Mechanistic Role of Heavy Metals in Driving Antimicrobial Resistance: From Rhizosphere to Phyllosphere

Abstract

Heavy metal pollution represents a pervasive environmental challenge that significantly exacerbates the ever-increasing crisis of antimicrobial resistance and the capacity of microorganisms to endure and proliferate despite antibiotic interventions. This review examines the intricate relationship between heavy metals and AMR, with an emphasis on the underlying molecular mechanisms and ecological ramifications. Common environmental metals, including arsenic, mercury, cadmium, and lead, exert substantial selective pressures on microbial communities. These induce oxidative stress and DNA damage, potentially leading to mutations that enhance antibiotic resistance. Key microbial responses include the overexpression of efflux pumps that expel both metals and antibiotics, production of detoxifying enzymes, and formation of protective biofilms, all of which contribute to the emergence of multidrug-resistant strains. In the soil environment, particularly the rhizosphere, heavy metals disrupt plant–microbe interactions by inhibiting beneficial organisms, such as rhizobacteria, mycorrhizal fungi, and actinomycetes, thereby impairing nutrient cycling and plant health. Nonetheless, certain microbial consortia can tolerate and detoxify heavy metals through sequestration and biotransformation, rendering them valuable for bioremediation. Advances in biotechnology, including gene editing and the development of engineered metal-resistant microbes, offer promising solutions for mitigating the spread of metal-driven AMR and restoring ecological balance. By understanding the interplay between metal pollution and microbial resistance, we can more effectively devise strategies for environmental protection and public health.

1. Introduction

The continuing increase in antimicrobial resistance (AMR) is an international health crisis that threatens to destroy the pillars of contemporary medicine [1]. The World Health Organization (WHO) has ranked AMR as a global health threat that threatens a post-antibiotic era in which routine infections become lethal [2]. As estimated recently AMR accounted fully for 1.27 million deaths in 2019, and antimicrobial resistance remains an increasingly looming global health and economic danger [3]. In 2019, AMR was attributable to 1.27 million deaths and linked to 4.95 million deaths worldwide [4]. The most recent exhaustive estimate in 2021 indicates a decline with 1.14 million directly attributable deaths due to AMR and 4.71 million linked deaths [5]. AMR will be responsible for a maximum of 169 million deaths between 2025 and 2050 [6]. The mortality rates for individuals above the age of 70 are anticipated to increase to 1.26 million by 2050 [7]. Antimicrobial resistance refers to the capacity of microorganisms, including bacteria, fungi, parasites, and viruses, to respond to medications previously effective in treating infections. When microbes develop resistance, standard treatments become ineffective, infections persist, and the risk of transmission increases. While AMR occurs naturally through genetic mutations, its progression is accelerated by misuse and overuse of medicines for human and veterinary pesticides and biofertilizers for agriculture [8,9,10], including the use of inappropriate prescribing, lack of diagnostic tools, incomplete treatment courses, and extensive antibiotic use in animal feed. Resistant organisms can endure multiple antibiotics, causing common infections, such as pneumonia, urinary tract infections, and bloodstream infections, which are increasingly difficult to treat [11]. This resistance results in prolonged illness, elevated medical costs, increased mortality, and jeopardizes modern medical procedures, including surgery, chemotherapy, and organ transplants, which depend on effective antimicrobial [12].

The WHO recognizes AMR as one of the top ten global public health threats requiring urgent coordinated efforts across sectors to monitor, prevent, and control its spread [13]. This mounting crisis requires an in-depth understanding of the complex factors that fuel AMR, such as the frequently neglected contribution of heavy metal pollution [14]. Heavy metals (HMs) such as mercury (Hg), lead (Pb), cadmium (Cd), arsenic (As), copper (Cu), and zinc (Zn) are widespread environmental contaminants released from industrial effluents, mining, agricultural activities, and inadequate waste management [15,16]. Repeated exposure to soil, water, and sediments imposes constant selective pressure on microbial populations, enabling the development and growth of metal-resistant bacteria [17]. A surprisingly large percentage of these metal-resistant bacteria are cross-resistant to antibiotics, constituting a formidable public health threat [18]. Nonetheless, resource mobilization is unbalanced because sharp cuts in aid for low- and middle-income countries (LMICs) have threatened AMR programs [19].

Surveillance and diagnostic capacity are also at risk, with more than 700 global laboratories facing closure [20], whereas areas such as Africa strengthen their pathogen surveillance systems using a One Health approach [21]. Innovation is encouraged by international platforms such as the GAMRIF Summit 2025 [22], complemented by regional research such as India’s Symposium Conference, which focuses on AI-assisted diagnostics [23]. Policymaking remains a process, although 10% of the 178 nations with National Action Plans (NAPs) currently allocate AMR budgets [24]. The pathways through which HMs drive AMR are both multifaceted and interlinked. HMs trigger oxidative stress in bacterial cells through the production of reactive oxygen species (ROS) that harm DNA, proteins, and lipids [25]. They also directly interact with cellular structures, interfering with important metabolic processes and cellular functions [26]. Recent research has reaffirmed previous reservations regarding trace heavy metals, especially Cd, which are key to the development of bacterial resistance. A study conducted by Ali et al. (2022) revealed that concentrations of Cd as low as 0.1 mg/L were able to suppress microbial growth and initiate adaptive resistance processes [27]. Following this, Shaw and Dussan (2015) indicated that above 0.5 mg/L concentrations triggered the induction of metal efflux pumps in Pseudomonas and Escherichia coli [28].

Recent research (2021–2024) has identified even more complex mechanisms. For example, regulatory factors such as CadR and CzcR3 control resistance genes [29] and emphasize microbial mechanisms such as sequestration and enzymatic detoxification of Cd ions. Synthetic biology strategies have also facilitated increased resistance by designing efflux systems and biosensors [30]. Similarly, exposure to lead (Pb) at concentrations of 0.5 and 1.0 mg/L has been proven to increase biofilm development and horizontal gene transfer (HGT), both determinants of AMR dissemination [31]. Mercury (Hg), although at very low levels (>0.01 mg/L), particularly in its methylated state (MeHg), interferes with DNA repair and enhances mutagenesis within bacterial populations [32]. Arsenic (As) tolerance and resistance gene expressions occur at levels greater than 0.5 mg/L, and Bacillus and Pseudomonas exhibit arsenate reductase ability [33]. Copper between 1.5 and 2.5 mg/L causes oxidative stress and enhances multidrug resistance (MDR) gene expression [34]. Zinc levels of 5–10 mg/L have been correlated with enhanced antibiotic resistance through co-selection [35].

These mechanisms tend to overlap with those that confer antibiotic resistance, resulting in the co-selection and spread of MDR [36]. Existing evidence suggests that co-selection of metal and antibiotic resistance genes is ubiquitous, with integrons, transposons, and plasmids acting as vectors for the transmission of resistance [37]. Co-selection is the most concerning in heavy-metal- and antibiotic-contaminated environments, including hospital wastewater, industrial effluents, and agricultural soils [38]. Recent studies have revealed highly evolved mechanisms through which microbes interact with and alter plant cell walls, a dynamic interaction that is at the heart of both plant defense and pathogen invasion [39]. Pathogenic microbes release a versatile repertoire of cell wall-degrading enzymes (CWDEs), including cellulases, pectinases, xylanases, and ligninases, that break down structural polysaccharides and allow penetration into plant tissues [40]. Several bacteria and fungi also secrete effector proteins that regulate host cell wall remodeling pathways, inhibit immune responses, or take over host metabolism to facilitate colonization [41]. Conversely, valuable microbes, such as rhizobacteria and mycorrhizal fungi, can activate plant genes that mediate cell wall strengthening, including callose deposition and lignification, within systemic mechanisms of resistance [42]. Recent developments in imaging, transcriptomics, and metabolomics have shown that the microbial impact on plant cell wall structure is more suitable than had previously been appreciated, including not just degradation but also structural remodeling and signaling crosstalk that redefine host-microbe interactions.

A study in India found a strong correlation between heavy metal pollution in hospital effluents and the occurrence of multidrug-resistant bacteria, emphasizing the clinical significance of this phenomenon [43]. Heavy metals have implications beyond the clinical environment, affecting soil microbial populations and plant–microbe interactions [44]. The rhizosphere, an important region for plant growth, is highly susceptible to metal toxicity. HMs such as Pb, Cd, and Hg inhibit nitrogen fixation, causing a decline in crop yield and soil fertility [45]. For example, research has indicated that Cd pollution can decrease nitrogen fixation in legumes by as much as 50% [46]. Nevertheless, some rhizospheric bacteria such as Pseudomonas and Bacillus have impressive metal tolerance through detoxification enzymes, biosorption, and bioaccumulation. These microorganisms are important for reducing metal toxicity and for soil health. This review provides mechanistic information regarding the effects of HMs on antimicrobial resistance.

1.1. Molecular Mechanisms

Heavy metal contamination imposes a severe selective pressure on microorganisms, inducing molecular reactions that unintentionally foster AMR. Major environmental metals such as arsenic (As), mercury (Hg), cadmium (Cd), and lead (Pb) impose oxidative stress, destabilize the cellular redox balance, and cause DNA damage, all of which have the potential to contribute to mutations [47]. These stressors induce global regulatory systems, such as the SOS response, where RecA and LexA proteins control error-prone DNA repair, leading to the accumulation of resistance mutations [48]. Moreover, heavy metals induce biofilm development by activating quorum sensing and stress-response regulators such as rpoS to ensure survival in adverse environments [49]. Detoxifying enzymes, such as arsenate reductases, superoxide dismutase, and catalase, are also expressed to neutralize the toxicity of metals. Antibiotic and metal resistance genes tend to co-locate on plasmids, integrons, or transposons to facilitate their transfer through HGT [50]. Consequently, without antibiotic pressure, heavy metal exposure can select for antibiotic resistance traits through co-selection mechanisms. The molecular co-overlap between antibiotic resistance and metal resistance emphasizes the importance of controlling AMR in metal-contaminated environments and indicates that control measures must be integrated and account for both selective agents at the same time.

1.2. Ecological Impacts

Heavy metal pollution has significant ecological implications, particularly in terms of microbial diversity and ecosystem processes [51]. On land, particularly in the rhizosphere, the region around plant roots that is affected by metal buildup interferes with symbiotic plant–microbe relationships. Heavy metals decrease the populations of Plant Growth-Promoting Rhizobacteria (PGPR), arbuscular mycorrhizal fungi, and actinomycetes, which are involved in nutrient cycling, nitrogen fixation, and soil fertility [52]. The resulting microbial imbalance inhibits plant growth, diminishes crop yield, and degrades the long-term soil health. Freshwater ecosystems are also targeted; heavy metal inputs in industrial effluents, mining, and agriculture reshape microbial community composition, repressing indigenous, non-resistant species in favor of metal- and drug-resistant bacteria. These resistant populations are potential reservoirs of AMR genes, enabling their dissemination through horizontal gene transfer to environmental and pathogenic microbes [53]. Furthermore, metals such as Cu and Zn are commonly applied as agricultural fertilizers and feed additives, inadvertently favoring AMR in animals and nearby soil or water environments [54]. Bioaccumulation of metals in microbial food webs also amplifies environmental risks, with ripples extending to soil fauna, aquatic life, and human health via tainted produce or water. Metal-induced microbial stress also increases the generation of reactive oxygen species (ROS), triggering inflammation and DNA damage in higher organisms [55]. Hence, heavy metal pollution not only endangers microbial ecosystem services but also intensifies the global AMR burden. Unraveling these interactive processes is critical for ecosystem restoration and formulating sustainable agriculture and waste management practices in metal-affected areas [56,57].

1.3. Bioremediation Strategies

Bioremediation, or the application of microorganisms to decontaminate toxic environments, has immense potential for reducing heavy metal pollution and its role in AMR. Pseudomonas, Bacillus, Rhizobium, and Streptomyces are among the microbial groups that have developed resistance to toxic metals and can transform them into less toxic forms using mechanisms such as biosorption, biotransformation, bioaccumulation, and biomineralization [58]. These microbes sequester metal ions from their cell walls, extracellular polymeric substances (EPS), or metal-chelating proteins such as metallothioneins. Others form enzymes such as arsenate reductase, mercuric reductase, and peroxidases to enzymatically convert metals into insoluble or less toxic forms [59]. When integrated with phytoremediation, these microbes increase the plant uptake of metals and prevent oxidative damage, facilitating the recovery of contaminated soils. The use of engineered microbial communities composed of strains with specially designed detoxification abilities can also enhance remediation in situations where contamination is complex. Advancements in synthetic biology and CRISPR-mediated gene editing enable the creation of super-tolerant strains that are more resistant and effective at metal transformation [60]. Microbial bioreactors and engineered wetlands inoculated with these microbes have been found to effectively remediate wastewater and industrial effluents. In addition, horizontal gene transfer suppression and quorum-sensing inhibition research has the potential to minimize the risk of resistance spreading during remediation [61]. To achieve optimal efficiency, bioremediation needs to be complemented by environmental regulations that control the release of metals and limit metal-based antimicrobial use in agriculture [62]. Finally, microbial bioremediation presents a sustainable, low-cost means of tackling both environmental pollution and AMR risks, conserving soil fertility and water quality.

2. Effect of Metals on Plant Rhizospheric Flora

HMs such as Cd, Pb, Hg, and As are key environmental pollutants that harm rhizospheric microbiota and are very important for plant health, nutrient cycling, and soil fertility [63]. Contaminants can cause toxicity, alter microbial populations, and impede physiological functions. They bind with cellular proteins, DNA, and enzymes, causing structural and functional injuries. The primary damage is the suppression of microbial variety and growth, especially in beneficial actinomycetes, mycorrhizal fungi, and rhizobacteria [64]. Rhizobacteria provide nitrogen fixation and phosphorus solubilization, but heavy metal pollution diminishes their populations, decreases nutrient content, and damages plant growth. Mycorrhizal fungi, such as Glomus spp., enhance nutrient acquisition and resistance to soil pathogens; however, heavy metal toxicity inhibits fungal spore germination, hyphal growth, and mycorrhizal development, thereby increasing plant susceptibility to environmental stress [65]. Actinomycetes that decompose organic matter and produce antibiotics are adversely affected by heavy metal pollution (HMP) [66]. Bioremediation, organic amendments, and phytoremediation-based remediation are helpful for achieving microbial equilibrium, ensuring soil ecosystem sustainability, and enhancing agricultural productivity [67].

2.1. Nitrogen-Fixing and Phosphorus-Solubilizing Rhizobacteria

Rhizobacteria play a critical role in promoting plant growth through nitrogen fixation and phosphorus solubilization, which are essential for plant nutrition and soil fertility [68]. These bacteria, including Rhizobium, Azospirillum, and Bacillus species, convert atmospheric nitrogen into bioavailable forms and release organic acids that solubilize insoluble phosphorus compounds. However, heavy metal contamination severely disrupts the microbial communities. Cadmium, lead, arsenic, and mercury exert toxic effects by damaging cell membranes, interfering with enzyme functions, and generating oxidative stress [69]. This leads to a decline in bacterial population density and enzymatic activity, which, in turn, reduces nutrient availability to plants. Consequently, plants grown in contaminated soils often show stunted growth, chlorosis, and reduced yields [70]. Moreover, the loss of rhizobacterial functionality weakens the soil structure and resilience, further compounding the ecological impact. Restoring these microbial populations through organic amendments or microbial inoculants is crucial for sustaining soil health and ensuring efficient nutrient cycling in agroecosystems affected by heavy-metal pollution [71,72].

2.2. Mycorrhizal Fungi

Mycorrhizal fungi, particularly arbuscular mycorrhizal fungi (AMF), such as Glomus spp., form symbiotic associations with plant roots, enhance nutrient uptake, especially phosphorus, and improve plant resistance to biotic and abiotic stressors [73]. These fungi extend their hyphal networks into the soil, thereby increasing the root surface area and facilitating nutrient and water absorption. However, heavy metals such as cadmium and arsenic adversely affect mycorrhizal fungi by inhibiting spore germination, disrupting hyphal elongation, and impairing the colonization of plant roots [74]. This diminishes the ability of fungi to protect plants against droughts, pathogens, and other environmental stressors. Additionally, heavy metal stress can alter the community structure and biodiversity of mycorrhizal fungi, weaken their ecological functions, and compromise their mutualistic relationship with host plants [75]. The resulting nutrient deficiency and stress sensitivity in plants negatively affect growth and productivity. To mitigate these effects, practices such as applying mycorrhizal bioinoculants and organic soil amendments are recommended to promote mycorrhizal recovery and support plant–microbe symbiosis in contaminated environments [76].

3. Impact of Metal on Soil and Plant Health

3.1. Antioxidant Enzymes in Microbial Ros Detoxification

Microbes synthesize antioxidant enzymes to counteract oxidative stress, which neutralizes ROS and restores cellular homeostasis [77]. The three most important enzymes involved in ROS detoxification are superoxide dismutase (SOD), catalase (CAT), and peroxidases [78]. SOD is a protective mechanism against ROS, catalyzing the dismutation of superoxide radicals into hydrogen peroxide (H₂O₂) and molecular oxygen [79]. Several forms of SOD in bacteria increase SOD expression in metal-contaminated environments to avoid oxidative damage [80]. Catalase, in addition to SOD, destroys hydrogen peroxide, a stable ROS, and generates hydroxyl radicals in the presence of transition metals such as iron [81]. Most metal-resistant bacteria exhibit high catalase activity to prevent oxidative damage. Peroxidases, including glutathione peroxidase and alkyl hydroperoxide reductase, also break down hydrogen peroxide and organic peroxides using reducing agents such as glutathione or NADPH [82]. Peroxidases are essential in metal-tolerant bacteria to avoid lipid peroxidation, which is the primary effect of oxidative stress that causes membrane damage [83].

3.2. Metal-Reducing Enzymes: Detoxification Through Biotransformation

Metal-reducing enzymes in microbes, such as arsenate reductase (ArsC) in Pseudomonas and other metal-resistant bacteria, help transform toxic metal ions into less toxic or less bioavailable forms [84]. Arsenic contamination is a serious environmental problem, particularly in groundwater and agricultural soil. Pseudomonas, along with ArsC, can thrive in arsenic-polluted environments and has bioremediation applications. Other metal-reducing enzymes include Mercury Reductase (MerA), Chromate Reductase, and Ferric Reductase, which oxidize toxic metals into less toxic or bioavailable forms [85]. Heavy metal pollution, including Cd, Cu, Pb, Hg, and Zn, is toxic to bacteria, even at low doses, interfering with cell functions and forming reactive oxygen species. Metal efflux pumps are membrane-bound proteins that are transported across the bacterial cell membrane and play a critical role in bacterial survival in metal-contaminated niches and bioremediation [86]. Efflux pumps enable bacteria to endure and remove heavy metals from the ecosystem, thereby maintaining metal homeostasis and minimizing intracellular toxicity [87].

3.3. Relationships of Symbiotic Alteration

Mycorrhizal fungi, such as Glomus spp., form symbiotic associations with plant roots to enhance water and nutrient acquisition. However, heavy metals, such as Cd, Pb, and Zn, disrupt the germination of fungal spores, elongation of hyphae, and root colonization. This leads to reduced mycorrhizal benefits and phosphorus availability, nutrient starvation, reduced growth, and increased exposure to environmental stresses [88]. Legume–rhizobial symbiosis, an important process in biological nitrogen fixation, is negatively affected by heavy metals. Rhizobia develop nodules on leguminous plant roots, which fix atmospheric nitrogen to ammonia, which can be absorbed by the plant, suppress rhizobial adherence to host roots, decrease nodule formation, and disrupt nitrogenase enzyme action, leaving less nitrogen available to support plant development [89]. In addition, heavy metals restructure the synthesis of chemical signaling molecules, including flavonoids and lipochitooligosaccharides, which allows communication between plants and symbiotic microorganisms [90]. This modification compromises the mutualistic relationships required by plants to achieve improved nutrient uptake and stress resistance. To counteract these effects, interventions such as soil amendments, bioremediation using metal-tolerant microbial strains, and phytoremediation with metal-accumulating plants can assist in the recovery of microbial symbiosis and enhance plant resistance in polluted environments [91].

3.4. Increased Pathogen Susceptibility

HM contamination in the soil disturbs microbial equilibrium, weakening beneficial microbes that are pivotal to plant defense and disease susceptibility. Beneficial bacteria and fungi suppress plant diseases by competing for nutrients, synthesizing antimicrobial substances, and boosting the plant immune system [92]. This imbalance makes plants more vulnerable to disease, resulting in tremendous agricultural losses. One of the major effects of HM stress is the reduction of PGPR, such as Pseudomonas and Bacillus, which are responsible for the production of secondary metabolites that inhibit the growth of soil-borne pathogens [93]. Heavy metals disrupt bacterial metabolism and decrease their capacity to produce protective agents; hence, pathogens such as Fusarium and Pythium have a competitive edge [94]. Mycorrhizal fungi, which create symbiotic relationships with plant roots and act as protectors against soil pathogens, are negatively affected by heavy metals. The collective effects of heavy metal stress on beneficial microorganisms and plant immunity lead to increased disease prevalence and reduced agricultural yields [95]. To reduce the impact of heavy-metal-induced pathogen susceptibility, bioremediation processes involving metal-tolerant microbial strains, organic amendments, and phytoremediation with metal-hyperaccumulating plants can be used to reverse the loss of microbial diversity and increase plant resistance.

4. Metal Efflux Pumps in Bacteria Mechanisms

Microorganisms employ diverse and specialized metal efflux systems to maintain metal homeostasis and prevent toxicity. Among them, P-type ATPases like CopA actively export toxic metal ions such as copper (Cu²⁺) from the cytoplasm using ATP hydrolysis, thus protecting bacterial enzymes and DNA from metal-induced damage [96]. Resistance-Nodulation-Division (RND) transporters, common in Gram-negative bacteria, utilize proton motive force to export heavy metals and antibiotics, exemplified by the CzcABC system in Cupriavidus metallidurans, which facilitates the efflux of cobalt, zinc, and cadmium [97]. Cation Diffusion Facilitators (CDFs), such as ZntA in Escherichia coli, operate via passive transport or ion exchange to export divalent metals like Zn²⁺ and Cd²⁺, preventing metabolic disruption [98] (Figure 1). ATP-Binding Cassette (ABC) transporters, including the ArsAB system, use ATP hydrolysis to actively expel metals like arsenite (As³⁺) and are involved in both import and efflux, impacting stress response, antibiotic resistance, and virulence [99] (Figure 2). These systems are vital for microbial survival in metal-rich environments and hold therapeutic and agricultural relevance.

5. Positive Effects: Role of Metal-Tolerant Microbes

5.1. Metal Immobilization and Detoxification

Metal-resistant fungi and bacteria have developed mechanisms to immobilize and clean toxic metals via biosorption, biotransformation, and biomineralization [100]. Such strategies reduce the access of metals to plants for root uptake and limit toxicity. Bioremediation is a non-polluting green technology, in which microbial processes are employed to detoxify HMs [101]. Biosorption immobilizes heavy metals by the biotransformation of cell wall components biotransformation converting metals into less toxic or insoluble states, and biomineralization precipitates metals into stable mineral phases (Table 1).

5.2. Metal Stress Enhancement of Plant Growth

Plant Growth-Promoting Rhizobacteria (PGPR) are very important in plant adaptation to metal stress through physio-biochemical mechanisms to grow resistance [102]. These environmentally beneficial microbes neutralize metal toxicity by producing stress-relieving enzymes, enhancing nutrient availability, and activating plant defense systems, ultimately optimizing the health and productivity of plants under contaminated conditions [103,104]. Another important method for facilitating plant growth under metal stress is the production of 1-aminocyclopropane-1-carboxylate (ACC) deaminase [105]. The enzyme breaks down ACC into α-ketobutyrate and ammonia, which decreases the ethylene content in plants, promoting root elongation, nutrient uptake, and overall plant growth [106]. PGPR also increase metal stress tolerance in plants by triggering system resistance to oxidative stress. Exposure to heavy metals, such as cadmium, lead, and arsenic, produces reactive oxygen species (ROS), leading to lipid peroxidation, DNA damage, and protein oxidation (Table 1).

Table 1. Some examples of PGPR with demonstrated efficacy in mitigating heavy metal stress.

PGPR Strain	Target Heavy Metal (s)	Host Plant	Mechanism of Action	Reference
Pseudomonas fluorescens	Zinc (Zn), Cadmium (Cd)	Brassica juncea	ACC deaminase activity, Zn/Cd biosorption, antioxidant enzyme induction	[107]
Bacillus subtilis	Lead (Pb)	Zea mays	Cell wall binding, phytohormone production, Pb detoxification	[108]
Enterobacter cloacae	Arsenic (As)	Oryza sativa (rice)	Arsenite oxidation, metal exclusion, enhanced root architecture	[109]
Azospirillum brasilense	Nickel (Ni)	Triticum aestivum	Indole-3-acetic acid (IAA) production, Ni stress alleviation	[110]
Rhizobium leguminosarum	Chromium (Cr)	Lens culinaris	Siderophore production, improved nutrient uptake, Cr sequestration	[111]
Serratia marcescens	Copper (Cu)	Solanum lycopersicum	Biofilm formation, Cu efflux, antioxidant enzyme upregulation	[112]

Table 1. Some examples of PGPR with demonstrated efficacy in mitigating heavy metal stress.

PGPR Strain	Target Heavy Metal (s)	Host Plant	Mechanism of Action	Reference
Pseudomonas fluorescens	Zinc (Zn), Cadmium (Cd)	Brassica juncea	ACC deaminase activity, Zn/Cd biosorption, antioxidant enzyme induction	[107]
Bacillus subtilis	Lead (Pb)	Zea mays	Cell wall binding, phytohormone production, Pb detoxification	[108]
Enterobacter cloacae	Arsenic (As)	Oryza sativa (rice)	Arsenite oxidation, metal exclusion, enhanced root architecture	[109]
Azospirillum brasilense	Nickel (Ni)	Triticum aestivum	Indole-3-acetic acid (IAA) production, Ni stress alleviation	[110]
Rhizobium leguminosarum	Chromium (Cr)	Lens culinaris	Siderophore production, improved nutrient uptake, Cr sequestration	[111]
Serratia marcescens	Copper (Cu)	Solanum lycopersicum	Biofilm formation, Cu efflux, antioxidant enzyme upregulation	[112]

5.3. Reactive Oxygen Species (Ros) Generation

Management of bacterial ROS under metal stress is crucial for their survival, affecting microbial diversity and ecological processes in contaminated environments. One of the major sources of ROS in bacteria exposed to heavy metal stress is the Fenton reaction between Fe²⁺ and hydrogen peroxide, which forms hydroxyl radicals (•OH) [113]. Such harmful ROS may interact with cellular macromolecules and induce mutations, enzyme inactivation, and membrane disruptions. Redox cycling metals, such as iron and copper, also help produce ROS by being involved in electron transfer reactions, shuttling between their oxidized and reduced forms, and unintentionally causing persistent generation of ROS [114]. In the absence of functional SOD and catalase, bacterial cells accumulate toxic ROS, resulting in damage to the cell membrane, protein misfolding, and apoptosis-like cell death. Heavy metals also interfere with the bacterial electron transport chain (ETC) of cellular respiration, enhancing ROS leakage [115]. Arsenic and chromium interfere with electron transfer in the ETC, resulting in electron leakage and suboptimal oxygen reduction, with the formation of excessive superoxide and hydrogen peroxide [116]. Hydrogen-mediated ROS formation has significant ecological impacts, modifying the microbial community composition and function. Metal-resistant organisms, such as Pseudomonas and Bacillus strains, develop adaptive processes to endure oxidative stress and strengthen antioxidant systems, metal efflux pumps, and biofilm formation capabilities [117]. Knowledge of these processes is essential for creating bioremediation applications that utilize metal-resistant bacteria to recover from contaminated environments and avoid heavy metal toxicity.

5.4. Plant-Related Oxidative Stress Impacts

Oxidative stress in plants occurs when reactive oxygen species (ROS), such as superoxide (O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radicals (•OH), accumulate beyond the detoxifying ability of plant defense mechanisms. This accumulation is generally due to environmental stresses caused by heavy metal toxicity, salinity, drought, and pathogen infection [118]. The effects of ROS overproduction include lipid peroxidation, which disrupts cellular membrane integrity, DNA, and protein oxidation, which disrupts genetic stability and enzyme activity and inhibits photosynthesis and cellular signaling [119]. To offset these effects, plants trigger a set of enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX), which act in combination to neutralize ROS [120]. Plant Growth-Promoting Rhizobacteria (PGPR) further develop plant resistance through the synthesis of antioxidant enzymes, nutrient mobilization, and root growth promotion [121,122]. PGPR also aid metal detoxification by biosorption and ACC deaminase activity, thus reducing oxidative stress and enhancing plant health under stressful conditions.

5.5. Bioremediation Applications and Link to AMR

Bioremediation uses metal-tolerant microorganisms to remove heavy metals by detoxification via processes such as biosorption, biotransformation, and biomineralization, which enhance the quality of soil and facilitate plant growth in polluted environments. Microbial activities not only reduce metal toxicity but also enhance sustainable ecosystem recovery [123]. However, exposure to pollutants causes oxidative stress in microbes, resulting in the buildup of reactive oxygen species (ROS) that damage DNA, initiate genetic mutations, and induce biofilm growth as a defense mechanism [124]. Oxidative stress also initiates stress response regulons, which increase microbial survival in unfavorable environments. Such adverse environments are highly associated with the development and dissemination of AMR [125]. Chronic oxidative stress enhances horizontal gene transfer, whereas selective pressure from metal exposure enhances the survival of resistant populations [126]. Heavy metal pollution also tends to co-select antibiotic resistance genes in addition to the AMR threat. Thus, microbial bioremediation not only rehabilitates environmental well-being, but is also critical in truncating the spread of AMR, providing both ecological and public health advantages [127].

5.6. Oxidative Damage to Cellular Components

Oxidative stress compromises bacterial viability and modulates microbial communities in metal-polluted habitats [128]. DNA damage is a serious outcome, because ROS target nucleotides, resulting in base alterations, strand breaks, and mutations. Hydroxyl radicals form double-strand breaks (DSBs), which are extremely toxic if not repaired accurately. Additionally, oxidative stress enhances the potential for mutagenesis, possibly resulting in antibiotic-resistant mutations [129]. Bacteria subjected to heavy metal stress can acquire adaptive mutations in DNA repair genes, efflux pump regulators, or ribosomal proteins, which increases their survival in metal-contaminated and antibiotic-exposed environments [130]. Such interactions between oxidative stress and genetic adaptation are of concern regarding the evolution of multidrug-resistant bacterial strains in contaminated environments [131]. Certain metal-resistant bacteria have developed adaptive strategies to survive in polluted soils and water bodies, including increased production of antioxidant enzymes, biofilm formation, and activation of DNA repair processes [132]. Uncovering the molecular effects of oxidative damage is important for designing efficient bioremediation approaches and alleviating the ecological hazards caused by heavy metal contamination.

6. Link Between Oxidative Stress and Antimicrobial Resistance

Oxidative stress plays a critical role in the rapid development of AMR. Reactive oxygen species, such as superoxide, hydroxyl radicals, and hydrogen peroxide, damage bacterial DNA, proteins, and membranes, thereby inducing genetic instability [133]. Damage enhances the mutation frequency and facilitates HGT, resulting in the development of multidrug-resistant (MDR) bacterial strains. DNA damage may cause single-strand breaks, double-strand breaks, and base modifications, especially if they take place in antibiotic target site-containing genes, efflux pump control genes, and DNA repair pathway genes [134]. Alterations in these genes may lead to resistance to fluoroquinolone antibiotics and aminoglycosides such as streptomycin and kanamycin [135]. The SOS response is a bacterial global regulatory network that responds to DNA damage, especially under stress conditions such as oxidative exposure [136]. This response allows cells to trigger DNA repair processes in addition to ensuring survival under genotoxic stress. RecA, the central regulator of the SOS response, is a highly significant DNA-binding protein [137]. When detecting single-stranded DNA resulting from damage, RecA is activated and promotes autocleavage of LexA, a repressor of transcription that normally suppresses SOS genes [138,139]. Cleavage derepresses DNA repair, cell cycle control, and error-prone replication genes. Therefore, mutagenic DNA polymerases are produced, elevating the mutation frequency and allowing rapid adaptation of bacterial populations to adverse environments [140]. In addition to beneficial mutations, lethal mutations confer adaptive advantages such as resistance to several antibiotics. Hybrid gene transfer is another major determinant of AMR evolution [141]. Metal-resistant bacteria have metal and antibiotic resistance genes co-located in the same MGEs, resulting in co-selection for AMR [142]. Oxidative stress also affects efflux pump expression and drug resistance. Oxidative stress promotes the development of multidrug-resistant bacteria by increasing the rate of mutation, SOS induction, horizontal gene transfer, and efflux pump regulation [143].

6.1. Fluoroquinolone Resistance Results from Mutations in DNA Gyrase (gyrA and gyrB) Caused by ROS Damage

Reactive oxygen species play a role in bacterial mutagenesis by inducing mutations in the DNA gyrase genes gyrA and gyrB which are critical for DNA replication and supercoiling [144]. Oxidative damage results in fluoroquinolone resistance, which is a considerable problem in both clinical and environmental settings. Fluoroquinolone antibiotics such as ciprofloxacin and levofloxacin inhibit the enzymatic activity of DNA gyrase, resulting in double-strand breaks and bacterial cell death [145]. However, oxidative stress due to heavy metals or antimicrobial compounds can trigger mutations in gyrA and gyrB changing the conformation of the DNA gyrase enzyme and decreasing the fluoroquinolone-binding affinity [146,147]. ROS-mediated DNA damage triggers the SOS response, a RecA- and LexA-regulated bacterial stress response [148]. The error-prone DNA polymerases Pol IV and Pol V are induced by inserting random mutations into the bacterial genome, including gyrA and gyrB [149]. This accelerates bacterial adaptation and favors the evolution of fluoroquinolone resistance. The heavy metals Cd, Pb, and As induce ROS production, enhancing mutation rates in bacteria [150]. Such bacteria co-evolve resistance mechanisms and tend to develop cross-resistance to both fluoroquinolones and metals owing to genetic mutations in DNA gyrase [151]. It is important to understand these mechanisms to develop a new therapeutic approach to combat antibiotic resistance and restrict the transfer of drug-resistant bacteria into contaminated ecosystems [152].

6.2. Mutations in Ribosomal Proteins (rpsL and rrl) Confer Aminoglycoside Resistance

Aminoglycoside antibiotics such as streptomycin, gentamicin, kanamycin, and amikacin bind to bacterial ribosomes, inhibit protein synthesis, and cause cell death [153]. However, mutations in ribosomal protein genes (rpsL and rrl) modify the structure of ribosomes, decreasing the binding affinity of aminoglycosides and giving rise to resistance [154]. Oxidative stress increases these mutations, which, in turn, drives the emergence of aminoglycoside-resistant bacterial strains. Aminoglycosides interact with the 30S ribosomal subunit, where they bind to 16S rRNA and ribosomal protein S12, inducing misreading of mRNA and inclusion of incorrect amino acids, resulting in defective protein synthesis and cell death [155,156]. Such rpsL resistance mutations are K43R and K88R in Escherichia coli and Mycobacterium tuberculosis, respectively, which compromise the ability of the antibiotic to cause translational errors and allow bacteria to survive despite treatment [157]. Universal resistance mutations in rrl involve alterations in nucleotide interactions and reduced aminoglycoside affinities [158]. General resistance mutations in rrl are A1408G and C1409U in Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively, which disrupt hydrogen bonding with aminoglycosides, thereby reducing their effectiveness [159]. HMs and antibiotic-induced oxidative stress cause ROS-mediated DNA damage, activation of the SOS response, and selective pressure, favoring the survival of aminoglycoside-resistant mutants [160,161]. Aminoglycoside-resistant microorganisms pose a significant challenge for the treatment of E. coli, Mycobacterium tuberculosis, and Staphylococcus aureus infections [162]. The horizontal transfer of genes in resistant bacteria occurs at a high rate, increasing the possibility of drug resistance in hospitals and environmental settings. Identification of such mechanisms is critical for designing alternative therapies and mitigating the development of drug-resistant bacterial infections.

6.3. Metal Stress-Induced SOS Response Increasing Resistance Mutations

Heavy metal (HM) stress can cause direct damage to bacterial DNA, thus inducing the SOS response, a RecA- and LexA-regulated conserved bacterial survival strategy [163]. Under unstressed, normal conditions, LexA is a transcriptional repressor that maintains the repressed status of DNA repair genes [164]. However, when HMs create DNA lesions, RecA, which detects single-stranded DNA, is activated and induces autocleavage of LexA [165]. This depression in SOS genes triggers a DNA repair response. Although the SOS response is crucial for the survival of bacteria under genotoxic stress, it occurs at the expense of genomic stability [166]. These mutations may result in clinically relevant resistance, such as changes in DNA gyrase genes, causing resistance to fluoroquinolones, or altering target sites for aminoglycosides. Furthermore, SOS induction increases the mobilization of mobile genetic elements, promoting increased horizontal transfer of resistance genes. As a result, metal stress not only causes mutations in individual cells, but also selects and enables the transmission of multidrug-resistant (MDR) bacterial strains in the environment [167]. It is important to identify this causal mechanism to design novel therapeutic interventions and policies to reduce the co-selection pressure exerted by environmental metal pollution on antimicrobial resistance.

6.4. Horizontal Gene Transfer (HGT) and Co-Selection of AMR Genes

HGT is a system by which bacteria share genetic information regardless of cell division, enabling the rapid establishment of new traits, including AMR. HGT occurs through three principal mechanisms: transformation (free DNA uptake), transduction (phage-mediated gene transfer), and conjugation (plasmid transfer among cells). Stress factors such as heavy metals, antibiotics, and oxidative stress may boost HGT through enhanced genetic mobility and stress-induced mutagenesis [168]. This provides a context in which the resistance genes, although not related to immediate selective pressure, are maintained because of co-selection. Co-selection occurs when antibiotic and heavy metal resistance genes exist on the same mobile genetic elements as plasmids, integrons, or transposons and are exchanged during HGT. Exposure to a single selective agent such as heavy metals can induce persistence and transmission of antibiotic resistance genes, exacerbating the AMR crisis in both clinical and environmental contexts [169].

HM and antibiotics exert selective pressures on bacterial populations that lead to the co-selection of resistance genes as well as their accumulation (Table 1). Bacteria subjected to HM have evolved means of resistance, which often overlaps with those used for antibiotic resistance. This cross-protection is primarily brought about by efflux pumps, biofilms, enzymatic detoxification, and HGT, which enable bacteria to tolerate metal toxicity and antibiotic treatment, including CzcABC, P-type ATPases, and AcrAB-TolC, which actively export toxic metal ions and antibiotics [170]. Upregulation of biofilm production in response to HM stress indirectly enhances antibiotic resistance. Enzymatic detoxification pathways, such as arsenate reductase (arsC), catalase (CAT), and superoxide dismutase (SOD), are essential for preventing metal- and antibiotic-induced oxidative stress [171]. Heavy metals generate ROS, which oxidize bacterial lipids, proteins, and DNA, thereby triggering bacteria to activate detoxification enzymes. Hybrid gene transfer contributes to increased co-selection of metal and antibiotic resistance genes. Resistance genes are most often found in plasmids, transposons, and integrons and may be transferred between bacteria via conjugation, transformation, and transduction [172]. HM in the environment selects heavy-metal-resistant bacteria that may or may not carry resistance genes on plasmids, promoting the dissemination of antibiotic resistance, even in the absence of antibiotics (

Table 2. Heavy metal resistance genes and plasmid resistance sites.

Resistance Mechanism	Genes Involved	Binding Site	Resistance Site	References
Mercury	merA, merB, merC, merD, merE, merR, merT	Operon	Mercury detoxification and efflux	[173]
Copper	copA, copB, copC, copD, and pcoA, pcoC, pcoD	Operon	Involved in copper efflux	[174]
Zinc	zntA, zntB, zntC	Operon	Involved in zinc efflux	[175]
Arsenic	arsA, arsB, arsC, arsD, arsR, arsH	Operon	Arsenic detoxification and efflux	[176]
Cadmium	czcA, czcB, czcC, czcD	Operon	Cadmium involved in efflux	[177]
Lead	pbrA, pbrB, pbrC, pbrT	Locus	Lead involved in efflux and uptake	[178]
Nickel	ncrA, ncrB, ncrC	Operon	Involved in nickel efflux	[179]
Chromium	chrA, chrB, chrC	Operon	Involved in chromium efflux	[180]

).

6.5. Plasmid-Mediated Resistance Metal Stress

Plasmid-mediated resistance is facilitated by heavy metal stress, particularly with respect to the increased transfer of resistance plasmids carrying antibiotic resistance genes (ARGs) [181]. Under metal-polluted conditions, bacteria are subjected to selective pressure, which selects for the survival and growth of strains possessing mobile genetic elements (MGEs), such as plasmids, transposons, and integrons. This facilitates rapid adaptation and dissemination of resistance features by HGT, mostly through conjugation. Under heavy metal stress, bacteria induce stress response mechanisms such as the SOS response, which increases the expression of conjugative transfer genes [182]. Metal ions cause DNA damage and oxidative stress, leading to RecA-dependent induction of the SOS system. This enhances the mobility of R-plasmids and facilitates the exchange of resistance genes among bacterial populations [183]. Metal exposure upregulates type IV secretion systems (T4SS) necessary for plasmid transfer and promotes the propagation of AMR [184]. Numerous R-plasmids have both heavy metal resistance (HMR) and antibiotic resistance determinants; as a result, co-selection ensues where metal stress inadvertently results in antibiotic-resistant bacteria, even without exposure to antibiotics [185].

7. Biofilm Formation and Antibiotic Tolerance

Bacterial survival and resilience are facilitated by reactive oxygen species (ROS) and cellular ROS, which are produced as metabolic end products or triggered by extracellular stress agents, such as heavy metals, antibiotics, and host immunity, and affect the survival and tolerance of bacteria to extreme environmental conditions [186]. In accordance with oxidative stress, biofilm-associated regulatory mechanisms in bacteria induce biofilm formation as a mode of protective survival [187]. One major mechanism is the stimulation of quorum sensing (QS), a cell-to-cell communication system that controls gene expression as a function of cell population density [188]. Oxidative stress can activate QS gene expression by modifying redox-sensitive regulatory networks, thus increasing the synthesis of signaling molecules such as N-acyl homoserine lactones (AHLs) in gram-negative bacteria or autoinducing peptides in gram-positive bacteria [189]. These signaling molecules, in turn, orchestrate the collective behavior required for strong biofilm establishment and stress tolerance [190]. One key participant in this stress-adaptive mechanism is the rpoS gene, which produces the alternative sigma factor σ^S, a general stress response master regulator in most gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa [191]. During oxidative stress, higher ROS levels activate rpoS transcription and stabilization, which in turn activates a set of genes for antioxidant defense, DNA repair, and notably, biofilm formation [192]. rpoS-regulated responses favor the production of extracellular polymeric compounds (EPS) and increase the expression of QS-regulated biofilm genes [193], thus connecting oxidative stress perception to quorum-sensing-mediated communal behavior [194]. In the biofilm mode, the bacteria are ensconced in a protective matrix of EPS that is replete with antioxidant enzymes such as catalase and superoxide dismutase, which neutralize ROS and protect cells against antibiotics and host immune responses. The role of rpoS here is emphasized by the evidence that rpoS-defective mutants produce substantially reduced numbers of biofilms, with a crucial role in oxidative stress-regulated biofilm control [195]. Knowledge of the molecular crosstalk between oxidative stress, quorum sensing, and rpoS-controlled biofilm formation provides exciting prospects for anti-biofilm therapy development [196]. These involve quorum-sensing inhibitors, agents modulating ROS, and rpoS-targeting approaches to counteract multidrug-resistant (MDR) bacterial infections and environmental biofilm-related challenges [197].

Metals and Antibiotics Are Biofilms That Increase Multidrug Tolerance

Biofilms, which are colonies of microorganisms, are protected from environmental stressors such as heavy metals and antibiotics by an EPS matrix. Biofilms provide bacteria with the means to survive hostile conditions, which results in chronic infections and multidrug tolerance (MDT) [198]. The EPS matrix, consisting of proteins, lipids, polysaccharides, and extracellular DNA, creates a barrier that prevents the entry of metals and antibiotics and lowers the effective concentration of toxic chemicals [199]. Some bacteria produce negatively charged compounds that chelate metal ions, thereby lowering toxicity and bioavailability. Antibiotics experience limited diffusion and decreased efficacy in biofilms, allowing bacteria to trigger stress responses before reaching lethal concentrations [200]. β-lactamases and aminoglycoside-modifying enzymes are typically integrated into the matrix, degrading antibiotics before they reach bacterial cells. Biofilms create heterogeneous microenvironments, resulting in various metabolic states. Latent or slow-growing bacteria in the lower layers become tolerant to antibiotics through loss of sensitivity, and consequently, reiterative attacks produce chronic infections. Multidrug-resistant infections caused by biofilms are major contributors to hospital and environmental infections [201]. Determining how biofilms protect bacteria against metals and antibiotics is important for the development of new antibiofilm approaches. Exposure to high Cu concentrations triggers oxidative and envelope stress responses that stimulate biofilm production, a primary survival trait that increases bacterial resistance to environmental stress and antibiotics [202]. This stress also causes overproduction of efflux pumps, such as the MexAB-OprM system, which contributes to intrinsic and acquired resistance to several antibiotics, including carbapenems, a vital class of β-lactam antibiotics for the treatment of multidrug-resistant infections [203]. The MexAB-OprM efflux pump expels toxic metals and antibiotics that directly connect metal stress to antimicrobial resistance in a direct manner [204]. Moreover, exposure to copper has been found to induce the expression of quorum sensing and rpoS-associated genes, further contributing to biofilm maturation and persistence [205]. These are examples of how exposure to heavy metals indirectly promotes the evolution and persistence of AMR.

8. Environmental and Clinical Implications

Heavy metal contamination is a major factor in the development of antibiotic-resistant bacteria, making AMR a global health concern. Pb, Cd, Cu, and Ag are among the heavy metals released into the environment from mining, agricultural, and industrial effluents [206]. In addition, to directly poison microbes, these metals also function as selection pressures to promote the growth and survival of antibiotic-resistant bacteria. As most bacterial metal resistance mechanisms, such as efflux pumps, biofilm formation, and oxidative stress responses, are similar to those of antibiotic resistance, this choice was selected [207]. AMR hotspots have emerged in heavy-metal-contaminated environments, and resistant bacteria are likely to spread in clinical settings. Long-term pollution is caused by the discharge of hazardous metal ions into soil and water bodies through mining operations, metal processing businesses, and factory effluents. Selective pressure that supports resistant microbial communities is introduced by agricultural runoff from pesticides, fertilizers, and animal manure that contains trace metals [208]. Once bacteria acquire metal resistance, they often develop cross-resistance to antibiotics, owing to the shared resistance mechanisms of metal efflux pumps and stress response pathways. A specific source of AMR hotspots is hospital wastewater, which contains a cocktail of antibiotics, disinfectants, heavy metals from medical devices, plumbing agents, and sterilizing agents. Combined exposure to these stressors has a synergistic effect that promotes co-selection, favoring bacterial populations resistant to both metals and antibiotics [209]. In contrast to antibiotics, the long-term environmental persistence of HMs places a continuous selective pressure on microbial populations, enabling resistant bacteria to propagate and spread within polluted ecosystems, thus increasing the risk of human transmission via food, water, and direct exposure to the environment. Antimicrobials based on heavy metals, including silver nanoparticles and copper antimicrobials, have been used in medical devices, wound dressings, disinfectants, and agricultural products because of their high-spectrum antimicrobial effects and correlation metal and antibiotic resistance in clinical and environmental implications (

Table 3. According to some studies, there are clinical and environmental repercussions when metals and antibiotic resistance are linked.

Heavy Metals	Clinically Relevant Microorganism(s) Exhibiting Co-Selection	Antibiotics	Reference
Cadmium	Salmonella Typhi	Ciprofloxacin, ceftizoxime, ampicillin, chloramphenicol	[210]
Lead, cadmium, mercury, tellurite, cobalt, copper	Klebsiella pneumoniae	Aminoglycosides, Streptomycin, Rifampicin, Beta-lactams, Gentamicin, Trimethoprim, Chloramphenicol	[211]
Cadmium, copper	Streptococcus agalactiae	Lincosamide, Macrolide	[212]
Lead	Pseudomonas spp.	Cefepime, Colistin, Levofloxacin	[213]
Lead	Salmonella Typhi	Ampicillin-Sulbactam, Nalidixic Acid, Levofloxacin	[213]
Lead	Members of Enterobacteriaceae	Tetracycline, Co-Trimoxazole, Third and Fourth generation Cephalosporins, Ciprofloxacin, Gentamycin	[213]
Lead	Staphylococcus aureus	Amoxicillin/Clavulanic Acid, Cefoxitin, Co-Trimoxazole, Amoxicillin/Clavulanic Acid	[213]
Cadmium, Zinc	Staphylococcus aureus	Methicillin	[214]
Arsenic, Silver, Copper	Klebsiella pneumoniae, Escherichia coli	Macrolides, Trimethoprim, Beta-lactams, Tetracyclines, Aminoglycosides	[215]
Copper, Zinc	Pseudomonas aeruginosa	Carbapenem	[216]
Cadmium	Klebsiella pneumoniae, Pseudomonas aeruginosa	Sulphonamides, Kanamycin, Oxacillin, Nalidixic Acid	[217]
Chromium, Lead	Staphylococcus aureus	Oxacillin, Penicillin G, Methicillin	[218]
Cadmium	Stenotrophomonas maltophilia	Macrolide	[219]
Mercury	Members of Enterobacteriaceae, Oral Streptococci	Tetracycline, Ampicillin, Streptomycin	[220]
Mercury	Escherichia coli	Kanamycin, Chloramphenicol, Streptomycin, Tetracycline	[221]
Arsenic, Mercury, Cadmium	Pseudomonas aeruginosa	Chloramphenicol, Streptomycin, Kanamycin	[222]
Mercury, Silver	Salmonella Typhimurium	Ampicillin, Chloramphenicol	[223]
Mercury	Staphylococcus aureus	Penicillin	[224]

).

9. Bioremediation Using Metal-Resistant Bacteria

Bioremediation is a suggested approach to mitigate environmental metal pollution. This involves the use of metal-resistant fungi and bacteria to adsorb, convert, or precipitate poisonous metals, thereby decreasing their bioavailability [225]. Microorganisms such as Pseudomonas putida, Bacillus subtilis, and Rhodococcus spp. immobilize heavy metals via biosorption and bioaccumulation, producing exopolysaccharides and metallothioneins are produced [226]. This can reverse the ecological balance and minimize selective pressure on AMR bacteria. Control of HMP from industry and agriculture is necessary to curb pollution and affect bacterial resistance. The implementation of wastewater treatment procedures and sustainable farming practices can mitigate the accumulation of metals in agricultural fields and products [227]. The combination of drugs acting against efflux pumps and antibiotic resistance mechanisms is promising for the reversal of cross-resistance. Scientists are currently investigating efflux pump inhibitors (EPIs) to inhibit metal and antibiotic efflux in bacteria, thereby rendering pathogens more accessible for treatment. Combination treatments target bacterial vulnerabilities when stressed with metals. For example, antibiotics combined with metal chelators act synergistically [228]. EDTA and chelators have been established to increase β-lactam antibiotic activity against resistant bacteria through destabilization of biofilms and inhibition of metalloenzymes.

Table 4. Heavy metal accumulator species in soil.

Heavy Metals	Accumulator Species	Climate Condition	Experimental Condition	Concentration in Plants	References
Group of rare earth elements (REE)	Dicranopteris linearis	Annual Rainfall Temperature (ART)	Chinese plants grown from mining tailings	Dry Weight (DW) Biomass milligram/g Total REE; 2.70 billion	[229]
Sc	Cyperus Rotundus L.	ART	Plant grown on pH 4.4–7.5 media soil from a former mining region in Lahat, Malasia	Flower (8.21 µg/g), Leaves (204.60 µg/g), Stem (18.84 microgram/g), Root (280.83 µg/g) DW	[230]
Sc	Dicranopteris linearis (Burn) (B)	ART	Soil (pH 4.4–7.5); plant from a former mining region near Lahat, Malasia	Lamina (478.50 µg/g), Petiole (26.57 µg/g), Shoot (24.53 µg/g), Root (312.41 microgram/g) DW	[230]
Sc, REE	Dicranopteris dichotoma	ART	Plants from a former mining region in Lahat, Malasia Media; soil (pH 4.4–7.5); plants gathered from China	Biomass (mg/kg) Se 121 Cr 155 Nd 511 La 929 Roots (33.16 µg/g), Shoots (177.83 µg/g), Leaves (33.40 µg/g) DW	[230,231]
Se, Cr, Ba	Brassica juncea (glycophyte)	ART 26/21 °C	Media: perlite/gravel combination (2:1, v/v)	Mas. fresh weight; Roots (4017 mg), Shoots (9471mg), Whole plant (13,488 mg); (Ba concentration 100µM) Tolerance index; 112–183% of the whole plant leaf. Se 2600 mgCr/kg DW Cr 1000 mgSe/killogram DW Se 35 mgCr/kg/dl root Cr 1150 mg Se/kg DW	[232,233]
Ba	Abelmoshush esculentus L.	ART 12/25 °C (Night/Day)	Plant: Tunisia Media, Baddar Company; blend gravel and perlite/gravel (1:2, v/v)	Ba in Fruits (150–450 mg/kg), Shoots (200–900 microgram/killogram), Roots (450–1100 mg/kg) DW	[234]
Ba	Cakile maritima (Halophyes)	ART 25 ± 5 °C	Media: perlite/gravel combination (2:1, v/v)	Mas. Fresh weight in roots (1339 mg), Shoots (13,019 mg), Whole plants (14,358 mg), (Ba concentration: 500µM) 71–88% of whole plants	[233]
Cr	Spartina argentinensis	ART 21–25 °C	Plants; Argentina Media; inert substrate, pearlite in glass	Cr absorption in root and cultivator dry masses; 4–15 milligram/gram	[235]
Ba	Helianthus annuss	ART 25 ± 5 °C	Sunflower-seed land farm located north of Tunisia Media; mixture of perlite and gravel substrate (2:1, v/v)	Shoots 1350 µg/g DW	[236]
Ba	Limbarda crithmoides	ART	North seeds shore of the Bizerte lagon in Menzel emil, Bizerte, Tunisia	In each organ; be around 3000 µg/g DW	[236]
Ba, Pb	Brachiaria decumbens	ART	Media; soil tainted by waste from exploration and oil well drilling (pH soil 8.3) Cv. Basilisk plants from Brazil Including EDTA in the therapy	In Leaf (Pb 0.5–9.02 mg/kg), (Ba; 24.3–27.3 mg/kg) DW In Root (Pb; 1.41–5.3 mg/kg), (Ba; 17.6–20.9 mg/kg) DW	[237]
Zn, Cu	Salicornia spp.	ART	Sediment samples from Restronguet Creek	Cu in Sediment (3420), Aerial water (551), Roots (1954) mg/kg DW Zn in Sediment (1991), Aerial water (4831), Roots (720) mg/kg DW	[238]
Ni, Cu, Pb, As, Hg, Cr	Amaranthus dubius	ART	Soil pH 7–8 Plants dispersed in media throughout Africa, Asia, and South America	In Leaves Cr, Hg, As, Pb, Cu, Ni (17–118, 3–12, 4–188, 3–9, 20–45, 9–36) ppm In Stems Cr, Hg, As, Pb, Cu, Ni (17–126, 17–61, 13–201, 6–21, 27–67, 9–38) ppm In Roots Cr, Hg, As, Pb, Cu, Ni (30–308, 24–66-, 7–127, 10–138, 118–173, 38–106) ppm	[239]
Zn, Ti, Pb, Cd	Minuartia verna subsp. Verna	Total annual rainfall: 2100 mm The temperature was 2.4 °C in January and 16.4 °C in August.	Soil Raibl Lead/Zinc mining site, Cave del Predial, Italy; Media and Plants (pH 7.84–8.44)	M. verna subsp. In shoot Zn, Ti, Pb, Cd (24.1–18,372, 18.3–3632, 40–5998, 0.55–24.7) mg/kg In Root Cd, Pb, Ti, Zn (0.60–29.2, 151–9329, 0–1286, 342–27,521) mg/kg	[240]
Zn, Ti, Pb, Cd	Thlaspo rotundifolium subsp. Cepaeifolium	Annual rainfall 2100 mm Temperature 2.4 °C January and 16.4 °C August	Plant and Media; Cave del Predial, Soil Raibl lead, zinc mining site, Italy (pH 784–8.44)	Root and Shoot (mg/kg) Cd; 1.30–47.9 and 1.35–78 Pb; 282–14,435 and 29.2–2817 Ti; 35.8–2275 and 0–874 Zn; 71.7–11,548 and 28.1–11,573	[240]
Cd, Pb, Ti, Zn	Biscutella laevigata subsp.	Annual rainfall 2100 mm Temperature 2.4 °C January and 16.4 °C August	Media and Plants; Zinc mining site, Soil Raibl lead, Cave del Predial, Italy (pH 7.84–8.44)	Shoot and Root (mg/kg) Cd; 0–4.75 and 0–8.45 Pb; 0–874 and 0–1939 Ti; 33.4–32,661 and 0–9984 Zn; 20.2–20,980 and 34.7–5692	[240]
Cd, Pb, Ti, Zn	Alyssum wulfenianum	Annual rainfall 2100 mm Temperature 2.4 °C January and 16.4 °C August	Media and Plants; Cave del Predial, Soil Raibl lead, Zinc mining site, Italy (pH 7.84–8.44)	Root and Shoot (mg/kg) Cd; 2.20–6.23 and 0.59–5.95 Pb; 253–1504 and 28–826 Ti; 0–4347 and 31.5–1946 Zn; 354–5670 and 194–1934	[240]
Zn, Cd	Atriplex halimus L. (Halophyte species Mediterranean saltbush)	ART 25 ± 2 °C	Media; soil Plant; Spain	Leaves, Roots, Stems (mg/kg DW) Zn; 460, 1423, 431 Cd; 618, 3174, 1151	[241]
Cd, Cr, Cu, Mn, Fe, Zn	Cressa critica (Halophytes)	Rainfall range: 650–700 mm annually	Gujrat, India’s Gulf of Bhabha soil, pH 8.93, EC 112 dS/m	Stems and Leaves (mg/kg DW) Cd; 2 and 2.1 Cu; 11 and 12 Mn; 30 and 35 Fe; 160 nm and 150 Zn; 15 and 14	[242]
Zn, Fe, Mn, Cu, Cr, Cd	Tamarix indica (Halophytes)	Annual rainfall; 650–700 mm per year	Soil from Gulf of Bhabha, Gujrat, India, pH 8.93, EC 112 dS/m	In Stems Zn, Fe, Mn, Cu, Cd (19,150, 25, 10, 3.5) mg/kg DW In Leaves Zn, Fe, Mn, Cu, Cd (17, 160, 39, 9, 3.6) mg/kg DW	[242]
Zn, Pb, Cu	Halophyte Atriplex species; A. rosea	ART	Plants; CN Seed Ltd., Ely, UK Media; Contaminated soil in France	mg/kg DW In Root Pb (725) In Roots Cu (385) In Shoots Cu (48) In Root Zn (1179)	[243]
Cu, Pb	Halophytes Atriplex species; A. hortensis var. purpurea	ART	Media; French plants with contaminated soil; CN Seed Ltd., Ely, UK	In Root Cu (265 mg/kg DW) and Pb (1064 mg/kg DW)	[243]
Cu, Ni, Zn, Pb	Halophyte Atriplex species: Atriplex hortensis var. rubra	ART	Media; Contaminated soil in France Plants; CN Seed Ltd., Ely, UK	In Root Ni, Pb, Zn (1593, 982, 2512) mg/kg DW In Shoot Ni, Cu (61, 30 min) mg/kg DW	[243]
Zn, Cu, Cr, Cd	Sesuvium portulacastrum (Halophytes)	Rainfall total during the year: 135.6 cm Temperature range: 33.26 °C in the summer to 29.68 °C in the winter	Media: soil treated with tanning effluent (pH 8.3, EC 5.25 dSm-1) and salt (pH 7., EC 4.48 dSm-1) Plants from the Cuddalore District’s Pichavaram Mangrove Forest in Tail Nasa, India	Zn (70.10), Cu (35.10), Cd (22.10), Cr (49.82) mg/g DW	[244]
Zn, Cu, Cr, Cd	Suaeda monoica (Salt marsh halophyte)	Rainfall totals: 135.6 cm annually Maximum summer temperature: 33.26 °C; minimum winter temperature: 29.68 °C	Media; soil (pH 8.40, EC 4.75 dS/m) treated with paper mill effluent; plants; Tamil Nadu, India. Media: Salt-treated soil (pH 7.7, EC 4.48 dSm-1) and tannery wastewater samples (pH 8.3, EC 5.25 dSm-1). Gujrat, India’s Gulf of Bhabha soil, pH 8.93, EC 112 dS/m Plants from the Cuddalore District’s Pichavaram Mangrove Forest in Tail Nasa, India	Mg/kg DW Zn (60.20) Cu (29.2) Cd (17.50) Cr (40.89) Stems and Leaves (mg/kg DW) Cr (2.5 and 2) Cd (4.0 and 4.5) Cu (10 °C and 12) Mn (40 and 45) Fr (160 and 170) Zn (21 and 20) Mg/kg DW Zn 22.33 Cu 23.89 Cr 18.66 Cd 15	[244]

and

Table 5. Heavy metal accumulator species in water.

Heavy Metals	Accumulator Species	Climate Condition	Experimental Condition	Concentration in Plants	References
Rare earth elements (REEs)	Atriplex rosea Phytolacca bogotensis P. acinosa Roxb. P. icosandra L. P. clavigera W.W. Smith P. americana L.	Annual rainfall Temperature (ART) 23/18 °C	Media: water Plants: UK, Canada, France	Dry Weight (DW) Shoot Ni; 90–460 microgram/gram DW Cu; 160–390 µg/g DW Cd; 210–340 µg/g DW Zn; 126–1341 microgram/g DW Pb; 157–1184 µg/g DW Leaves and Roots; 180–500 and 1500–8000 mg/kg Leaves and Roots; 150–250 and 1600–10,000 mg/kg Leaves and Roots; 50–400 and 1600–13,000 mg/kg Leaves and Roots; 250–500 and 1500–6000 mg/kg Leaves and Roots; 300–900 and 1500–5000 mg/kg	[245]
Cd, Cu, Zn, Pb	Atriplex hortensis	ART	Media; hydroponic Plants from Denmark	Shoot Zn; 351–1257 microgram/gram DW Pb; 773–2276 µg/g DW Cd; 210–340 microgram/g DW Ni; 210–770 µg/g DW Cu; 340–400 µg/gram DW	[243]
Zn	Halophytes Lepidium latifolium L.	ART 25/17 °C	Media; Water Plants; Meghan Playa, Iran	Old Leaves, Roots, Young Leaves (0.7, 2.9, 1 mg/g DW)	[246]
Cr III	Leersia hexandra (Swartz)	ART 25/18 °C Day/Night	Media; Water The Taohua River in Guilin	Uptake Cr(III) 48 h; 3300 mg/kg DW	[247]
Cr, As	Pterus vittata (Ecotype)	ART 30–35 °C	Media; Hoagland medium (water) Plants in India	Root, Leaf, Stem AS; (1173–10,170, 2307–3474, 1299–6400) microgram/kg DW Cr; 9200–17,427, 611–2609, 1556–20,675 mg/kg DW	[248]
Cu, Cd, Zn	Sesuvium portulacastrum (Halophytes)	ART	MS Medium; water for Indian plants	Roots and Shoots Cd; 300–800 and 340–620 µg/g DW Zn; 910–1200 and 420–650 µg/g DW	[249,250]
Zn, Cd	Carpobrotus edulis L.	ART	Media; water	Roots and Shoots Zn; 660–1450 and 560–700 µg/g DW Cd; 670–1250 and 330–670 µg/g DW	[250]
Cd, Cu	Sesuvium portulacastrum (Halophyte)	ART	Media; water Plant from Halling Levee, Shatoulong Village, Yangjiang, China	Leaf, Root, Stem (mg/kg DW) Cu; 29.3–1032, 22.9–2090, 33.4–106.1 Cd; 16.26–64.7, 1707–3815, 77.8–251	[251]
Cr	Suaeda maritima Halophyte	ART	Media: Central Salt and Marine Chemical Research Institute (CSMCRI), Bhavnagar, Gujarat, India; hydroponic plant from a salt farm. 400 µM Cr was applied to the plant.	Cr. In Shoot (90.83 µg/g DW) Cr. In Root (1874.97 µg/g DW)	[252]
Cr (VI)	Pteridium aquilinum (Dennstaedtiaceae)	ART	Media; in vitro and via hydroponic treatment Spores in La Cantera, Maxico Use of the gametophyte and sporophytes phase	Sporophytes 11,854 mg Cr/kg DW in underground part. Gametophytes 915 mg Cr/kg DW	[253]
Se, Cr	Stanleya pinnata	ART 26/21 °C	Media; Water	In leaf; Se (12 microgram Cr/kg DW), Cr (1500 microgram Se/killogram DW) In Root; Se (500 mg Cr/kg DW), Cr (950 mg Se/kg DW)	[232]
Cu	Spartina alterniflora (Poaceae) Halophyte	ART 22–28 °C (Day) and 16–22 °C (Night)	Media: Hoagland’s nutrition solution pH 6.5, clean, dry vermiculite Seeds, China’s Bohai Bay	Rhozomes; 49 µg/g DW Steam; 49 µg/g DW Fine roots; 197.12 µg/g DW Leaves; 47 µg/g DW	[254]
Cr, Cd	Prosopis laevigata	ART 25 ± 2 °C	Media; liquid culture media, often known as Murashige and Skoog (MS) medium Humb and Bonel Seed. Ex. Mexican State’s Willd. M. C. Johnston 3.4 mM Cr (VI) and 0.65 mM Cd (II) were used to cultivate the plants.	In Root; (Cr 8090 mg/kg DW), (Cd; 21,437 mg/kg DW) In Shoot; (Cr 5461 mg/kg DW), (Cd; 8176 mg/kg DW)	[255]
Cr (VI)	Nopalea cochenillifera	ART	Media; Shivaji University, Kolhapur, India seeds; Murashige and Skoog’s (MS) basal medium (pH 5.80 corrected)	Shoots; 705.714 microgram Cr/kg DW Roots; 25,263.396 microgram Cr/kg DW	[256]
Pb	Scirpus grossus	ART	Medium sand and water with spikes	Pb Treatment 3236 mg/kg for 50 mg/L 4909 mg/kg for 30 mg/L 1343 milligram/killogram for 10 milligram/L	[257,258]

provide a comprehensive summary of the bioremediation of heavy metals, highlighting metal-accumulating bacteria in soil and their remediation potential as well as the bacterial species in water and the corresponding heavy metal concentrations that they mitigate.

10. Conclusions

Heavy metal contamination markedly promotes AMR by imposing selective pressure on microbial populations in environmental niches ranging from the rhizosphere to the phyllosphere. Cadmium, lead, mercury, and arsenic cause oxidative stress, DNA damage, and mutations that increase antibiotic resistance through mechanisms such as overexpression of efflux pumps, detoxification enzyme expression, and biofilm formation. These processes, combined with horizontal gene transfer and the co-selection of resistance genes, accelerate the development of multidrug-resistant strains, which pose an extreme danger to global health. The rhizosphere, which is essential for plant–microbe interactions, is affected by heavy metal toxicity, which hampers beneficial microbes, such as rhizobacteria and mycorrhizal fungi, affecting nutrient cycling and plant health. Nevertheless, metal-tolerant microorganisms provide promising solutions through bioremediation strategies involving biosorption, biotransformation, and biomineralization, which counteract metal toxicity and promote the recovery of ecosystems. Advances in synthetic biology and gene editing continue to boost the chances of engineered microbes tackling metal-induced AMR. Notwithstanding, challenges exist, such as resource inequalities in low- and middle-income nations and disparities in global surveillance systems. Mitigating the intersection of heavy metal pollution and AMR necessitates interconnected strategies, including the amalgamation of bioremediation, policy measures, and optimal resource utilization. By understanding and addressing the molecular and ecological processes connecting heavy metals and AMR, we can establish sustainable approaches to stem resistance, ensure environmental health, and preserve public health for generations.