The dark side of drug repurposing. From clinical trial challenges to antimicrobial resistance: analysis based on three major fields

Introduction

Drug repurposing, otherwise referred to as drug repositioning, is a tactical attempt encompassing the identification of novel therapeutic applications for already existing pharmaceuticals. It presents itself as a highly advantageous strategy due to its cost-effective nature and ability to save time in the drug discovery process, all while mitigating the risks of failure as opposed to customary approaches (1). Drug repurposing is an extremely advantageous technique in the field of pharmaceutical research because it capitalizes on the unintentional off-target effects of extant medications (2). This novel approach includes the use of pharmaceuticals that have previously been approved, drugs that have been declared ineffective in clinical trials, and drugs that have been removed from the market for a variety of reasons (3). By venturing into the realm of drug repurposing, researchers can unlock a vast reservoir of therapeutic potential that has hitherto remained untapped.

However, the question posed by several readers, researchers, and patients is as follows: “Have any drugs that have been repurposed actually received approval for their new indications?” At first, one may find oneself engaged in confident mental processes, but with an impassive countenance, while seeking to recall enough examples to confirm the current reaction. Still, a memorable case, such as thalidomide, will spring to mind (4). The drug, infamously recognized in its devastating original form as a sedative and curative for morning sickness, returned to the medical world for the treatment of leprosy and, subsequently, multiple myeloma (5). It is worth noting that the discovery of thalidomide’s efficacy in treating leprosy, specifically erythema nodosum leprosum, was a serendipitous occurrence (6). The story behind this accidental discovery is recounted in the book Dark Remedy. In this tale, a physician administered the only sedative available in the hospital’s pharmacy, which had not been previously attempted, to a suffering leprosy patient. Astonishingly, the drug had a dramatic and unexpected effect on the patient’s condition (7). This is a perfect example of repurposing a medicine that was authorized and then abandoned (and the method in which it was abandoned) to treat a completely other ailment (8). Another example of drug repurposing that is widely recognized is sildenafil, which is also commonly known as Viagra. Initially, this medication was prescribed for the treatment of arterial narrowness, hypertension, and heart disease in both humans and animals. However, it was fortuitously discovered that sildenafil has beneficial effects on erectile tissue dysfunction in male genital organs (9). Following its approval by the US Food and Drug Administration (FDA) in 1998, sildenafil has brought about a significant transformation in the management of erectile dysfunction (ED) and has contributed to a deeper comprehension of the underlying scientific principles behind ED and its impact on men’s overall well-being (10). In addition to its application in treating ED, sildenafil has also demonstrated efficacy in addressing pulmonary arterial hypertension (PAH) (11). Early investigations and clinical trials have explored the potential favorable impacts of sildenafil on various organs, including the heart, liver, kidney, brain, and intestines (12). Nevertheless, further research is necessary in order to fully comprehend the effects of sildenafil on different diseases and organs (13). Despite the numerous obstacles and unsuccessful attempts that we have elaborated on in the preceding sections, there have been instances of drug repurposing that have achieved success. Notable examples include the utilization of zidovudine (azidothymidine, AZT) as a therapeutic agent against human immunodeficiency virus (HIV) (14) and the repurposing of tocilizumab for the treatment of COVID-19 (15). The practice of repurposing drugs has demonstrated its effectiveness in the development of therapeutic strategies for various diseases and holds promise in addressing rare and difficult conditions (3). This approach entails a combination of experimental and computational methods, leveraging existing safety data and redirecting the application of drugs based on validated target molecules (16). The utilization of Application Programming Interfaces (APIs) in drug repurposing is increasingly being acknowledged as a promising technique for expediting the process of drug discovery and development (17). Integrative approaches that extract data from multiple sources through APIs offer the advantages of adaptability, reusability, and transparency (18). One particular study outlined a strategy for ligand-based in silico drug repurposing utilizing the analytical platform KNIME, which entailed targeted data retrieval, data curation, and substructure searches in DrugBank and other databases (19). Another study developed a fully automated and parameter-free virtual screening server called DrugRep, which conducted molecular structure construction, docking, similarity comparison, and binding affinity screening in a completely autonomous manner (20). These computational tools furnish researchers with user-friendly interfaces and interactive predictions, thereby enhancing the accessibility and efficiency of drug repurposing (21). Through the optimization of the therapeutic potential of already existing drugs, drug repurposing enhances the likelihood of attaining successful outcomes and offers a means to promptly identify effective treatments (22). Thinking deeply, we can conclude that the development of repurposed medications necessitates the application of creativity and innovation in designing the development program, as the body of evidence differs for each individual case not depending on the chance (23).

Several research studies have focused their attention on investigating and understanding the potential advantages and positive outcomes associated with the practice of drug repurposing. However, it is worth noting that, up until now, there has been a lack of comprehensive reviews that shed light on the potential drawbacks and negative aspects of drug repurposing. Therefore, the main aim of this particular review is to provide an in-depth analysis and exploration of the various challenges that arise when considering drug repurposing from a clinical perspective in the fields of cardiovascular disease, cancer, and diabetes. Additionally, the primary objective of this analysis is to underscore the heightened risk associated with the development of AMR that arises from the utilization of antibiotics for purposes other than their original intended use, whether it be for treating various infectious diseases or noninfectious conditions that deviate from their initial approved indications.

Drug repurposing challenges in clinical view

The process of drug repurposing has a number of drawbacks. One key barrier is the pharmaceutical industry’s restricted focus on diseases that provide more financial rewards, lowering the amount of repurposing chances for orphan diseases and neglected tropical disorders (24). Furthermore, there are legal concerns surrounding repurposed medications, including restricted patent coverage and obstacles encountered during the execution of clinical trials, both of which decrease the likelihood of success (25). It is imperative to address additional challenges that require attention, such as the generation of false-positive signals during data mining and the vulnerability of hypothesis validation to bias and confounding (26). Moreover, the absence of clear regulatory guidance poses yet another hindrance in the field of drug repurposing (27). Despite the inherent advantages of this technique, such as cheaper costs and faster time frames, it is crucial to recognize substantial failures found during clinical trials, when the repurposed medicine may fail to exhibit a good balance of benefits and risks (28). Consequently, a comprehensive analysis of these challenges and limitations must precede the pursuit of drug repurposing strategies.

Challenges in cardiovascular endeavor

The clinical perspective on drug repurposing has faced numerous challenges and trials that have not been successful. Despite the potential benefits of repurposing current drugs for unique applications, there are specific limitations that hinder success in this endeavor. These limitations encompass a lack of resources, difficulties with accessing data, and concerns regarding personnel, all of which can impede the process of drug profiling (29). Within the realm of cardiovascular disease, repurposing anti-inflammatory medicines has proven to be challenging due to unforeseen consequences and the necessity for prolonged therapy (30). In a study conducted by Ridker et al (31), it was found that the repurposing of the therapeutic agent canakinumab possesses the capacity to induce unfavorable outcomes, which encompasses the occurrence of neutropenia as well as an elevated susceptibility to mortality specifically attributed to infection or sepsis, as illustrated in Figure 1.

Another instance exemplified in Figure 1 arises when etanercept is employed as a repurposed therapeutic agent for the management of cardiovascular ailments. The clinical trials were terminated prematurely due to the conspicuous absence of any discernible benefit (32). In the same domain, another agent, colchicine, which had been repurposed, was subjected to different clinical trials as illustrated in Figure 2. These trials brought to light a noteworthy escalation in adverse gastrointestinal symptoms and an increased vulnerability to pneumonia (33,34). Moreover, it is important to note that there was no significant discrepancy observed in major adverse cardiovascular events (MACEs) between the group administered with colchicine and the group administered with a placebo (35). However, it is worth mentioning that the incidence of total mortality exhibited an augmentation in the colchicine group, primarily due to sepsis (35). Additionally, in a study conducted by Mewton et al (36), it was observed that there was no substantial reduction in the size of the infarct at the conclusion of a 5-day period (36). Within the same clinical trial, there was no significant decrease in MACE during the 3-month follow-up period. Furthermore, no disparity was discovered in the levels of inflammatory markers, including white blood cell count and C-reactive protein (CRP), within the initial 48 hours.

On the other hand, etanercept is a pharmaceutical agent employed for the purpose of managing and addressing autoimmune disorders, such as plaque psoriasis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis. It belongs to the class of biologic fusion proteins categorized as tumor necrosis factor (TNF) blockers (39). Although the approval of systemic etanercept for adults occurred in 2004, the FDA declined to approve its use in children with psoriasis in 2018 (40). However, the FDA later revised their risk-benefit assessment in light of a better understanding of the disease burden, the unmet medical needs, and the impact of off-label use in children with psoriasis. Consequently, in 2016, this led to the approval of etanercept as the first systemic biologic product for the treatment of moderate to severe psoriasis in children aged 4-17. Despite these findings, some researchers have attempted to repurpose this drug for the treatment of cardiovascular diseases. An example of such an attempt is seen in a clinical trial, depicted in the accompanying figure, which was terminated due to the absence of any significant advantages (32).

Another drug repurposed for cardiovascular diseases that faces challenges during clinical trials is methotrexate. As indicated by the study conducted by Moreira et al (48), methotrexate demonstrates no disparity in the duration of a 6-minute walk before and after treatment. It also exhibits no impact on the levels of CRP, nor does it affect the incidence of MACE when compared to a placebo. Moreover, the same author’s additional study (49) reveals that methotrexate has no effect on the release of creatine kinase during the initial 72 hours, no discrepancy in CRP levels, a significantly poorer left ventricular ejection fraction (LVEF) in the methotrexate group at 3 months, and no impact on the incidence of MACE. Conversely, in Ridker et al’s (50) study, the trial was terminated prematurely due to the absence of any benefits. No difference was observed in the incidence of MACE or in the levels of inflammatory markers (white blood cell count, CRP, interleukin-1β, interleukin-6) at 8 months. However, an increased occurrence of leukopenia and non-basal cell skin cancer was noted.

The final example in the realm of cardiovascular medicine is the drug known as cyclosporine. Since its introduction into clinical practice in the late 1970s (51), the discovery and utilization of cyclosporine has had a significant impact on the advancement of transplant medicine (52,53). While it has shown improvements in the rates of acute rejection and early graft survival, the evidence regarding long-term survival of renal allografts is less convincing (54). The identification of acute reversible nephrotoxicity and nephrotoxicity in nonrenal transplants has subsequently led to the widely accepted notion that there is also a chronic and more irreversible component to this drug (55). Consequently, there has been a strong interest in developing protocols that aim to minimize or even eliminate the use of calcineurin inhibitors altogether (56). Despite these considerations, cyclosporine has been repurposed for various other diseases, including cardiovascular diseases (57,58). In two separate trials involving patients with ST-segment elevation myocardial infarction (STEMI), cyclosporine failed to demonstrate any beneficial effects on ST-segment resolution, left ventricular remodeling, or the incidence of cardiovascular events during the respective trial periods of 6 months and 1 year (57,58). Moreover, the use of cyclosporine in cardiovascular medicine has been associated with certain side effects such as hypertension, hyperlipidemia, and diabetes mellitus (59). These side effects may contribute to the high cardiovascular morbidity in renal transplant patients and the development of chronic transplant nephropathy (60). In conclusion, while cyclosporine has revolutionized transplant medicine, its use in cardiovascular medicine comes with potential side effects that must be carefully monitored and managed to ensure patient safety and optimal outcomes (61).

Challenges in cancer endeavor

In the field of hematological malignancies, despite the introduction of drug repurposing, which presents new possibilities for innovative treatments, achieving complete remission remains an arduous task (62). Clinical trials that explore the repurposing of drugs in oncology have exhibited varying levels of success, with certain limitations such as limited sample sizes and participant heterogeneity (63). An illustration of repurposing challenges in multiple clinical trials has come to light. One such instance involves the repurposing of bortezomib to target hematological malignancies. However, this drug proved to be ineffective as a stand-alone treatment for other malignancies, including acute myelogenous leukemia (AML) (62). Another example that showcases the act of appropriating preexisting resources for alternative purposes pertains to the potential drawbacks that arise when repurposing the chemical compound valproic acid (VPA) for various medical applications. These disadvantages, such as its lack of improvement in clinical outcomes for patients with myelodysplastic syndrome (MDS) or elderly patients with AML in a randomized phase II study of low-dose decitabine with VPA, have been observed (64). Additionally, another study found that VPA did not have an impact on the objective response rate or overall survival (65). Furthermore, a randomized phase III study examining the safety and efficacy of combining VPA and all-trans retinoic acid (ATRA) with induction therapy (idarubicin and cytarabine) for the treatment of elderly AML patients was terminated prematurely due to the absence of clinical improvement in the VPA group compared to standard treatment (66). This lack of improvement was further compounded by hematologic toxicity and higher mortality rates associated with VPA (67). All of these clinical studies shed light on the limitations and challenges inherent in using VPA in contexts other than its original intention. However, there is promising potential for computational drug repurposing to forecast the effectiveness of repurposed medications in phase III clinical trials, thereby streamlining the process (68).

Challenges in diabetes endeavor

Drug repurposing trials in the field of diabetes have encountered numerous hurdles and instances of failure. A particular study examined the inability of prominent pharmaceutical companies to develop novel treatments for type 2 diabetes (T2D) despite significant investments in traditional drug development pipelines (69). Another scholarly article highlighted the challenges faced by potentially effective medications during the advanced stages of clinical trials for diabetes management (70). Researchers in the same field are presently attempting to repurpose antidiabetic medications with the aim of addressing dementia, characterized by the prevalence of insulin sensitizers and insulin substrates. Despite the initial appearance of promise and the potential for success, none of the clinical trials conducted thus far have achieved the desired outcome of mitigating the cognitive deterioration associated with late-onset dementia (71).

In recent years, there has been a significant focus on the repurposing of antidiabetic drugs for the purpose of weight control, alongside the use of other medications. The use of antidiabetic drugs, such as metformin, glyburide, and SGLT-2 inhibitors, has shown promising results in terms of promoting weight loss, which has garnered considerable attention (72). Additionally, disulfiram, a medication commonly prescribed for chronic alcoholism, has demonstrated a significant capability to counteract obesity in rats (73). Although the specific mechanisms by which these drugs facilitate weight loss are still being investigated, their potential as treatments for obesity should not be underestimated. It is important to note that despite the positive effects of these repurposed drugs for obesity, there is also a focus on the repurposing of antidiabetic drugs such as semaglutide and tirzepatide, which were initially developed to address the challenges associated with T2D (74). These drugs can be traced back to a peptide that was discovered in the venom of the Gila monster and have the ability to mimic the actions of a naturally occurring hormone that is released after food consumption. As a result, they have shown promising results in terms of inducing weight loss. However, it is essential to acknowledge that these drugs do come with their fair share of adverse effects, particularly in the gastrointestinal realm. Potential side effects such as nausea, vomiting, diarrhea, and constipation have been reported with their use. Therefore, it is crucial to strike a careful balance between the beneficial effects and the potential adverse effects when considering the use of these drugs for the treatment of obesity.

Potential risk of repurposed antibiotics

One of the foremost concerns that need careful study is the repurposing of antibiotics for noninfectious disorders, some antibiotics of which are listed in Table 1. In this context, it is crucial to assess both the efficacy of these repurposed drugs and their potential to exacerbate the problem of multidrug resistance (75). In a study conducted by Wang et al (76), it was shown that some non-antibiotic medications, when present at levels that are both clinically and ecologically relevant, had a notable impact on the dissemination of antibiotic resistance. This effect was shown through the absorption of exogenous antibiotic resistance genes (ARGs) (77,78), due to the fact that the administration of non-antibiotic substances has the potential to increase the likelihood of the development of multidrug resistance at the clinical level (79). It is plausible to suggest that the utilization of repurposed drugs could exacerbate this issue even further. Therefore, the present work strives to clarify this threat in the subsequent section. The phenomenon of antibiotic resistance has been steadily increasing over the past few decades, with no new categories of antibiotics or viable alternatives receiving clinical approval within the last three decades (75,80).

There is an ongoing endeavor to discover novel drugs or alternative approaches to combat bacterial infections, but unfortunately, the rate at which bacterial resistance develops surpasses the pace of these endeavors (81).

While the notion of repurposing drugs may appear rational and a scientific approach to addressing previously incurable ailments such as Alzheimer’s, cancer, and Parkinson’s, the repurposing of antibiotic medications has generated concerns regarding their use in treating such diseases, particularly in light of the widespread prevalence of AMR that has wreaked havoc in our contemporary era. AMR is well-known for its devastating impact, with over 700,000 deaths occurring globally as a result, and projections indicating that this number could escalate to approximately 10 million people worldwide by the year 2050 (95). A number of research studies have delved into the utilization of antibiotics for the treatment of conditions other than bacterial infections, attempting to repurpose these medications (96-98). However, these studies have failed to adequately acknowledge the grave peril associated with employing antibiotics for repurposing, namely the progression of AMR (as depicted in Fig. 1).

The antibiotic levofloxacin has recently been proposed as a potential repurposed medication for Alzheimer’s disease (AD) (98). However, several other studies examining the effects of this antibiotic on Alzheimer’s patients have been disregarded. One of these studies involves a case report that observed an increase in seizures in an AD patient who was administered a dose of 500 mg/day of levofloxacin (99). Additionally, research on the gut microbiome of Alzheimer’s patients has indicated that Helicobacter pylori infection may serve as a trigger for the release of inflammatory mediators in AD patients (104). It is worth noting that H. pylori is known for its resistance to levofloxacin (Tab. 1) (105). The primary concern with repurposed antibiotics lies in their dosage, duration of use, and their impact on AMR. Antibiotics are typically administered at doses significantly higher than non-antibiotic drugs (27). In fact, a concentration of 400 mg of minocycline was found to be ineffective in delaying the progression of cognitive or functional impairment in patients with mild AD over a 2-year period (106). Despite their potential as candidates in laboratory settings, the efficacy of these antibiotics in vivo is not guaranteed. Moreover, long-term exposure to antibiotics, whether at clinical or sub-stoichiometric doses, can lead to the development of drug resistance among gut microbes. Chronic administration of these antibiotics is necessary for the treatment or management of AD. Consequently, the chronic use of antibiotics at clinical doses may result in antibiotic resistance, making it challenging to treat common infections. Furthermore, prolonged antibiotic use may increase a patient’s susceptibility to infections. If any antibiotics demonstrate potential as anti-Alzheimer’s agents in either laboratory or clinical studies, it is imperative to assess their long-term consequences.

There has been a lack of comprehensive research aimed at comprehending the prolonged implications of utilizing repurposed antibiotics to enhance AMR. However, existing data have demonstrated a direct correlation between the consumption of antibiotics and the emergence of AMR (107). Consequently, an escalation of multidrug resistance may occur as the consumption of these repurposed antibiotics increases. For example, doxycycline is an antibiotic that has been repurposed for the treatment of malaria (Tab. 1). While there is no documented evidence of increased AMR due to the use of doxycycline for malaria prophylaxis, reports have indicated the development of doxycycline resistance and coresistance to other antibiotics when used to treat other diseases. A study revealed that doxycycline-induced stress led to the emergence of coresistance to colistin, which is considered a last-resort antibiotic for extensively drug-resistant bacteria (108). This study shed light on a potential mechanism of doxycycline-selected resistance and coresistance in Vibrio cholerae, emphasizing the need for stringent regulations regarding the indiscriminate use of antibiotics. Another aspect to consider is the unrestricted sale of these antibiotics without prescription, particularly in developing countries such as India, which is one of the largest consumers of antibiotics (109). Consequently, the controlled usage of these repurposed antibiotics may be compromised. Prolonged use of repurposed antibiotics could exert selective pressure, resulting in the survival of multidrug-resistant and extremely drug-resistant bacteria. In the absence of a competitive environment, these drug-resistant strains may thrive more successfully, leading to the elimination of phenotypically sensitive strains, as illustrated in Figure 3 (110).

During the COVID-19 pandemic, health professionals turned to the administration of azithromycin alone or in combination with drugs like hydroxychloroquine. This repurposing of an antibiotic without any evidence of its antiviral properties became a highly controversial practice. However, its utilization continued to increase with the successive waves of COVID-19. The future implications of such unregulated and unscientific use of antibiotics remain uncertain. The consequences of this practice on AMR will further exacerbate the situation (111). In addition to the repurposing of azithromycin in the context of the COVID-19 pandemic, numerous studies have revealed its antimalarial properties. The eradication of Plasmodium falciparum parasites is accomplished through two distinct mechanisms: delayed death by means of inhibiting the apicoplast ribosomes and rapid elimination throughout the blood stage development (112). A trial carried out in Burkina Faso discovered that a solitary oral dose of azithromycin did not result in a reduction in malaria positivity; however, it did alleviate caregiver-reported fever as an adverse event (113). Furthermore, an additional study determined that the supplementation of azithromycin to seasonal malaria chemoprevention did not yield improved nutritional outcomes among children (114). Furthermore, novel derivatives of azithromycin that exhibit swift action have been developed, manifesting exceptional antimalarial activity in both in vitro and in vivo settings, while employing a distinct mode of action compared to the more gradual acting azithromycin (115). Although azithromycin has indeed exhibited potential as an antimalarial agent, further investigation is necessary to optimize its efficacy and comprehend its mechanisms of action. Considering the positive correlation between extensive antibiotic usage and the worsening of the antibiotic resistance crisis in the present era, it is imperative to enhance AMR stewardship at an international level in order to mitigate the impact of antibiotic use on the menace of antibiotic resistance. Particular emphasis should be placed on comprehending the ramifications of antibiotic repurposing.

There is a profound necessity to explore alternatives to antibiotics in the context of repurposing, especially those that have already demonstrated resistance. The successful repurposing of non-antibiotic drugs for cancer treatment has been documented (116,117) and a similar approach can be adopted for other diseases as well. While the repurposed antibiotics may circumvent clinical trials, the absence of substantial studies addressing the grave issue of AMR may prove to be catastrophic for the already advancing AMR against most antibiotics. The role of AMR in exacerbating challenges in the management of nosocomial infections and the resulting mortality due to multidrug resistance should not be underestimated, particularly in an era where the efficacy of most antibiotics is waning and treatment regimens rely on last-resort antibiotics (118). It is imperative to find a solution that does not further burden the existing load of AMR. Therefore, we propose that clinicians and researchers raise awareness about the rampant problem of AMR and its consequences, while discouraging the use of antibiotics in drug repurposing.

After considering the knowledge mentioned above, one could potentially inquire whether the practice of repurposing antibiotics to address noninfectious ailments could potentially elevate the likelihood of AMR. Furthermore, one may also wonder about the implications of reusing antibiotics that were originally approved for the treatment of one specific infection in the context of treating a different infection.

In previous times, newer antibiotics were consistently being surpassed by more recent ones, which were devised to circumvent the most recent resistance mechanism discovered in clinical isolates. Nevertheless, numerous companies have abandoned initiatives aimed at developing novel anti-infectives due to the time and expense associated with clinical trials. The insufficient availability of new drugs has provided a compelling impetus to repurpose older antibiotics for treating multidrug-resistant strains or to combine them with agents capable of targeting multiple distinct pathways within the pathogen or activating the resistance pathways of host cells. This approach is anticipated to result in heightened effectiveness and reduce the likelihood of resistance emergence (119).

Reverting to previous antibiotics can, under certain circumstances, overcome antibiotic resistance. For instance, strains of tuberculosis that are resistant to the drug combinations currently in use can be found in all regions of the world. One effective tuberculosis medication, known as isoniazid, hinders the enzyme InhA, thereby obstructing the synthesis of the mycolic acids that constitute the cell wall of the mycobacterium. The resistance to isoniazid, which is a prodrug, largely arises from mutations in the bacterial enzymes that are necessary for its activation. Recently, it has been discovered that an older antibiotic derived from natural sources, called pyridomycin and first identified in the 1950s, directly inhibits InhA. Consequently, it can be employed to treat infections caused by drug-resistant strains of tuberculosis that survive due to their inability to activate isoniazid (120). The comprehension of this mechanism of action may also promote the utilization of pyridomycin in conjunction with other medications (121). However, there are several difficulties in repurposing drugs for infectious diseases, and the subsequent sections will outline some of the primary challenges that arise in this domain.

The complexity of microorganisms and the limited understanding of the complicated interactions between pathogens and their hosts

Identifying appropriate therapeutic targets for anti-infective medications is a challenging endeavor due to the complex nature of infection processes and the intricate interplay between hosts and pathogens (122). Pathogens, encompassing viruses, bacteria, protozoa, and nematodes, acquire significant genetic diversity through mutation and recombination, resulting in the emergence of drug-resistant mutants (123). Consequently, the development of drugs that can effectively target all viral variations becomes arduous. Hence, it is imperative to consistently exert efforts to stay ahead of evolving resistance mechanisms (124). Furthermore, certain infections, including Neisseria spp. or Plasmodium spp., possess the capability to undergo antigenic variation, wherein they modify the surface proteins on their cells to evade detection and attack by the host organism’s immune system. This ongoing process of adaptation poses challenges in identifying consistent therapeutic targets and potential candidates for vaccination (125). Additionally, several pathogens like Trypanosoma cruzi, Mycobacterium tuberculosis, and herpes viruses can establish latent or chronic infections, wherein they remain inactive within host cells and successfully evade immune detection (126,127). Effectively managing such infections requires medications that can specifically target the pathogen during both its active and latent stages. Moreover, certain bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus can form biofilms, which augment their resistance to drugs and impede drug accessibility, thereby making the eradication of infections more formidable (75,128).

Lack of efficient animal models

Developing animal models that accurately replicate human infections is essential for preclinical testing. However, creating suitable models for specific infectious diseases can pose challenges due to the intricate interactions between hosts and pathogens that are difficult to accurately simulate (129). The absence of appropriate predictive models can hinder the progress of drug development, as it becomes arduous to comprehend the disease mechanisms and evaluate the effectiveness of potential medications (130). An example is the complexity involved in modeling diseases like COVID-19 that necessitates the consideration of various factors such as stochasticity, evolving transmission dynamics, and spatial configurations (131).

A significant advancement in the field of antimalarial drug research and development was the establishment of a NOD-SCID mouse model for P. falciparum infection, which proved valuable for testing drug efficacy (132). Moreover, the utilization of organoid cultures derived from stem cells holds significant promise in providing valuable insights into infectious diseases by effectively mimicking in vivo disease characteristics and enhancing the comprehension of host-microbe interactions (133,134). In addition, the integration of sophisticated mathematical models such as the SEIR model, incorporating multiple variables, can greatly assist in forecasting disease dissemination, particularly for infections characterized by prolonged incubation periods and asymptomatic carriers (135). The optimization of the modeling process through the formulation of well-defined research questions, implementation of quality assurance measures, and meticulous reporting practices can substantially elevate the relevance and comprehensibility of findings, thereby playing a pivotal role in improving decision-making processes related to disease management (136).

On the other hand, epidemiological models, such as agent-based simulation models and compartmental models, play a crucial role in understanding disease spread dynamics and evaluating intervention strategies (137-139). These models often involve making assumptions that may limit their scope, such as focusing on single-strain and single-vector scenarios, simplistic human behavior modeling, and ignoring data quality evaluation (140). To improve the reliability of these models, it is essential to consider factors like information quality, human behavior, multi-vector, and multi-strain scenarios, as they significantly impact the model outcomes without significantly increasing computational costs (141). Collaborative efforts between researchers and modelers are crucial to enhancing the accuracy of predictions and optimizing models for effective public health decision-making and for repurposing antibiotics.

Elevated likelihood of clinical failure

Clinical trials for anti-infective medications frequently encounter significant attrition rates as a result of inadequate effectiveness, apprehensions regarding safety, or difficulties in the recruitment of patients (142). Additionally, the execution of clinical trials and the subsequent monitoring in resource-constrained environments, along with the absence of suitable surrogate endpoints for infectious diseases, collectively contribute to the elevated levels of unsuccessful outcomes (143).

In conclusion, while there is potential in repurposing drugs to overcome antibiotic resistance in infectious diseases, several difficulties arise in this domain. The complexity of microorganisms and the intricate interactions between pathogens and their hosts pose challenges in identifying suitable therapeutic targets. Pathogens’ ability to evolve, undergo antigenic variation, establish latent or chronic infections, and form biofilms further complicate the development of effective medications. Addressing these challenges will require continued research and collaboration to develop novel strategies and therapies to combat drug-resistant infections.

Conclusion

Drug repurposing is a strategic initiative that involves the exploration and identification of fresh therapeutic applications for pharmaceuticals that already exist in the market. This approach has proven to be beneficial due to its cost-effectiveness and ability to save time in the drug discovery process. However, it is important to consider various factors before fully embracing this strategy. One such factor is the fact that numerous repurposed drugs have failed to achieve their intended targets during clinical trials, leading to concerns about the effectiveness of this approach. Additionally, there is a growing apprehension about the potential increase in the risk of multidrug resistance, which further emphasizes the need for caution when repurposing drugs.

The development of repurposed medications requires a high level of creativity and innovation in designing the development program. This is because each case presents a unique set of circumstances and evidence that must be thoroughly evaluated. Therefore, it is crucial to approach each drug repurposing project with a comprehensive understanding of the ethical and pharmaceutical considerations involved. Furthermore, it is imperative that repurposed drugs undergo rigorous clinical trials before they can be approved for use. This ensures that the safety and efficacy of these drugs are thoroughly evaluated, and any potential risks and side effects are identified and mitigated. In conclusion, the process of selecting a repurposed drug should be guided by a range of ethical and pharmaceutical considerations. It is important to acknowledge the limitations and challenges associated with drug repurposing, such as the potential failure to reach therapeutic targets and the risk of multidrug resistance. By prioritizing the application of creativity and innovation in the development program, as well as ensuring the completion of rigorous clinical trials, we can maximize the potential benefits of repurposed drugs while minimizing the associated risks.

Disclosures

Conflicts of interest: The authors declare no conflict of interest.

Funding: This research received no external funding.

Data availability statement: The data presented in this study are available on request from the corresponding author.

Author contributions: Conceptualization, I.Y.N. and M.M.A.; software, D.K.A. and M.M.D.; validation, I.Y.N. and A.K.A.; formal analysis, D.K.A. and M.M.A.; investigation, A.K.A. and M.M.D.; resources, I.Y.N., M.M.D., MJ.A.S., and A.K.A.; data curation, D.K.A. and M.M.A.; writing—original draft preparation, M.M.A. and I.Y.N.; writing—review and editing, M.M.A., MJ.A.S., and D.K.A.; visualization, I.Y.N., MJ.A.S., and A.K.A.; supervision, M.M.A. and I.Y.N.; project administration, I.Y.N. All authors have read and agreed to the published version of the manuscript.