Abstract
With the emergence of post-antibiotic era, antivirulence therapy against Pseudomonas aeruginosa was conceived as a rational escape from the global antimicrobial resistance crisis. Built on the foundation of virulence attenuation/disarmament rather than pathogen elimination, antivirulence therapy has not achieved any tangible clinical translation. This misfortune shows a reproducible pattern rooted in a series of compounding conceptual limitations. This perspective argues that the translational challenges of antivirulence strategies reflect not pharmacological inadequacy, but a fundamental misalignment between therapeutic design and infection biology. We dissect four structurally-interconnected explanations driving this impasse. First, antivirulence agents have been evaluated using defined endpoints that are engineered for bactericidal drugs, rendering precision disarmament strategies invisible by design. Second, P. aeruginosa itself outsmarts and resists single-node perturbations of virulence pathways not through conventional resistance mechanisms but by deploying intricately connected networks that rewire bacterial virulence in response to therapeutic pressure. Thirdly, the aspiration for broad-spectrum antivirulence therapy negates that pseudomonal virulence is neither fixed nor universal, but a shifting, niche-sculpted, and strain-variable phenomenon that defies a universal target. Finally, antivirulence therapies rely heavily on host immunity-mediated bacterial clearance, which is grossly eroded/compromised in patients infected with P. aeruginosa. We argue that clinical translation of antivirulence therapy requires abandoning the reductionist, target-centric paradigm and adopting a state-control framework that treats pseudomonal infections as dynamic, multifactorial, and coupled host-pathogen interactions. This strategic shift, from targeting molecules to redirecting biological trajectories, can potentially reposition antivirulence agents as precision tools for destabilising pathological states and combating P. aeruginosa infections.
1 The translational paradox: a crisis of biological philosophy
Antivirulence therapy against Pseudomonas aeruginosa was proposed as a rational alternative to conventional antibiotics, offering a viable alternative to antimicrobial regimens (). However, despite substantial bench-based experimentation and preclinical trials, its translation into successful clinical interventions has remained limited. Decades of rigorous biological experimentation have delivered virtually no tangible clinical impact. Across vaccines, monoclonal antibodies, small-molecule inhibitors, phytochemicals, and repurposed FDA-approved drugs, candidates that attenuate bacterial virulence in vitro and in animal models have repeatedly failed to improve outcomes in human trials (; ). Rather than representing isolated setbacks, multiple antivirulence strategies targeted against P. aeruginosa have encountered similar translational challenges, highlighting recurring barriers to successful clinical development (). In an era where antibiotic discovery is stagnating, particularly against Gram-negative pathogens, antivirulence strategies were anticipated to serve as a viable counterweight to antimicrobial resistance (). Instead, they have demonstrated high rates of developmental collapse and limited momentum towards clinical adoption (; ). The standard explanations for translational insufficiency include lack of specific/defined targets, limited field trials, and patient heterogeneity. Importantly, the limited clinical translation of antivirulence therapies should not be interpreted as definitive evidence of biological constraints, but rather as a reflection of the currently available clinical data relative to conventional antibiotics. For these reasons, a significant gap exists between bench-based research and clinical outcomes that needs to be bridged to advance the scope of antivirulence therapies against P. aeruginosa.
Evidence from both regulatory review and clinical experience highlights a significant disconnect. Mere display of biological activity against P. aeruginosa does not necessarily translate into clinical efficacy. Reductions in bacterial load and inhibition of key virulence pathways have repeatedly failed to improve patient survival or yield meaningful outcomes during disease progression (). Patients can meet microbiological endpoints but still deteriorate due to weakened immunological status. This is not merely a problem of measurement, but it suggests a broader conceptual challenge as to how therapeutic efficacy is defined. The antivirulence field has relied on a framework built for bactericidal drugs to evaluate agents that work via a ‘disarm-don’t kill’ approach (). In parallel, advances in systems biology have dismantled the underlying assumption that virulence is accessory/auxiliary and targetable in isolation. In P. aeruginosa, pathogenicity arises from a densely interconnected, hierarchical regulatory architecture that encompasses hundreds of transcription factors and overlapping signalling circuits (; ). These networks are not fragile and are designed for promoting bacterial resilience, i.e., perturbation of a single node triggers compensatory rewiring rather than collapse. Targets that appear well defined in vitro are embedded within a flexible regulatory system in vivo that reorganises in response to stress. The translational gap is amplified by standard laboratory models, which fail to capture the spatial, metabolic and immunological constraints of human infection, generating a virulence landscape that is experimentally convenient but biologically misleading (). The consequence is a persistent preclinical-clinical disjunction that cannot be explained by randomness or execution alone. To date, antivirulence strategies have developed within a reductionist assumption that pathogenicity consists of discrete functions that can be independently silenced. In reality, pseudomonal virulence is not a fixed trait, but a context-dependent, versatile, communal behaviour arising from intricately coupled dynamics of host-pathogen interactions. The limited translation of antivirulence therapeutics reflects a fundamental biological misalignment between therapeutic design and infection biology. Meaningful progress will require moving beyond single-target hits and adopting a more comprehensive network-based, host-specific framework that positions antivirulence agents as ‘next-generation precision tools’ for disrupting defined pathogenic states, attenuating bacterial virulence, and ultimately showing promise with respect to biomedical applications. Therefore, this article presents a distinct perspective towards antivirulence therapies, providing insights into conceptual, biological, and translational factors that have constrained their clinical success against P. aeruginosa. We also aim to push for a paradigm shift from reductionist, target-centric approaches towards more context-aware, systems-level intervention strategies to reposition antivirulence therapies against pseudomonal infections.
2 Beyond the endpoint: why traditional metrics mask therapeutic value
The limited clinical translation of antivirulence therapies is often attributed to pharmacological weakness. However, this conclusion may reflect a deeper conceptual issue regarding how therapeutic success is defined and measured. The core issue lies in how we measure success. Researchers have been applying a framework designed for bactericidal drugs to fundamentally different therapeutic principles. For decades, clinical success has been anchored to reductions in colony-forming units (CFU), a metric engineered for drugs that kill bacterial pathogens. However, antivirulence agents do not eliminate bacteria, and instead, they alter the dynamics of pathogenicity and infection. Nonetheless, experimental perspectives have been grossly flawed, as they largely focus on assessing the antibacterial efficacy (infection clearance) of antivirulence drugs. Therefore, the current system of evaluating such antivirulence interventions is rendered invisible by design (). CFU reduction remains a necessary baseline; it is an inadequate endpoint for non-bactericidal strategies. It captures bacterial presence and not the pathogenic consequence. Antivirulence approaches act precisely within this gap by separating bacterial burden from host damage. These implications are not merely theoretical but have far-reaching consequences. For instance, the quinazolinone, QZN-34, has been shown to disrupt biofilm architecture and collapse extracellular DNA networks without suppressing planktonic growth (). Anti-PcrV monoclonal antibodies similarly prevented lethal outcomes (septicaemia) and dampened inflammatory cascades in vivo while leaving bacterial counts largely unchanged (). On a realistic cum mechanistic perspective, these studies depict precise disarmament of pathogenic/virulence traits resulting in improved pre-clinical outcome against pseudomonal infections. However, under current evaluative standards, these outcomes do not present clinical potential. Therefore, the shortcoming is not in therapeutic performance but in the choice of outcome.
This misalignment becomes more consequential when considered alongside clinical variability, revealing an additional constraint best described as an effect-size problem. Even when antivirulence agents exert meaningful biological effects, their signals are inherently modest and easily obscured by systemic noise. Within clinical settings characterised by elevated mortality, including ventilator-associated pneumonia, pseudomonal infection itself accounts for only a minority of deaths. The attributable mortality ranges from 3-10%, whereas most fatalities are driven by underlying co-morbidities (). Within such a diluted signal environment, expecting antivirulence interventions to shift all-cause mortality is unrealistic. This challenge has recently been illustrated in phase II clinical trials that deployed the anti-pseudomonal antibody gremubamab (MEDI3902, a bispecific human monoclonal antibody against the PcrV protein) to prevent pneumonia in mechanically ventilated intensive care unit patients (, ). In the EVADE trial with MEDI3902, the primary efficacy endpoint was not met in the overall study population, and intravenous administration did not reduce the incidence of nosocomial pneumonia in subjects. Moreover, the authors suggested that treatment responses to pseudomonal infection were influenced by baseline inflammatory status, highlighting the importance of patient stratification and appropriate efficacy assessment. This reflects a conceptual gap and fundamental inconsistency. The issue is not the absence of effect, but insufficient effect size relative to background noise. This tension creates a structural paradox, i.e., therapies optimised for precision are evaluated using endpoints optimised for magnitude, and the consequences are predictable. Promising antivirulence strategies are therefore systematically excluded from clinical advancement, not because they lack biological efficacy, but because they are evaluated within a framework ill-suited to detect their therapeutic impact. Unless clinical success is redefined to capture functional virulence attenuation rather than microbial eradication alone, scientists may overlook some of its most strategically valuable therapeutic interventions.
3 The redundancy wall: virulence as a robust network
The limited clinical translation of antivirulence therapy may, in fact, reflect a conceptual limitation. P. aeruginosa is still interpreted as a collection of separable virulence determinants that can be individually silenced. In reality, pseudomonal virulence is an emergent property of a distributed regulatory network engineered for improving bacterial fitness and resilience. The decisive feature is not any individual toxin or regulator, but capacity of the bacterial system to compensate, reroute signalling, and preserve pathogenic function under stress. This robustness constitutes the Redundancy Wall and exposes the central limitation that drives much of the field, i.e., the single-target fallacy.
Clinical isolates repeatedly demonstrate that disabling canonical “master regulators” does not reliably collapse virulence. LasR, long treated as a key quorum sensing (QS) regulator, is often inactivated in patient strains without abolishing pathogenic behaviour. Instead, compensatory evolution restores quorum output through alternative wiring. reported that single-nucleotide polymorphisms in rhlI can recalibrate signalling and bypass dependence on LasR, thereby preserving virulence phenotypes in P. aeruginosa. Environmental triggers can further accelerate this bypass logic. Under phosphate limitation, PhoB-mediated rewiring sustains quorum-controlled outputs through sRNA-dependent derepression (). In this architecture, the network adapts dynamically in response to disruption rather than collapsing. More concerningly, perturbing QS can shift the system into a different, sometimes more damaging, configuration. Disruption of QS can also produce regulatory inversions, in which repression of the Type III secretion system (T3SS) is lifted, promoting more acute, aggressive, and cytotoxic phenotypes (). At the population level, quorum quenching interventions can also reshape ecological competition, selectively favouring strains that retain virulence advantages under therapeutic pressure (). The implication is uncomfortable but unavoidable. Therefore, single-node antivirulence not only risks therapeutic inefficacy but also drives the system towards alternative pathogenic equilibria.
This robustness is amplified by extensive strain-level diversity. Regulatory circuits, including sRNA-mediated interaction networks, vary substantially across lineages, and key interactions are absent in large fractions of clinical isolates (; ). Even conserved regulators exhibit divergence in network connectivity and binding architecture, undermining the existence of a universal regulatory choke point suitable for therapeutic targeting (). Clinically, las-independent lineages can sustain infection through alternative signalling architectures (). Collectively, these findings suggest that the repeated collapse of single-target antivirulence approaches is not primarily a pharmacological constraint. It is a predictable consequence of targeting a pathogen whose virulence logic is distributed, redundant, and evolutionarily flexible.
4 Why is broad-spectrum antivirulence a myth?
Attempts to establish broad-spectrum antivirulence therapies rest on the assumption that virulence is a stable, conserved, and universally targetable feature. However, pathogenesis in P. aeruginosa is a transient system that is continually reshaped by stage of infection, host physiology, and lineage-specific regulatory architecture (). Under these conditions, the promise of a universally effective antivirulence agent reflects less a translational challenge than a misunderstanding of the context-dependent nature of virulence.
The principal constraint is also inherently time-dependent. Virulence determinants such as T3SS and siderophores are preferentially deployed during acute infection and are subsequently downregulated as populations transition to biofilm-dominated persistence (). Longitudinal clinical observations indicate that P. aeruginosa rapidly shifts towards chronic phenotypes, which indicates that targets identified in acute laboratory models may no longer be functionally central at the time of therapeutic intervention (; ). The second constraint is spatial. Distinct anatomical niches impose divergent selective pressures that reshape regulatory networks. The adaptive landscape of a cystic fibrosis lung differs fundamentally from that of a chronic wound or bloodstream infection. These environments drive independent evolutionary trajectories in central regulators such as lasR and fleQ, producing niche-specific network configurations in P. aeruginosa (). A target that is functionally central in one tissue may be peripheral or entirely bypassed in another tissue. Host microenvironments further tighten this constraint by making drug activity conditional rather than intrinsic. Some antivirulence phenotypes emerge only under specific host stresses, such as nitric oxide exposure or hypoxia-linked regulation, and may remain silent under standard laboratory conditions (; ). The implication is direct. A single antivirulence agent cannot plausibly remain uniformly relevant across the shifting temporal and spatial landscape of pseudomonal infection. The third constraint is lineage variability. As mentioned in previous sections, P. aeruginosa operates through strain-specific interactomes in which key regulatory circuits are variably distributed across strains (; ). In practical terms, this suggests that a target validated in one strain may be absent, rewired, or functionally irrelevant in another. No single regulatory node can therefore sustain universal therapeutic relevance across patient populations.
Insights from structural biology reinforce this fragmentation. The transition from planktonic growth to biofilm formation is not merely a phenotypic shift but a hierarchical reconfiguration of both accessibility and regulatory function (). Bacterial targets for antivirulence agents that are readily accessible in planktonic cells become physically shielded by the EPS matrix or are bypassed within redundant regulatory networks (). Diffusion barriers, metabolic gradients, and localised microenvironments further create heterogeneous zones, in which drug penetration and activity differ remarkably from standard in vitro conditions (; ). These constraints suggest that broad-spectrum antivirulence strategies are not failing because the field is yet to identify the appropriate target. Rather, it is failing because the bacterial target does not exist in a stable form across different infections and pathogenic states. Labelling such antivirulence agents as broad-spectrum sets unrealistic expectations that infection biology cannot justify. Further, partial suppression of virulence can reshape population-level dynamics in ways that stabilise pathogenic cooperation/synchronisation rather than disrupt it (; ). The field must abandon the myth of universal antivirulence “silver-bullet” and embrace a precision medicine framework that accounts for extreme environmental and regulatory plasticity of P. aeruginosa. Only by addressing this can we design potent antivirulence therapies biologically matched to the reality of disarming bacterial infections and improving human pathology.
5 The clearance dilemma: host as a silent failure point
Translational limitations in antivirulence research are commonly framed as a problem of drug properties or trial design. This view overlooks a deeper biological limitation, as these therapies are intrinsically dependent on host-mediated clearance. Unlike conventional antibiotics, antivirulence agents do not directly eliminate bacteria; they reduce pathogenic activity and rely on host immune responses to achieve resolution. In clinical settings where P. aeruginosa inflicts the greatest morbidity, including bronchiectatic lungs and chronic wounds in intensive care unit patients, this assumption collapses. The patient’s natural immune defences are significantly compromised, and disarming the pathogen under these conditions does not lead to clearance, but promotes persistence.
The limitations of the “gentle antibiotic” concept become most apparent during the resolution phase of infection. In a healthy host, infection resolution requires active, efficient phagocytosis of apoptotic neutrophils and bacterial debris. P. aeruginosa, however, disrupts neutrophil homeostasis through secreted factors such as pyocyanin and rhamnolipids, which induce premature apoptosis or necrotic death of neutrophils (; ). In the absence of efficient macrophage-mediated clearance, these cells undergo secondary necrosis, releasing damage-associated molecular patterns and intracellular elastases into the local tissue (; ). As a result, even when virulence factors are successfully neutralised, the inflammatory environment remains self-sustaining. Tissue injury continues in the relative absence of active bacterial aggression. This creates a critical mismatch between preclinical validation and clinical reality. Antivirulence strategies are typically evaluated in immunocompetent animal models, where intact innate immunity compensates for the lack of bactericidal activity. Under these conditions, disarmament is sufficient to enable clearance. In contrast, the target patient populations often exhibit impaired immune function, including defective neutrophil activity, reduced macrophage clearance capacity, or systemic immunosuppression. Under these circumstances, antivirulence intervention produces a distinct pathological state: a disarmed but persistent bacterial population that remains at high density and continues to sustain chronic inflammation. The dependence on host competence also constrains combination strategies. Interventions designed to enhance clearance, such as biofilm dispersal using nitric oxide donors or enzymatic degradation (using glycoside hydrolases) of extracellular matrices, can paradoxically destabilise the system. By increasing bacterial exposure beyond the processing capacity of a compromised immune system, these approaches risk precipitating systemic spread, sepsis, or acute tissue injury (; ). The outcome is not resolution, but loss of containment and spread within the infected host.
A further limitation arises from the host’s impaired capacity to repair damaged tissues. In chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease, epithelial regeneration is already compromised. P. aeruginosa exacerbates this deficit by producing extracellular proteases such as LasB, which degrades key structural and signalling components involved in epithelial repair (; ). Antivirulence strategies that neutralise ongoing bacterial damage do not restore these host repair proteins/pathways. The system, therefore, remains locked in a state, in which injury accumulates faster than it can be repaired, even in the presence of reduced bacterial virulence. This directly implies that antivirulence therapies are not functionally equivalent to “gentle antibiotics,” and treating them as such obscures their primary limitation. Their efficacy is conditional on a level of host competence that is frequently absent in clinical reality. Without sufficient immune capacity to complete clearance and restore tissue integrity, disarmament of virulence arsenals alone cannot resolve infection. Ultimately, the “clearance dilemma” necessitates a paradigm shift in trial design. Antivirulence agents should not be treated as standalone anti-infectives but as “precision pro-resolving” interventions. Clinical success will depend on deploying them within defined immune-active windows in stratified patient groups where host function and immunity remain sufficient to support resolution (). Until we align our therapeutic expectations with the host’s immunological dynamics, the most potent antivirulence agents will remain clinically invisible.
An alternative strategy to overcome some of the limitations of antivirulence monotherapy is its use in combination with conventional antibiotics. Such combinations may provide complementary benefits by simultaneously attenuating virulence-associated tissue damage or immune dysregulation through targeted antivirulence interventions and bacterial killing via antibiotic activity. Indeed, several preclinical studies have demonstrated synergistic or additive effects of antibiotic-antivirulence combinations, including enhanced bacterial clearance, disruption of pre-formed biofilms, and reduced emergence of antibiotic tolerance or resistance (). Apart from attenuating virulence, such antivirulence agents can also be co-administered with broad-spectrum antibiotics to prevent biofilm establishment during the planktonic phase and eradicate pre-formed biofilms in persistent infections. In this regard, FDA-approved drugs that display anti-inflammatory and/or antibacterial activity (e.g., paracetamol, ibuprofen), along with promising antivirulence potential, can be effectively repurposed and supplemented with potent antibiotics to combat different pseudomonal infections (). Additionally, naturally occurring multifarious phytochemicals such as zingerone, cinnamaldehyde, α-terpineol and numerous others, in conjunction with antibiotics, not only confer protection against inflammation and reactive oxygen species but have also been reported to synergistically attenuate QS circuitry and virulence pathways, thereby preventing P. aeruginosa-associated infections in different animal models in vivo (; , ; ). However, despite these encouraging findings, the clinical translation of combination strategies remains limited and continues to face many of the same challenges discussed above, including patient heterogeneity, appropriate timing of intervention, biomarker-guided patient selection, and the use of clinical endpoints that align with the mechanisms of antivirulence therapies. Consequently, combination therapy should be viewed not as a replacement for improved translational frameworks but as a complementary strategy that may itself benefit from state-guided therapeutic deployment.
6 From disarmament to state control: reframing the therapeutic objective
The persistent challenge of antivirulence strategies in producing durable clinical benefit reflects a deeper conceptual problem within the field. Antivirulence research has largely been constructed around the assumption that virulence is an intrinsic property of discrete molecular determinants that can be independently neutralised to attenuate disease progression. This assumption is fundamentally incomplete. In vivo, pathogenesis does not emerge from isolated virulence factors operating independently, but from the behaviour of a coupled and adaptive host-pathogen system, shaped by reciprocal interactions between bacterial networks and host responses (Figure 1). Within this framework, infection is better understood not as a linear progression of events but as a dynamic, multifactorial system capable of occupying relatively stable pathological configurations.
Figure 1
In P. aeruginosa, at least three such configurations repeatedly emerge across experimental and clinical settings (Figure 1). One state is characterised by acute invasive disease associated with rapid tissue destruction, intense inflammatory activation, and expression of cytotoxic mechanisms (T3SS), often despite relatively low bacterial density (; ). A second state is defined by chronic persistence in which biofilm-embedded populations exhibit metabolic constraint, reduced expression of canonical virulence factors, and pronounced tolerance to both immune clearance and antimicrobial therapy (). A third configuration arises when host-mediated inflammation itself becomes the dominant driver of pathology, such that tissue injury is sustained primarily through neutrophil proteases, reactive oxygen species, cytokine amplification, and impaired epithelial repair, even when bacterial burden remains comparatively modest (; ; ). These configurations should not be interpreted as sequential stages along a predetermined trajectory. Rather, they represent alternative equilibria within a complex biological system (Figure 1). Chronic airway infection in cystic fibrosis can persist for years despite repeated antibiotic exposure, fluctuating bacterial density, and extensive within host diversification, illustrating the remarkable stability of specific pathological programs once established (). Similarly, biofilm-associated persistence frequently remains preserved even when expression of major virulence determinants is substantially reduced. Conversely, tissue damage may persist despite partial suppression of bacterial activity because pathology is increasingly sustained by self-amplifying inflammatory circuits rather than direct microbial aggression (; ). Collectively, these observations suggest that disease severity depends less on the isolated presence of individual virulence factors than on the pathological state that becomes stabilised within infected tissue, the resistance of that state to perturbation, and whether transition toward resolution remains biologically accessible (Figure 1).
This perspective helps in explaining several longstanding inconsistencies that continue to undermine the antivirulence field. Mechanistically successful inhibition of a virulence pathway may produce little clinical improvement because the broader pathological configuration remains intact. Inhibition of T3SS, for instance, may restrict entry into an acute cytotoxic state, thereby reducing early tissue injury without substantially lowering bacterial burden (; ; ). In contrast, disruption of biofilm architecture cannot be considered intrinsically beneficial in isolation. Under favourable conditions, it may facilitate immune clearance, whereas under inadequate host control, it may instead promote dissemination and systemic injury (; ). The biological consequences of intervention, therefore, remain contingent on when and where the perturbation is introduced within the evolving state of infection.
Increasing evidence indicates that chronic P. aeruginosa infection exhibits several hallmarks of dynamical stability, including adaptive robustness, phenotypic convergence, hysteretic regulatory behaviour, and persistence despite therapeutic perturbation (; ). Under such conditions, pathological states are maintained not by individual regulators alone but by interconnected feedback loops linking bacterial adaptation, inflammatory amplification, tissue damage, immune activity, and metabolic restructuring. The implications for antivirulence therapy are substantial. Biological responses to intervention are unlikely to be linear or proportional. Relatively modest perturbations introduced at critical transition points may redirect the system toward resolution, whereas even potent inhibitors may produce negligible clinical benefit once a pathological state has stabilised. The central therapeutic objective must therefore be reconsidered. The problem is not simply the failure to identify sufficiently important virulence targets, but the persistence of a reductionist framework that seeks to dismantle isolated components of a fundamentally state-based biological system. This reframing shifts the unit of pathogenesis away from isolated virulence determinants and towards system-level behaviour. The future of antivirulence therapy may therefore depend less on molecular disarmament and more on the ability to identify, destabilise, and redirect pathological trajectories governing infection over time.
7 From targets to trajectories and future directives: positioning P. aeruginosa as a dynamic system for antivirulence therapy
If infection behaves as a state-dependent system, then the central therapeutic challenge changes fundamentally. The objective is no longer comprehensive suppression of every virulence determinant, but selective destabilisation of regulatory and immunological configurations that maintain harmful disease states. This distinction is important because many pathogenic behaviours in P. aeruginosa are governed by higher-order regulatory transitions rather than isolated virulence outputs. Biofilm commitment, dispersal behaviour, QS-dependent virulence activation, metabolic adaptation to hypoxia, inflammatory amplification, and persistence-associated stress responses all involve coordinated shifts in network activity rather than activation of single pathways (; ). Under these conditions, inhibition of one virulence factor may leave the broader pathological state largely intact.
A state-control framework instead prioritises intervention at points that govern transition behaviour within the bacterial system (Figure 1). Potential examples may include regulatory programs linked to QS state-switching, cyclic-di-GMP signalling, hypoxia adaptation, iron sensing, persistence-associated metabolic reprogramming, or inflammatory feed-forward loops that sustain tissue injury independent of bacterial expansion (; ; ). These processes may function less as isolated targets and more as control layers that influence whether infection stabilises towards acute cytotoxicity, chronic persistence, inflammatory escalation, or resolution-compatible states. Within this framework, therapeutic success does not necessarily require eradication of bacterial populations. A clinically meaningful antivirulence intervention may instead prevent transition into highly damaging configurations, destabilise persistence-associated pathways sufficiently to permit immune clearance, or interrupt inflammatory circuits that perpetuate tissue injury after bacterial aggression has partially subsided (Figure 1).
A transition from target-centric intervention to state-control therapy also requires rethinking how therapeutic success is evaluated clinically. Current evaluative frameworks remain heavily anchored to bacterial eradication, reduction in CFU, and all-cause mortality. These endpoints were developed primarily for bactericidal therapies and may be poorly aligned with interventions intended to modify infection behaviour rather than eliminate bacterial presence outright. If the objective of therapy is to redirect pathological trajectories, then evaluation must also capture trajectory-level biological change. In this context, clinically meaningful improvement may include prevention of transition into acute inflammatory deterioration, destabilisation of persistence-associated programs, restoration of epithelial repair activity, attenuation of neutrophil-mediated tissue injury, or recovery of immune equilibrium despite incomplete bacterial clearance (; ; ). This may require the integration of multidimensional biological readouts capable of distinguishing changes in system behaviour from simple reductions in bacterial burden. Potential dimensions or indicators could include temporal inflammatory signatures, markers of epithelial injury, and tissue regeneration (; ). Additional measures involve transcriptomic profiles associated with persistence or cytotoxic activation states, imaging-based assessment of biofilm organisation, or dynamic measures of host physiological stability (; ). Importantly, these approaches would not entirely replace conventional microbiological metrics, but would contextualise them within a broader systems-level assessment of disease evolution.
The insufficiency of clinical datasets is paramount to the translational hurdles faced by antivirulence therapy. The current gap primarily arises from the extremely limited progression of bench-based studies into clinical trials, thereby halting scientific advancements in the field and narrowing opportunities to fully validate their clinical potential. This has been a common trend, not limited to P. aeruginosa, but has also been observed among other ESKAPE pathogens (). Additionally, the existing trials do not meet the desired standards for validating the therapeutic potential of antivirulence strategies against P. aeruginosa, with deficiencies in trial design, patient stratification, and efficacy assessment. This may be attributed to several factors, one of which is a bias towards antimicrobial therapies. For decades, pharmaceutical companies have been betting on the development and large-scale production of antibiotics, which has been the conventional model that has overshadowed alternative medicine and established the antibiotic monopoly. Another contributing factor may be the hesitation among clinicians to adopt antivirulence strategies over existing antimicrobials, which serve as the first-line treatment option for combating resistant bacterial infections. Moreover, clinicians place emphasis on saving the patient’s life and are therefore generally inclined to administer multiple antibiotics or their synergistic combinations that have already been clinically validated against pathogenic microorganisms. Collectively, all these factors may have underscored the therapeutic potential of antivirulence therapies, thereby impeding their clinical development and future biomedical applications. Nevertheless, these pitfalls can be addressed by adopting a holistic mindset, embracing emerging therapies, and establishing collaborative frameworks among academia, clinicians, and pharmaceutical companies to conduct large-cohort clinical trials. Ultimately, this will help generate large-scale trial datasets that will provide a clear picture and validate the therapeutic efficacy of antivirulence approaches, thereby gaining widespread acceptance and successful future application.
The practical implications for clinical trial design are substantial. Rather than evaluating antivirulence agents solely by mortality reduction or CFU endpoints, future studies may need to identify biologically defined intervention windows and stratify patients according to dominant infection states. For example, therapies targeting acute cytotoxic programs may be most relevant during early invasive phases characterised by strong inflammatory activation, whereas persistence-destabilising interventions may require evidence of established biofilm-associated adaptation before deployment. However, such an approach remains experimentally and clinically challenging. Many proposed infection states are still incompletely defined, reliable biomarkers for transition dynamics remain underdeveloped, and real-time characterisation of host-pathogen system behaviour is not yet routinely feasible in clinical practice. Addressing these translational shortcomings will require coordinated improvements across both preclinical and clinical research. Future studies should prioritise (i) the development of standardised preclinical models that better recapitulate clinically relevant host-pathogen interactions, (ii) biomarker-guided patient stratification to identify individuals most likely to benefit from antivirulence interventions, (iii) mechanism-appropriate clinical endpoints that extend beyond bacterial clearance to include measures of inflammation, tissue damage, host recovery, and disease resolution, and (iv) adequately powered, multicentre clinical trials to generate robust evidence for therapeutic efficacy. Integrating these strategies with systems-level approaches, such as the proposed state-control framework, may provide a more comprehensive basis for evaluating and translating antivirulence therapies into clinical practice.
Moving forward, the advancement of antivirulence research will require a shift from target-centric approaches toward systems-oriented therapeutic design. Priority should be given to defining dynamic infection states and their molecular signatures, developing biomarkers for real-time monitoring of host-pathogen interactions, and integrating multi-omics with computational modelling to predict disease-state transitions. Future studies should also focus on rational combination therapies (e.g., antibiotics with antivirulence phytochemicals, drugs, or enzymes), optimising intervention according to infection stage, and establishing standardised preclinical models and mechanism-appropriate clinical endpoints. Collectively, these advances will strengthen the evaluation of therapeutic efficacy and accelerate the clinical translation of precision antivirulence strategies. Nevertheless, the broader conceptual implication remains important. The recurring translational constraints associated with antivirulence therapies may not indicate that virulence is biologically irrelevant but rather that the field has often intervened at the level of isolated molecular outputs while leaving the broader pathological system relatively unchanged. Viewed through this lens, the next generation of antivirulence strategies may depend less on developing increasingly potent silencers of individual virulence factors and more on designing precision interventions that reshape the trajectories governing infection persistence, inflammatory injury, and recovery.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Author contributions
GM: Formal Analysis, Writing – original draft. LK: Formal Analysis, Writing – review & editing. JC: Conceptualization, Supervision, Validation, Writing – review & editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was used in the creation of this manuscript. The authors used Grammarly to improve the use of vocabulary/grammar in this manuscript. ChatGPT was also used for removing redundancy within the manuscript, between different sections.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
CFU, Colony-forming units; QS, Quorum sensing; T3SS, Type-3 secretion system.
References
1
AllenL.DockrellD. H.PatteryT.LeeD. G.CornelisP.HellewellP. G.et al. (2005). Pyocyanin production by Pseudomonas aeruginosa induces neutrophil apoptosis and impairs neutrophil-mediated host defenses in vivo. J. Immunol.174, 3643–3649. doi: 10.4049/jimmunol.174.6.3643
2
AnantharajahA.Mingeot-LeclercqM. P.Van BambekeF. (2016). Targeting the type three secretion system in Pseudomonas aeruginosa. Trends Pharmacol. Sci.37 (9), 734–749. doi: 10.1016/j.tips.2016.05.011
3
BenseS.WitteJ.PreußeM.KoskaM.PezoldtL.DrögeA.et al. (2022). Pseudomonas aeruginosa post-translational responses to elevated c-di-GMP levels. Mol. Microbiol.117 (5), 1213–1226. doi: 10.1111/mmi.14902
4
BianchiS. M.PrinceL. R.McPhillipsK.AllenL.MarriottH. M.TaylorG. W.et al. (2008). Impairment of apoptotic cell engulfment by pyocyanin, a toxic metabolite of Pseudomonas aeruginosa. Am. J. Respir. Crit. Care Med.177, 35–43. doi: 10.1164/rccm.200612-1804oc
5
BoseS. K.SharmaK.ChhibberS.HarjaiK. (2021). Therapeutic potential of nanolipoidal α-terpineol in combating keratitis induced by Pseudomonas aeruginosa in the murine model. Int. J. Pharmaceut594, 120175. doi: 10.1016/j.ijpharm.2020.120175
6
BrattonD. L.HensonP. M. (2011). Neutrophil clearance: when the party is over, clean-up begins. Trends Immunol.32, 350–357. doi: 10.1016/j.it.2011.04.009
7
CabreraR.Rovira-RibaltaN.MotosA.Bueno-FreireL.VázquezN.Soler-ComasA.et al. (2025). Virulence factors of Pseudomonas aeruginosa and immune response during exacerbations and stable phase in bronchiectasis. Sci. Rep.15, 6520. doi: 10.21161/mjm.180307
8
CaiY. M.HutchinA.CraddockJ.WalshM. A.WebbJ. S.TewsI. (2020). Differential impact on motility and biofilm dispersal of closely related phosphodiesterases in Pseudomonas aeruginosa. Sci. Rep.10, 6232. doi: 10.1038/s41598-020-63008-5
9
Cammarata-MouchtourisA.Moncada GiraldoD.CollinsG. L.ParrillaM. M.KimS. O.MansourS.et al. (2025). People with cystic fibrosis with high sputum neutrophil elastase on elexacaftor-tezacaftor-ivacaftor exhibit worse pulmonary function and pro-inflammatory airway milieu. Sci. Rep.15, 43430. doi: 10.1038/s41598-025-26263-y
10
CaoP.FlemingD.MoustafaD. A.DolanS. K.SzymanikK. H.RedmanW. K.et al. (2023). A Pseudomonas aeruginosa small RNA regulates chronic and acute infection. Nature618, 358–364. doi: 10.1038/s41586-023-06111-7
11
ChadhaJ.HarjaiK.ChhibberS. (2022a). Repurposing phytochemicals as anti-virulent agents to attenuate quorum sensing-regulated virulence factors and biofilm formation in Pseudomonas aeruginosa. Microb. Biotechnol.15, 1695–1718. doi: 10.1111/1751-7915.13981
12
ChadhaJ.HarjaiK.ChhibberS. (2022b). Revisiting the virulence hallmarks of Pseudomonas aeruginosa: a chronicle through the perspective of quorum sensing. Environ. Microbiol.24, 2630–2656. doi: 10.1111/1462-2920.15784
13
ChadhaJ.RaviSinghJ.ChhibberS.HarjaiK. (2022c). Gentamicin augments the quorum quenching potential of cinnamaldehyde in vitro and protects Caenorhabditis elegans from Pseudomonas aeruginosa infection. Front. Cell. Infect. Microbiol.12, 899566. doi: 10.3389/fcimb.2022.899566
14
ChadhaJ.SinghJ.HarjaiK. (2023). α-Terpineol synergizes with gentamicin to rescue Caenorhabditis elegans from Pseudomonas aeruginosa infection by attenuating quorum sensing-regulated virulence. Life Sci.313, 121267. doi: 10.1016/j.lfs.2022.121267
15
ChastreJ.FrançoisB.BourgeoisM.KomnosA.FerrerR.RahavG.et al. (2020). Efficacy, pharmacokinetics (PK), and safety profile of MEDI3902, an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody in mechanically ventilated intensive care unit patients; Results of the phase 2 EVADE study conducted by the public-private COMBACTE-MAGNET consortium in the innovative medicines initiative (IMI) program. Open Forum Infect. Dis.7, S377–S378. doi: 10.1093/ofid/ofaa439.829
16
ChastreJ.FrançoisB.BourgeoisM.KomnosA.FerrerR.RahavG.et al. (2022). Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial. Crit. Care26, 355. doi: 10.1186/s13054-022-04204-9
17
ChuangS. K.VrlaG. D.FröhlichK. S.GitaiZ. (2019). Surface association sensitizes Pseudomonas aeruginosa to quorum sensing. Nat. Commun.10, 4118. doi: 10.1038/s41467-019-12153-1
18
CollaltoD.GiallonardiG.FortunaA.MeneghiniC.FiscarelliE.ViscaP.et al. (2022). In vitro activity of antivirulence drugs targeting the Las or Pqs quorum sensing systems against cystic fibrosis Pseudomonas aeruginosa isolates. Front. Microbiol.13, 845231. doi: 10.3389/fmicb.2022.845231
19
DesveauxJ. M.FaudryE.Contreras-MartelC.CretinF.Dergan-DylonL. S.AmenA.et al. (2026). Neutralizing human monoclonal antibodies that target the PcrV component of the type III secretion system of Pseudomonas aeruginosa act through distinct mechanisms. eLife14, RP105195. doi: 10.7554/elife.105195.2
20
DickeyS. W.CheungG. Y.OttoM. (2017). Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat. Rev. Drug Discov.16, 457–471. doi: 10.1038/nrd.2017.23
21
ElmassryM. M.Colmer-HamoodJ. A.KopelJ.San FranciscoM. J.HamoodA. N. (2023). Anti-Pseudomonas aeruginosa vaccines and therapies: an assessment of clinical trials. Microorganisms11, 916. doi: 10.3390/microorganisms11040916
22
FilipićB.UšjakD.RambaherM. H.OljacicS.MilenkovićM. T. (2024). Evaluation of novel compounds as anti-bacterial or anti-virulence agents. Front. Cell. Infect. Microbiol.14, 1370062. doi: 10.3389/fcimb.2024.1370062
23
FlemingD.RumbaughK. (2018). The consequences of biofilm dispersal on the host. Sci. Rep.8, 10738. doi: 10.1038/s41598-018-29121-2
24
FuT.WrightR. C.GiffordD. R.KnightC. G.BrockhurstM. A. (2025). Inflammation-like environments limit the loss of quorum sensing in Pseudomonas aeruginosa. mSystems10, e01722-24. doi: 10.1128/msystems.01722-24
25
García-ContrerasR. (2016). Is quorum sensing interference a viable alternative to treat Pseudomonas aeruginosa infections? Front. Microbiol.7, 1454. doi: 10.3389/fmicb.2016.01454
26
GarrattL. W.BreuerO.SchofieldC. J.McLeanS. A.LauciricaD. R.TirouvanziamR.et al. (2021). Changes in airway inflammation with Pseudomonas eradication in early cystic fibrosis. J. Cyst Fibros20, 941–948. doi: 10.1016/j.jcf.2020.12.015
27
HibbertT. M.WhiteleyM.RenshawS. A.NeillD. R.FothergillJ. L. (2024). Emerging strategies to target virulence in Pseudomonas aeruginosa respiratory infections. Crit. Rev. Microbiol.50, 1037–1052. doi: 10.1080/1040841x.2023.2285995
28
HolderI. A.NeelyA. N.FrankD. W. (2001). PcrV immunization enhances survival of burned Pseudomonas aeruginosa-infected mice. Infect. Immun.69, 5908–5910. doi: 10.1128/iai.69.9.5908-5910.2001
29
HuangJ.SunY.ChenF.LiS.YouX.HanL.et al. (2026). Global transcription factors analyses reveal hierarchy and synergism of regulatory networks and master virulence regulators in Pseudomonas aeruginosa. eLife14, RP103346. doi: 10.7554/elife.103346.1
30
LiaoC.HuangX.WangQ.YaoD.LuW. (2022). Virulence factors of Pseudomonas aeruginosa and antivirulence strategies to combat its drug resistance. Front. Cell. Infect. Microbiol.12, 926758. doi: 10.1016/j.vetmic.2013.07.027
31
LissensM.JoosM.LoriesB.SteenackersH. P. (2022). Evolution-proof inhibitors of public good cooperation: a screening strategy inspired by social evolution theory. FEMS Microbiol. Rev.46, fuac019. doi: 10.1093/femsre/fuac019
32
MauraD.BallokA. E.RahmeL. G. (2016). Considerations and caveats in anti-virulence drug development. Curr. Opin. Microbiol.33, 41–46. doi: 10.1016/j.mib.2016.06.001
33
MauriceN. M.BediB.SadikotR. T. (2018). Pseudomonas aeruginosa biofilms: host response and clinical implications in lung infections. Am. J. Respir. Cell Mol. Biol.58, 428–439. doi: 10.1165/rcmb.2017-0321TR
34
MessinaF.RotondoC.LadeiraL.CrosettiS.ProperziM.DimartinoV.et al. (2025). Molecular exploration of host-pathogen interactions in severe Pseudomonas aeruginosa infection through a multi-level data integration approach. Front. Med.12, 1600509. doi: 10.3389/fmed.2025.1600509
35
MoserC.JensenP.Ø.ThomsenK.KolpenM.RybtkeM.LaulandA. S.et al. (2021). Immune responses to Pseudomonas aeruginosa biofilm infections. Front. Immunol.12, 625597. doi: 10.3389/fimmu.2021.625597
36
MudgilU.KhullarL.ChadhaJ.HarjaiK. (2024). Beyond antibiotics: emerging antivirulence strategies to combat Pseudomonas aeruginosa in cystic fibrosis. Microb. Pathog.193, 106730. doi: 10.1016/j.micpath.2024.106730
37
MurrayE. J.DubernJ. F.ChanW. C.ChhabraS. R.WilliamsP. (2022). A Pseudomonas aeruginosa PQS quorum-sensing system inhibitor with anti-staphylococcal activity sensitizes polymicrobial biofilms to tobramycin. Cell Chem. Biol.29, 1187–1199. doi: 10.1016/j.chembiol.2022.02.007
38
NickersonR.ThorntonC. S.JohnstonB.LeeA. H.ChengZ. (2024). Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response. Front. Immunol.15, 1405376. doi: 10.3389/fimmu.2024.1405376
39
OrababaO. Q.CornbillC.KadeA.ReddyN.GulatiR.HarrisonF. (2025). Low concentrations of tetrasodium EDTA cause significant killing of biofilm-associated Pseudomonas aeruginosa in high-validity models of chronic wound and cystic fibrosis lung infections but not in a model of endotracheal tube colonisation. Access Microbiol.7, 1155. doi: 10.1099/acmi.0.001155.v4
40
PanX.YinL.ZhouD.JinY.ChengZ.HaU. H.et al. (2025). Pseudomonas aeruginosa lasR-deficient mutant contributes to bacterial virulence through enhancing the PhoB-mediated pathway in response to host environment. mBio16, e01788-25. doi: 10.1128/mbio.01788-25
41
RashpaS.ChadhaJ.KhullarL.SharmaB.HarjaiK. (2025). Revisiting the multifaceted phytochemical: an updated review on therapeutic potential, pharmaceutical formulations, pre-clinical studies, and clinical trials of zingerone. Eur. J. Med. Chem.297, 117971. doi: 10.1016/j.ejmech.2025.117971
42
RossiE.La RosaR.BartellJ. A.MarvigR. L.HaagensenJ. A. J.SommerL. M.et al. (2021). Pseudomonas aeruginosa adaptation and evolution in patients with cystic fibrosis. Nat. Rev. Microbiol.19, 331–342. doi: 10.1038/s41579-020-00477-5
43
RuffinM.BrochieroE. (2019). Repair process impairment by Pseudomonas aeruginosa in epithelial tissues: major features and potential therapeutic avenues. Front. Cell. Infect. Microbiol.9, 182. doi: 10.3389/fcimb.2019.00182
44
Saint-CriqV.VilleretB.BastaertF.KheirS.HattonA.CazesA.et al. (2018). Pseudomonas aeruginosa LasB protease impairs innate immunity in mice and humans by targeting a lung epithelial CFTR–IL-6–antimicrobial–repair pathway. Thorax73, 49–61. doi: 10.1136/thoraxjnl-2017-210298
45
SharmaB.ChadhaJ.KhullarL.RashpaS.HarjaiK. (2025). FDA-approved drugs for targeting virulence of Pseudomonas aeruginosa: A drug repurposing approach to combat multidrug resistance. Microb. Pathog.206, 107781. doi: 10.1016/j.micpath.2025.107781
46
SimanekK. A.SchumacherM. L.MalleryC. P.ShenS.LiL.PaczkowskiJ. E. (2023). Quorum-sensing synthase mutations recalibrate autoinducer concentrations in clinical isolates of Pseudomonas aeruginosa to enhance pathogenesis. Nat. Commun.14, 7986. doi: 10.1038/s41467-023-43702-4
47
SuraweeraR. K.SpannK. M.WellsT. J.IslamN. (2025). Inhaled combined antibacterials against biofilm-forming antibiotic-resistant bacteria for the management of pulmonary bacterial infections. J. Drug Deliv Sci. Technol.104, 106555. doi: 10.1016/j.jddst.2024.106555
48
TaylorT. B.ShepherdM. J.HortonJ. S. (2024). Pseudomonas aeruginosa’s adaptive trajectory: diverse origins, convergent paths. Trends Microbiol.32, 825–827. doi: 10.1016/j.tim.2023.12.002
49
TimsitJ. F.de KrakerM. E.SommerH.WeissE.BettiolE.WolkewitzM.et al. (2017). Appropriate endpoints for evaluation of new antibiotic therapies for severe infections: a perspective from COMBACTE’s STAT-Net. Intensive Care Med.43, 1002–1012. doi: 10.1007/s00134-017-4802-4
50
TobaresR. A.MartinoR. A.ColqueC. A.Castillo MoroG. L.MoyanoA. J.Albarracín OrioA. G.et al. (2025). Hypermutability bypasses genetic constraints in SCV phenotypic switching in Pseudomonas aeruginosa biofilms. NPJ Biofilms Microbiomes11, 14. doi: 10.1038/s41522-024-00644-z
51
TranS. L.LebreuillyL.CormontagneD.SamsonS.TôT. B.StosskopfM.et al. (2025). An anti-virulence drug targeting the evolvability protein Mfd protects against infections with antimicrobial-resistant ESKAPE pathogens. Nat. Commun.16, 3324. doi: 10.1038/s41467-025-58282-8
52
TrouillonJ.HanK.AttréeI.LoryS. (2022). The core and accessory Hfq interactomes across Pseudomonas aeruginosa lineages. Nat. Commun.13, 1258. doi: 10.1038/s41467-022-28849-w
53
VanderwoudeJ.FlemingD.AzimiS.TrivediU.RumbaughK. P.DiggleS. P. (2020). The evolution of virulence in Pseudomonas aeruginosa during chronic wound infection. Proc. R. Soc B. Biol. Sci.287, 20202272. doi: 10.1098/rspb.2020.2272
54
Van GennipM.ChristensenL. D.AlhedeM.PhippsR.JensenP.Ø.ChristophersenL.et al. (2009). Inactivation of the rhlA gene in Pseudomonas aeruginosa prevents rhamnolipid production, disabling protection against polymorphonuclear leukocytes. Apmis117, 537–546. doi: 10.1128/jvi.72.1.151-157.1998
55
WangG.NauseefW. M. (2022). Neutrophil dysfunction in the pathogenesis of cystic fibrosis. Blood139, 2622–2631. doi: 10.1182/blood.2021014699
56
ZhanX.ZhangK.WangC.FanQ.TangX.ZhangX.et al. (2024). A c-di-GMP signaling module controls responses to iron in Pseudomonas aeruginosa. Nat. Commun.15, 1860. doi: 10.1038/s41467-024-46149-3
57
ZhangX.ZhangD.ZhouD.ZhengS.LiS.HouQ.et al. (2025). A comprehensive review of the pathogenic mechanisms of Pseudomonas aeruginosa: synergistic effects of virulence factors, quorum sensing, and biofilm formation. Front. Microbiol.16, 1619626. doi: 10.3389/fmicb.2025.1619626
Summary
Keywords
antivirulence therapy, clinical translation, host-pathogen interactions, Pseudomonas aeruginosa, state control framework, virulence attenuation
Citation
Moudgil G, Khullar L and Chadha J (2026) Rethinking antivirulence therapies against Pseudomonas aeruginosa: translational challenges and future directions through a state-control framework. Front. Bacteriol. 5:1892950. doi: 10.3389/fbrio.2026.1892950
Received
27 May 2026
Revised
05 July 2026
Accepted
27 July 2026
Published
10 August 2026
Volume
5 - 2026
Edited by
Manmohit Kalia, Binghamton University, United States
Reviewed by
Wedad M. Nageeb, Suez Canal University, Egypt
Walter Riofrio, Universidad Peruana Cayetano Heredia, Peru
Updates
Copyright
© 2026 Moudgil, Khullar and Chadha.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jatin Chadha, chadhajatin0406@gmail.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.