dissociating its activity. This retains the efficacy of the antibiotic against the pathogen. An example would be augmentin [combination of clavulanic acid (ß-lactamase inhibitor) and amoxicillin (antibiotic)], which causes irreversible inhibition of the ser- ß-lactamase (serine ß-lactamase) enzyme (Figure 3). These inhibitors possess broad spectrum inhibition against enzymes like extended spectrum ß-lactamase (ESBL) and carbapenemases [96–100]. Other examples are mentioned in Table 2.

Efflux pumps are cellular transport proteins that are found within pathogens. These molecules are utilized to remove the antibiotics by reducing their intracellular concentration and efficiency. This leads to antibiotic resistance within the pathogens. The efflux pumps found in only Gram negative bacteria include the resistance nodulation and cell division family; those found within both Gram positive and Gram negative bacteria includes ABC-ATP binding cassette; the SMR family of small multi drug resistance; the MFS major facilitator superfamily; the MATE multidrug and toxin extrusion family; and the PACE proteobacterial antimicrobial compound efflux superfamily. The inhibition in the activity of antibiotic transport by efflux pumps could be processed by Efflux Pump Inhibitors (EPI) [101–105].

EPI are class IB (passive resistance inhibitors) which, when administered with antibiotics, usually increase the intracellular concentration of antibiotics within the pathogens. When EPI are used as adjuvants in combination with antibiotics, they prevent the removal of the antibiotic from the pathogen, thereby improving the antibiotic efficiency. Examples of EPI used are PAßN- phenylalanine-arginine-ß-naphthylamide and CCCP carbonyl cyanide m-chlorophenylhydrazone in combination with antibiotics such as levofloxacin or erythromycin (Figure 4). Their antimicrobial effects have been shown against strains of Pseudomonas aeruginosa (Table 6).

Biofilms are defined as communities of properly organised microorganisms attached to a substrate and embedded in a self-produced extracellular matrix (extracellular polymeric substances - EPS), which aids cell interactions. It is a sequential phenomenon that depends on a plethora of factors (physical, chemical, and biological) in its different phases: attachment, microcolony formation, maturation, and dispersion. During these phases, which may vary a little in their complex pattern, microbial biofilms usually form three-dimensional structures separated by porous water channels and cavities. These channels and cavities allow nutrient entrance and waste discharge. The polysaccharides that comprise the EPS form the skeleton of the biofilm, providing structural stability. The 3D architecture of a biofilm can change its thickness, shape, and structure through time, but this evolution does not necessarily result in progressive orders. In fact, biofilms are dynamic structures whose evolution depends on both biotic and abiotic factors acting on time scales ranging from seconds to years. These biofilms have an anaerobic environment which is not favoured by antibiotics. Due to the formation of these biofilms, some species of Gram-positive and Gram-negative bacteria are developing resistance to antibiotics. There are certain enzyme and chemical agent adjuvants that may play an important role in the disruption of these biofilms by disturbing the phases of biofilm formation and improving the permeability of membranes. Through this, there occurs enhancement in the penetration of an antibiotic within the bacteria and increased antibiotic efficiency. The adjuvants that can prevent the maturation of EPS during biofilm formation include specific agents like enzymes like NAC (N-acetyl cysteine), Tween 80, D-amino acid, norspermidine, DspB (Dispersin B), polyamine and enzymes-glycosyl hydrolase, DNase I, and α-amylase (Figure 5) [106–110].

Along with these adjuvants, there are certain membrane permeabilizers which, when consumed together, help in improved localization and concentration of antibiotics within the bacteria. These include natural compounds like thymol, gallic acid, and glycosylated cationic block poly beta peptide (PAS8-b-PDM12), antimicrobial peptides such as colistin and detergents and nanoparticles such as PMBN (polymyxin B nanopeptide) and cerium oxide nanoparticles chitosan derivatives- 2,6-DAC (2,6- diamino chitosan), glycine-containing amino acid-conjugated polymer (ACP), polyurethanes, and polycarbonates (Table 6) [111–119].

The development of drug resistance amongst common bacterial pathogens has led to an alarming increase in immunocompromised patients with impaired immune function. Immunomodulatory therapies act by targeting the immune response modulations of the host rather than the pathogen. This is an alternative approach for the treatment of infectious diseases caused by anti-microbial resist pathogens [120]. Antimicrobial peptides (AMPs) are immunomodulators that have applications in targeted therapy, wound-healing, and drug delivery systems. Synergistic application of AMP-based strategies with current antibiotics might reduce drug load and provide improved results [121]. Mycograb, a human recombinant antibody fragment, combined with amphotericin B showed activity against resistant Candida species [122].

Dual action drugs with dual mechanistic approaches are the need of the hour in order to minimise multi drug administration, drug-drug interactions, and other adverse effects. The presence of multi-drug resistance efflux pump systems is why Gram-negative bacteria show higher resistance against anti-inflammatory drugs. Synergistic action of NSAIDs and antibiotics effectively combats the emergence of multi-drug resistance in microorganisms. Those NSAIDs that control the generation of pro-inflammatory mediators are considered as effective for treating infections. The following Table 7 lists the anti-inflammatory drugs repurposed for AMR and Table 8 lists the other non-antibiotic classes repurposed for AMR.

Widespread overuse and misuse of antibiotics has led to antimicrobial resistance and hence repurposing existing or older antibiotics has become increasingly important. Repurposing antibiotics eliminates selective strains and therefore causes co-resistance to other antibiotics which possess anti-microbial resistance [135]. Repurposed antibiotics are administered in higher dosages, which triggers multi-drug resistance. Levofloxacin and doxycycline are being repurposed with the aim to treat Alzheimer’s and malaria, respectively, although without satisfactory results. However, the optimisation or redevelopment of older and less explored antibiotics which have high potency and maintained efficacy = against microorganisms could help to tackle AMR in a strategic way.

The reintroduction of colistin and fosfomycin helped fight resistant pathogens causing neonatal sepsis [136]. The fosfomycin disodium formulation targeted key elements of the bacterial metabolism and thus showed virulence against fosfomycin-resistant bacterial strains. In vitro studies of a PEGylated colistin prodrug developed by Chongyu Zhu et al., showed similar or better antimicrobial performance against multi drug resistant isolates of Pseudomonas aeruginosa and Acinetobacter baumannii [137]. In vitro and in vivo studies of minocycline, an old broad-spectrum semisynthetic tetracycline antibiotic, proved its activity against MDR Acinetobacter species [138]. Ciclopirox, an anti-fungal agent with a unique mode of action affecting bacterial metabolism, showed activity against multidrug-resistant pathogens [139].

Monotherapy is no longer a promising strategy to treat AMR infections. The development of newer drugs involves cost input as well as time. Adopting combination therapies provides options to circumvent the substantial investment required for the development of new drugs. Combination therapy enhances the potency of drugs with low dosages. However, it also poses serious challenges when compared to monotherapy. Drug-drug interactions leading to adverse reactions is a common problem with combination therapy. Synergistic action with improved drug efficacy to suppress pathogen resistance and simultaneous reduction of drug toxicity towards the host cells is a major requirement of combination therapy [140].

Classical HTS performs the rapid identification of effective compounds from a vast compound library. For instance, many antibiotic compounds that displayed greater than 90% inhibition against Trypanosoma cruzi and Methicillin resistant Staphylococcus aureus (MRSA) have been identified from ReFRAME libraries [148].

High-content assays like DNA Encoded Chemical Libraries (DECLs) and cell painting technologies make phenotype-based repositioning more valuable than other techniques. DECL allows ligand-protein selection at unprecedented levels. Cell painting, meanwhile, enables the detection and reading of high-resolution images while recording treatment-based morphological changes. High-throughput LC/MS, NMR, FIA-MS, and MALDI-FT-MS and related techniques assist in rapid filtration of hits with undesirable pharmacology and safety profiles and thereby support early ADME/toxicity prediction [149].

Computer-based screening quickens the evaluation process of repurposing compounds from large known compound libraries. For instance, structure-based docking modules (such as AutoDock and Glide) prioritize docking scores, free enthalpy, and stability by incorporating drug-likeness properties and molecular dynamics simulations. During recent SARS-CoV-2 HTS screening, only three promising leads were identified after docking two million ligand-protein associations by applying filters such as drug likeliness and molecular dynamics [150]. Repurposing strategies based on networking enables link prediction and graph-containing algorithms by creating networks among target-drug, disease-drug, or target-target associations. The Heterogene Graph Transfer Module (HGTDR) can assimilate various drugs, proteins, and disorders to estimate new interactions in end-to-end drug discovery cycles.

Overall, experimental HTS methods and cutting edge in silico methods (particularly molecular docking, Pharmacophore/QSAR approaches, Network mapping, and Machine learning) have aided the drug repositioning process by quickly evaluating large libraries, estimating therapeutically useful drug-protein interactions, and establishing mechanistic approaches. These hybrid explorations promise faster therapeutic innovations.

For virtual screening and QSAR modelling studies, supervised ML techniques like support vector Machines (SVM), logistic regression, and Random forest and neural-based networks are successfully utilized. These approaches identify drug-protein interaction or detect compounds with high potential for novel therapeutic effectiveness for repurposing. Deep learning architectures and graph relying methods such as convolutional neural networks (CNNs), recurrent networks (RNs), graph neural networks (GNs), and Generative adversarial networks (GANs) are known to generate Structure activity relationships (SAR), predict drug coordination, standardize molecular entity, and analyse data from different models. Prior trained GNNs and knowledge-based graphic models such as NETTAG and Deep MDS allow polypharmacology forecasting across genetic-drug networks [155]. XAI techniques clarify why a drug is advised for a specific disease, providing increased ability to achieve regulatory acceptance. Approaches like Drug Agent install multi-agent frameworks that correlate different language models, drug-protein binding predictors, and knowledge graph agents aid in the discovery of drug repurposing candidates.

By applying a deep learning approach to a library of 39,000 compounds, researchers identified the antibiotic halicin. Previously this drug was not related to antibiotics. The model prioritized the candidates based on their potential to inhibit drug-resistant bacteria: Lab screening displayed potential activity in vitro and in vivo in mice against resistant microbes like Acinetobacter baurmannii and C. difficile [156].

Analysing the phenomenon by which the small molecules identify and associate with the proteins is of high priority in drug development. SBDD involves the rational use of data derived from macromolecular targets [159]. The main aim is to get ligands with sufficient electronic and stearic properties to achieve good binding. The active site’s environment, including the presence of cleft, cavities, sub-pockets, and electrostatic properties, are thoroughly analysed. Present SBDD approaches involve the design of ligands possessing necessary features to regulate the target molecule. Selective regulation of the target protein with high binding ligands will lead to efficient therapeutic benefit [160].

SBDD is a sequential process of specific information intake (Figure 6), initiated from a known target structure, followed by identification of active/binding sites, virtual screening and molecular docking of candidate ligands, lead optimization through structure–activity relationships, and subsequent validation using computational and experimental approaches to develop potent and selective therapeutic agents. In silico docking is performed to detect potent small molecules. These molecular modelling techniques are followed by the synthesis of the most potent molecules. After that, the estimation of biological properties such as affinity, binding potency and efficacy are determined by employing various experimental protocols. Provided that highly active molecules are recognized, the three-dimensional structure of Ligand-target complex can be mapped. These structures enable the observations of various intermolecular interactions, supporting the process of molecule recognition. Structural descriptors of ligand-protein complexes assist in establishing binding conformations. Unknown active sites are characterised and ligand-induced conformational changes are explored [161].

ADME parameters can vary based on the route of drug intake, target tissue, and also patient group. For example, chloroquine and hydroxychloroquine were initially used as antiplasmodial drugs but were repurposed for COVID-19. However, they exhibited modified pharmacokinetic properties due to extreme tissue binding and long half lives causing cardiac toxicity in some patients [170]. Likewise, antineoplastic tyrosine kinase blockers such as imatinib and nilotinib were repurposed as powerful antivirals. These investigations proved that plasma tissue accumulation levels are acceptable for antiviral potential [171]. Pharmacokinetic challenges are also well established in a case study of remdesivir. Its deprived bioavailabilty demanded intravenous injection of its phospahate ester to attain adequate concentration at the viral replication site. On the other hand, sildenafil, initially introduced for angina, was repurposed for penile dysfunction and later for pulmonary arterial hpertension after kinetic assays uncovered optimal blood concentration and alveolar distribution at medium doses [172].

The reinvestigation of pharmacodynamics is to ensure that repositioned drugs provide the desired target at therapeutic doses without causing new adverse actions. Thalidomide could be the best example of this. After being withdrawn due to its teratogenic effects, it was reintroduced as a immunomodulatory drug for multiple myeloma after thorough investigation of its cytokine-regualting PD effects and dose-mediated toxicity [173]. An antidiabetic biguanide, Metformin, has been studied for cancer therapy and age-related disorders, where PD studies explored AMPK-linked antiproliferative activity, without any relation to its anti-diabetic mechanism. Similarly, non-steroidal AntiInflammatory Drugs (NSAIDs), reintroduced as antineoplastic drugs, need to be thoroughly monitored for their dose-activity relationships and cyclooxygenase inhibition patterns to balance therapeutic efficieny against cardiovascular and gastrointestinal toxicity.

Drug repurposing approaches mostly depend on PK/PD modelling and physiology-based pharmacokinetic (PBPK) simulations to assess human susceptability, improve dose administration, and optimize translational precision. These models can predict whether current doses can attain sufficient drug exposure at novel target sites or if formualtion and dosing alterations are required. Some of the examples for PK/PD models are presented in Table 12 [174–176].

Drug repurposing for AMR often relies on compounds that are off-patent or near expiry, which creates weak intellectual property protection and limited commercial exclusivity for developers. Unlike novel chemical entities, repurposed agents rarely qualify for strong composition-of-matter patents; instead, protection is typically restricted to new-use, formulation, or combination patents, which are narrower and more easily challenged. This weakens a company’s ability to secure returns on investment in costly Phase II–III clinical trials [267].

Extra complexity ascends from fragmented compulsory licensing rules, global patent laws, and varying data exclusivity periods, which together create uncertainty around market access and freedom-to-operate. In a few cases, the original patent holder may still retain control over proprietary clinical data or manufacturing rights, which can complicate collaboration and licensing. For non-antibiotic drugs used as host-directed therapies or adjuvants, the off-label prescribing can further erode incentives to obtain formal AMR indications. Harmonizing incentives for novelty with public-health obligations—particularly for life-saving antimicrobials—is a challenge. Without better-quality IP frameworks, such as transferable exclusiveness vouchers, public-sector investments and incentives, extended data exclusivity, or stewardship-based rewards, the development pipeline for repurposed AMR therapies may continue to lag behind clinical need [268].

The financial situation for AMR therapeutics is exceptionally constrained. Repurposed drugs often require considerable new investment for clinical authentication, pharmacokinetic studies, formulation optimization, and regulatory approval—yet the expected economic return is comparatively low. Stewardship policies that confine antimicrobial use (appropriately) limit sales volume potential even for successful products.

Outdated “sales-based” market models therefore fail to incentivize investment in AMR-focused repurposing, low-price legacy drugs, or generic drugs. Small and theoretical inventers struggle to attract venture capital, while large pharmaceutical companies regularly prioritize higher-return beneficial areas. Fragmented payer policies, recompense uncertainty, and limited accessibility of push-funding mechanisms add further risk. To overcome these barriers, advanced financing and incentive models are progressively supported. These comprise subscription-style expenditures (“Netflix models”), market entrance rewards, public–private partnerships, milestone-based grants, and not-for-profit development models. Positioning regulatory pathways with these incentives, while ensuring reasonable global access, will be critical to translating hopeful repurposed candidates into widely deployable AMR treatments [269].