Heavy Metal Contamination and the Rise of Antibiotic Resistance

Introduction

Antibiotic resistance has escalated into a global health crisis, traditionally attributed to the selective pressure of antibiotic misuse. However, mounting evidence indicates that environmental pollution— particularly heavy metal contamination – is also propelling the proliferation of antimicrobial resistance
(AMR). ¹² Heavy metals such as lead (Pb), mercury (Hg), arsenic (As), chromium (Cr), cadmium (Cd), and nickel (Ni) are non-degradable toxic elements that persist in soils and waters, exerting long-term selective pressure on microbial communities. ³⁴ Unlike antibiotics (which can degrade over time), heavy metals can accumulate at concentrations orders of magnitude higher than typical antibiotic levels, creating hotspots for resistance development.⁵ Bacteria exposed to heavy metals often develop metal resistance genes (MRGs), and these may be genetically or mechanistically linked to antibiotic resistance genes (ARGs). This phenomenon of co-selection means heavy metals can enrich bacterial populations that are multidrug resistant, even in the absence of antibiotic exposure. ⁶¹

From a One Health perspective, heavy metal-induced antibiotic resistance spans environmental, agricultural, industrial, and clinical domains. Environmental reservoirs (soil, sediments, water) contaminated with metals show higher ARG abundance.⁷ In agriculture, metal-laden fertilizers and animal feed supplements (e.g., copper and zinc) select for resistant microbiota in soil and the livestock gut. ⁸⁹ Industrial activities and wastewater release metals that enrich multidrug-resistant bacteria in effluents and downstream ecosystems. ¹⁰ Even clinical and urban settings are not exempt: for example, wartime environmental damage disperses metals (from shrapnel, infrastructure) that co-select for drug-resistant pathogens in wounds. ¹¹Heavy metal resistance is an ancient trait – predating modern antibiotics – and may have set the stage for contemporary ARG evolution.¹² Notably, nickel (Ni) contamination has drawn special attention for its co-selective effects, and certain bacteria exhibit glyoxalase-positive phenotypes that enhance survival under metal stress. Glyoxalases are enzymes that detoxify methylglyoxal, a toxic metabolic byproduct; their activity (often Ni-dependent) may fortify bacteria against both metal toxicity and other stresses. ¹³¹⁴

In this review, we integrate recent findings on how heavy metals drive antibiotic resistance across multiple contexts, emphasizing mechanistic insights – from efflux pumps and co-resistance plasmids to stress responses (e.g. glyoxalase-mediated) and horizontal gene transfer. Key molecular mechanisms and case studies are summarized in tables for clarity.

Environmental and Industrial Perspectives on Metal-Driven AMR

Sources and Scope of Contamination: Heavy metals enter the environment through natural processes
(geothermal activity, mineral weathering) and myriad anthropogenic sources. ¹⁵ Industrial mining and
smelting, energy production, metal plating, and improper waste disposal have led to widespread
contamination of soils, sediments, and waterways with metals like As, Cd, Cr, Cu, Pb, Hg, Ni, and Zn.¹⁶ Agricultural runoff and sewage sludge can further introduce metals (e.g., from fertilizers, manure, or
wastewater) into ecosystems. ¹⁷ Unlike organic pollutants, metals do not biodegrade; they persist and accumulate, maintaining continuous pressure on local microbes. ³⁵ This sustained exposure has
selected for metal-tolerant bacteria that frequently also harbor antibiotic resistance. Indeed, a global survey found that many heavy-metal-polluted environments contain higher levels of ARGs than unpolluted sites, even without elevated antibiotics present.¹⁸ Heavy metals thereby act as chronic selectors of multidrug resistance in the environment.

Evidence from Polluted Environments: Diverse empirical studies link metal pollution to antibiotic
resistance. For example, river sediments impacted by historic mining and industry (e.g., in the UK’s River
Tyne catchment) showed significantly elevated ARG abundances correlating with high sediment
concentrations of Pb, Zn, Ni, and other metals¹⁸. In these sediments, genes conferring metal and
antibiotic resistance co-occurred, and bacterial communities were dominated by metal-tolerant groups
(Firmicutes, Bacteroidota) known to carry integron-based gene cassettes with both MRGs and ARGs¹⁸. A comparative study of polluted Indian rivers similarly found that sites with higher heavy metal levels had
markedly more ARGs, underscoring metal pollution as a driver of AMR on a global scale ¹⁸. Intriguingly,
certain metal combinations have synergistic effects: one study noted that cobalt plus nickel together, or a trio of Co, Zn, and Cd, produced the strongest enrichment of antibiotic-resistant bacteria in sediments ¹⁸. This suggests mixed-metal contamination can amplify co-selection pressures beyond what single metals do. Industrial waste streams and wastewater treatment plants (WWTPs) are important nodes where heavy metals and antibiotics converge. Wastewater effluents often contain a cocktail of metals (e.g., Cu, Zn, Mn, Cd from industrial discharges) along with antibiotic residues ¹⁹. Even at sub-inhibitory concentrations, these metals can alter bacterial physiology in ways that promote drug resistance. Notably, heavy metals can upregulate bacterial efflux pump systems, leading to cross-resistance against antibiotics²⁰. A study of WWTP bacterial isolates showed that exposure to low-level Cu²⁺+ or Zn²⁺+ triggered increased expression of multi-drug efflux pumps, resulting in decreased susceptibility to multiple antibiotics²⁰. Similarly, metal-rich industrial effluents can select for plasmids and integrons bearing both MRGs and ARGs, which are then disseminated in downstream environments. Long-term field investigations have confirmed that metal pollution creates a reservoir of mobile resistance elements: for instance, soil chronically contaminated with heavy metals near smelters or in mining areas harbors a higher abundance of class 1 integrons (intI1) and resistance plasmids than uncontaminated soil²¹. These integrons facilitate the capture and spread of ARGs under heavy metal selection. In summary, environmental and industrial contamination with heavy metals establishes an ideal breeding ground for antibiotic resistance by continuously selecting co-resistant organisms and enriching gene exchange platforms.

Agricultural Perspective: Metals in Farming and Food Production

Heavy Metals in Agriculture: Agricultural practices have inadvertently introduced substantial heavy metal loads into the biosphere. Common examples include the supplementation of animal feed with trace metals (notably copper and zinc in swine and poultry diets to promote growth or prevent disease), the use of arsenical compounds in pastured animals (historically, e.g., roxarsone in poultry), and the presence of metals in phosphate fertilizers and pesticides⁴. Manures and slurries from intensive livestock operations often contain elevated Cu, Zn, and other metals, which are subsequently applied to fields as fertilizer. Over time, this leads to metal accumulation in agricultural soils. These metals can co-select for antibiotic resistance in both the commensal flora of animals and environmental bacteria in soil and water runoff.

Co-selection in Livestock: There is compelling evidence that in-feed metals select for multidrug-resistant bacteria in farm animals. A well-documented case is the rise of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) in pig farms. In swine, high zinc diets have been linked to
increased MRSA carriage. The genetic basis is a zinc resistance gene (conferring Zn²⁺+/Cd²⁺+ efflux)
that is co-located with the methicillin resistance determinant (mecA) on the SCCmec element of LAMRSA.²² Studies in Denmark demonstrated that supplementing weanling pigs’ feed with zinc oxide
significantly increased nasal MRSA colonization in the herd. ²³ All MRSA isolates from zinc-fed pigs were
czrC-positive and zinc-resistant, indicating that Zn²⁺+ exposure had co-selected the MRSA strains.²⁴
Likewise, copper supplementation in pig diets has been implicated in selecting for enterococci carrying
coupled resistances. Enterococcus faecium isolates from copper-fed swine often harbor the tcrB gene (for
Cu²⁺+ tolerance) on the same conjugative plasmid as vanA (vancomycin resistance) and erm(B)
(erythromycin resistance).¹¹ Thus, a single plasmid endows these strains with both heavy metal and
antibiotic resistance – a textbook example of co-resistance in an agricultural setting. These plasmid-bearing enterococci can disseminate from farms to humans via the food chain or environmental pathways, raising concern that on-farm metal use contributes to clinical AMR.

Clinical and Public Health Perspectives

In clinical settings, direct heavy metal exposure is less common today than in the past, but heavy metal
resistance still plays a role in nosocomial pathogens and public health. Historically, metals like mercury,
arsenic, and silver were used as antimicrobials (e.g., mercurial skin antiseptics, arsenical therapeutics, silver nitrate in wound care). Pathogens evolved mechanisms to detoxify these metals – for example, the plasmid-encoded mer operon for mercury resistance became widespread in the mid-20th century due to mercurial disinfectant use.¹¹ Even though antibiotics replaced most metal-based therapies, the legacy of those metal resistance elements persists, often now co-existing with ARGs on the same mobile elements.

Modern healthcare still employs metals in limited ways, such as copper alloy surfaces (used in hospitals for their antimicrobial properties) and silver-coated medical devices. These measures can reduce overall microbial load, but paradoxically, they may favor any bacteria that carry metal resistance genes. For instance, vancomycin-resistant Enterococcus faecium (VRE) isolates from hospitals frequently also exhibit high-level copper resistance, attributed to the tcrYAZ locus on a plasmid that is often linked to the vanA gene¹¹.

A striking example linking heavy metals to clinical AMR emerged from war zones. Combat injuries with
embedded shrapnel or soil introduce metals (lead, antimony, copper from bullets and explosives) directly
into wounds¹¹. Researchers noted that during the Iraq war, multidrug-resistant Acinetobacter baumannii
(“Iraqibacter”) infections surged, and these isolates often carried genes for heavy metal efflux and
detoxification¹¹. It is hypothesized that battlefield heavy metal contamination co-selected for A.
baumannii strains that were also antibiotic-resistant, helping them outcompete susceptible bacteria in
wounds laced with metal fragments¹¹. This wartime scenario underscores how environmental metal
exposure can have a direct clinical impact by selecting hardier, drug-resistant opportunists. More broadly, heavy metal-driven AMR represents a pathway of resistance emergence that is independent of
antibiotic use¹¹. Improved antibiotic stewardship alone cannot address this, so public health efforts must
also target environmental contaminants. In summary, while antibiotics are the proximal cause of most
clinical resistance, heavy metals form an often overlooked background pressure that primes bacteria to be multi-resistant before they ever encounter a human patient.

Mechanistic Insights into Metal-Driven Co-selection

Heavy metal exposure and antibiotic resistance are mechanistically intertwined through several nonmutually exclusive routes. These include co-resistance (where different resistance genes are linked together), cross-resistance (where one mechanism provides dual resistance), co-regulatory responses, metal-induced stress physiology, and facilitation of horizontal gene transfer.

Co-resistance: Linked Genes on Mobile Elements
Co-resistance refers to the genetic linkage of resistance determinants so that a single bacterial strain (or
plasmid) resists both metals and antibiotics. In this scenario, the use of either selective agent (metal or drug) can enrich bacteria that incidentally carry resistance to the other agent, since the genes are inherited together.¹¹ Co-resistance most commonly arises from mobile genetic elements – plasmids, transposons, integrons – that accumulate multiple resistance genes. A classic example is the pIGRJ conjugative plasmid in Enterococcus faecium from swine, which harbors tcrB (teicoplanin/copper resistance gene) alongside erm(B) (erythromycin resistance) and vanA (vancomycin resistance). All these genes are transmitted as a unit during plasmid transfer. ¹¹ Under copper exposure (e.g. in pig intestines or on copper surfaces), bacteria carrying this plasmid are selected, thereby also propagating vancomycin and macrolide resistance. Another example is a plasmid in Serratia marcescens that was found to carry an array of metal resistance genes (to arsenic, copper, mercury, and silver) physically linked with multiple antibiotic resistance genes (conferring chloramphenicol, tetracycline, and kanamycin resistance).¹¹

Cross-resistance: Shared Mechanisms and Efflux Pumps

Cross-resistance occurs when a single molecular mechanism confers protection against both heavy metals and antibiotics¹¹². Unlike co-resistance (which involves separate genes hitchhiking together), cross-resistance often involves broad-spectrum resistance factors, the most prominent being multidrug efflux pumps. Many bacterial efflux systems can extrude a range of structurally dissimilar toxicants – including multiple antibiotic classes as well as certain metal ions – thereby reducing intracellular concentrations of both. Heavy metals can act as inducers or substrates of these pumps. For instance, the MdrL pump in Listeria monocytogenes transports Zn²⁺+, Co²⁺, and CrO₄²⁻ out of the cell, and the same pump also exports macrolide antibiotics like erythromycin and clindamycin¹¹. Exposure to any one of those agents can activate pump expression, leading to cross-protection. Similarly, the CmeABC efflux pump of Campylobacter jejuni, originally characterized for antibiotic resistance, has been shown to mediate resistance to cobalt and copper ions alongside fluoroquinolones, tetracycline, and ethidium bromide¹¹.

A striking case is the RND-family efflux system (DsbA-DsbB) in Burkholderia cepacia, which, when overexpressed, yields resistance to β-lactams, aminoglycosides, and fluoroquinolones and to zinc and cadmium ions¹¹². These pumps typically have low specificity and can bind/export diverse compounds. Heavy metal exposure can select for mutations or regulatory changes that upregulate efflux pumps, thereby concomitantly raising antibiotic MICs. Indeed, laboratory studies demonstrate that sub-lethal concentrations of Cu²⁺+ or Zn²⁺+ can select for mutants overproducing efflux pumps, resulting in antibiotic cross-resistance (e.g., increased tolerance to quinolones and β-lactams)²⁵. Thus, cross-resistance via efflux is a pervasive and insidious mechanism: heavy metals essentially “teach” bacteria to ramp up defenses that also work against antibiotics.

Beyond efflux, other cross-resistance mechanisms include enzymatic detoxification (e.g., some oxidoreductases can neutralize both metallic ions and certain antibiotics) and target modification (if a metal and an antibiotic act on the same cellular target, a protective mutation could confer resistance to both). However, such cases are less common than efflux-based cross-resistance. In summary, cross-resistance means a single biochemical shield is doing double duty – it is a key reason why heavy metal presence in an environment can directly increase the frequency of multi-drug-resistant phenotypes ²⁶.

Co-regulation of Metal and Antibiotic Resistance

While co-resistance and cross-resistance involve structural genes, co-regulatory resistance refers to
shared regulatory circuits that control disparate resistance determinants in response to one stimulus. This is a comparatively rarer phenomenon but provides elegant examples of the cell’s regulatory network linking metal and antibiotic responses¹¹. In essence, P. aeruginosa in a zinc-rich environment will turn on metal efflux and incidentally become more antibiotic-resistant (to imipenem) through co-regulation. Another potential example is the BaeSR two-component system in Escherichia coli, which responds to envelope stressors including heavy metals and triggers expression of the MdtABC multidrug efflux pump – linking metal sensing to antibiotic efflux, although the full scope of BaeSR’s role in co-selection is still under investigation. Overall, co-regulation underscores that bacteria’s stress responses are highly interconnected: a single regulatory switch can reconfigure the cell to withstand multiple threats. Though fewer cases are known compared to co- or cross-resistance, co-regulatory mechanisms are important as they can rapidly induce multidrug resistance in response to environmental metals without requiring new mutations or gene acquisitions¹¹.

Metal-Induced Stress Responses and Mutation

Beyond specific resistance mechanisms, heavy metals impose a general stress on bacteria that can lead to adaptive mutagenesis and enhanced survival traits. Many heavy metals participate in Fenton-like
reactions or disrupt redox balance, causing the generation of reactive oxygen species (ROS)¹¹. ROS inflict DNA damage, protein misfolding, and membrane lipid peroxidation. Bacteria respond by activating global stress response regulons (e.g. SoxRS, OxyR, RecA/LexA for SOS). A side effect of this is an increased mutation rate– error-prone DNA polymerases get deployed to rescue heavily damaged DNA, potentially introducing mutations that confer antibiotic resistance (for example, a gyrA mutation conferring quinolone resistance might arise under metal-induced SOS activation).

Indeed, some research has observed that metal exposure selects for rifampicin- or quinolone-resistant mutants in E. coli and Mycobacterium populations, presumably via ROS-mediated mutagenesis (though direct evidence is still emerging). Moreover, heavy metal stress can select for generally stress-tolerant phenotypes that incidentally weather antibiotic attacks better. One such phenotype involves the glyoxalase system. Methylglyoxal (MG) is a reactive cytotoxin that is overproduced in cells under stress (due to imbalances in glycolysis). Heavy metals have been shown to impair the glyoxalase pathway, causing MG accumulation as part of their toxicity²⁷.

Bacteria that can upregulate glyoxalase enzymes (principally glyoxalase I and II) can detoxify MG into harmless metabolites, thereby surviving metal stress more effectively. These “glyoxalase-positive” bacteria not only cope with metals but also resist MG-dependent toxicity mechanisms. This has implications for antibiotic resistance: methylglyoxal is known to have bactericidal activity and is actually employed by the immune system (e.g. human neutrophils generate MG to kill bacteria)¹⁶. Pathogens with robust glyoxalase activity can neutralize host-derived MG, thus contributing to virulence and survival during infection¹⁶. For example, Streptococcus agalactiae (Group B strep) requires a functional glyoxalase I (gloA) to withstand MG stress and survive in blood; gloA mutants are attenuated in infection models²⁷. Notably, glyoxalase I in many bacteria is a Ni²⁺-metalloenzyme¹⁴.

In E. coli and others, Ni²⁺ is the preferred cofactor for glyoxalase I activity, although Zn²⁺ can substitute in some species. This means nickel availability can enhance glyoxalase-mediated stress tolerance. If a bacterium is in a Ni-contaminated environment, it might activate Ni-dependent enzymes like glyoxalase I to counteract MG buildup, gaining a survival edge. Over time, communities exposed to Ni could become enriched in glyoxalase-positive, Ni-requiring bacteria that also happen to be hardy against other stresses. While research directly linking glyoxalase to antibiotic resistance is nascent, the correlation is plausible: glyoxalase reduces endogenous toxin stress and potentially frees up resources for bacteria to invest in defense against antibiotics. At minimum, glyoxalase illustrates how metal-induced physiological adaptations (managing oxidative and metabolic stress) can broadly increase bacterial robustness, indirectly facilitating antibiotic resistance.

In summary, heavy metal contamination pressures bacteria in multiple ways – genetic, biochemical, and
physiological – that all tilt the evolutionary balance towards antibiotic resistance. Table 2 (below) distills the key co-selection mechanisms and their molecular bases, and Table 3 lists several bacteria and plasmids exemplifying these mechanisms.

Case Studies and Evidence from Recent Research

To concretely link these concepts to real-world scenarios, we highlight a few representative case studies
spanning environmental, agricultural, and clinical contexts (summarized in Table 1):

Nickel-Contaminated Agricultural Soils: Hang-Wei Hu et al. (2017) conducted a long-term field. An
experiment in which agricultural plots were amended with nickel sulfate (up to 400 mg Ni/kg soil) for 4–5 years. ²⁸ Metagenomic and qPCR analyses revealed a significant increase in the diversity and abundance of ARGs in Ni-treated soils compared to controls.²⁸ Over 149 unique ARGs were detected, with Ni exposure selecting especially for multidrug and β-lactam resistance genes.²⁸ Importantly, Ni-amended soils showed elevated levels of class 1 integron integrase (intI1) and other mobile element markers, indicating enhanced horizontal gene transfer potential.²⁸ Network analysis in the study showed intI1 was centrally connected to many co-occurring ARGs, suggesting Ni was selected for integron-bearing bacteria that can collect resistance genes.²⁸ This provides direct evidence that a heavy metal (Ni) can drive ARG proliferation in soil over time.

Pig Farms – Zinc and MRSA: In Danish pig farms, zinc oxide is often added to piglet feed at high doses. A study by A. Moodley et al. found that this practice correlated with increased nasal carriage of MRSA in pigs. Molecular typing showed the MRSA strains were of the livestock-associated ST398 lineage and carried the czrC gene for zinc resistance on the SCCmec element. ⁹ All MRSA isolates from zinc-fed pigs were zinc-resistant, whereas MRSA from farms not using Zn feed had
lower zinc tolerance.²⁴ This indicates zinc use was selecting for MRSA specifically equipped with
zinc efflux machinery. Subsequent work demonstrated that the czrC and mecA genes are physically
linked. This case confirms that a heavy metal in the absence of any antibiotic can enrich a
dangerous antibiotic-resistant pathogen in livestock, exemplifying co-selection in agriculture.

War Wound Infections – Heavy Metals and A. baumannii: Military physicians observed an unusual
prevalence of MDR Acinetobacter baumannii infections in soldiers wounded by improvised explosive
devices (IEDs) in Iraq and Afghanistan.¹¹ Environmental analysis of wound debris and soil
from war zones showed high concentrations of metals like lead, antimony, copper, and tungsten
from munitions.¹¹ Bazzi et al. (2020) reviewed evidence that these heavy metals could be selecting
for A. baumannii strains with co-resistance. Many war-zone A. baumannii isolates carried genes for
Cu²⁺efflux, arsenic resistance, and mercury reductases in addition to β-lactamases and other
ARGs.¹¹ Copper resistance in particular (via cop and cue gene clusters) was enriched. The
timing and geography of outbreaks suggest that battlefield metal contamination created a niche
for metal-tolerant, MDR A. baumannii (“Iraqibacter”). This case underscores the One Health
principle: environmental destruction (through war) had clinical repercussions in the form of difficult-to-treat wound infections.¹¹

Wastewater Treatment Plants (WWTPs): Several investigations have looked at how heavy metals in wastewater impact microbial resistance. In one WWTP study, trace amounts of metals (particularly Cu and Zn) were shown to select for multi-drug efflux pump overexpression in E. coli isolates.¹⁰ Another experimental study by Wang et al. (2020) found that exposing a model bacterial community to a low level of Cr(VI) or Ag(I) significantly increased the conjugative transfer frequency of a multidrug resistance plasmid (RP4) among the bacteria.² Genome sequencing of transconjugants revealed no new resistance mutations, implying the effect was due to metal-stimulated transfer rather than selection of mutants.² These WWTP findings reinforce that even in modern engineered systems, heavy metals can bolster the persistence and spread of ARGs, complicating efforts to eliminate resistance in effluent discharges.

Together, such case studies affirm that heavy metal contamination is a tangible contributor to the rise of
antibiotic resistance across diverse settings. They also highlight the mechanistic themes discussed earlier. In each case, either co-resistance (linked genes) or cross-resistance (shared mechanisms like efflux) or HGT promotion was evident. By integrating these perspectives, we gain a more holistic understanding of AMR’s environmental dimensions. The following tables summarize key findings, mechanisms, and notable co-resident microbes from the literature:

Table 1. Selected Studies Linking Heavy Metal Contamination to Antibiotic Resistance

(environmental, agricultural, industrial examples with key findings):

Context / Study	Heavy Metal(s)	Key Findings on Antibiotic Resistance
Agricultural soil (China) – Long-term field trial with Ni supplementation for 5 years 28	Nickel (Ni)	ARG diversity and abundance increased along Ni gradient; highest at 400 mg/kg Ni. Enrichment of class 1 integrons (intI1) and mobile elements, indicating enhanced HGT. Ni exposure drove co-selection of multiple ARG classes (β-lactams, multidrug, etc.).28
Pig farm manure & soil (Europe) – Surveys of pig slurry and farm soil microbiomes.	Zinc (Zn), Copper (Cu), Cadmium (Cd)	Basis: Zn/Cu supplementation in feed → selection for bacteria carrying both metal- and antibiotic-resistance genes. Examples:Enterococcus with Cu- and vancomycin-resistance genes → enriched in pig manure and nearby soils. Result: High ARG–MRG co-occurrence → manure-borne metals sustain environmental ARG reservoirs.8
Livestock-associated MRSA in pigs (Denmark) – Effect of high-Zn feed on MRSA carriage9	Zinc (Zn)	Basis: Zn supplementation in feed → selection for MRSA with czrC (Zn/Cd efflux gene) co-located with mecA (methicillin resistance). Examples: All MRSA from Zn-treated pigs → Zn-resistant; Zn use → co-selection of MRSA → increased prevalence and persistence under ZnO therapy.9
River sediments near mines/industry (UK, India) – Newcastle University study6	Mixed metals (Pb, Ni, Zn, Cd, Co, etc.)	Basis: High metal levels in sediments → selection pressure → increased ARG (antibiotic resistance gene) and MRG abundance. Positive correlation observed between metal pollution indices and ARG/MRG levels. Examples: Contaminated sites dominated by Firmicutes and Bacteroidota → carried integron-linked ARG–MRG cassettes. Metal combinations (Co+Ni, Co+Zn+Cd) → strongest ARG proliferation.6
Battlefield wound infections (Iraq/ Afghanistan) – MDR “Iraqibacter” outbreaks11	Lead (Pb), Copper (Cu), Antimony (Sb), others in shrapnel	Basis: Sub-inhibitory metal levels in WWTPs → stress response activation → enhanced resistance mechanisms. Examples: Low Cu²⁺ and Zn²⁺ in WWTP cultures → overexpression of efflux pumps → increased tolerance to multiple antibiotics; exposure to low-dose Cr⁶⁺ or Ag⁺ → elevated conjugative plasmid transfer of ARG-bearing plasmids. Result: WWTP metal exposure → promotes cross-resistance and horizontal gene transfer (HGT) in situ.
Wastewater treatment plant bacteria – Lab exposure studies 10	Copper (Cu), Zinc (Zn), Chromium (Cr), Silver (Ag)	Sub-inhibitory Cu and Zn in WWTP cultures caused overexpression of efflux pumps and increased tolerance to multiple antibiotics.10 Exposure to low-dose Cr⁶⁺ or Ag⁺ significantly increased conjugative plasmid transfer rates of ARG-bearing plasmids. Suggests WWTP metals enhance cross-resistance and HGT in situ.10

Table 1: Case studies illustrating heavy metal-induced co-selection of antibiotic resistance. Each example shows how a particular metal contamination scenario led to increased antibiotic resistance in microbes, via co-resistance, cross-resistance, or enhanced gene transfer. ARG = antibiotic resistance gene; MRG = metal resistance gene; HGT = horizontal gene transfer.

Table 2. Mechanisms of Co-selection by Heavy Metals – Summary of Molecular Pathways:

Co-selection Mechanism	Description	Molecular Basis and Examples
Co-resistance (physical linkage)	Selection for one resistance trait (metal or antibiotic) co-selects another due to genetic linkage on same mobile element. Inherited together11	Basis: Multiple resistance genes located on mobile elements (plasmids, integrons, transposons) → co-selection under metal stress. Examples: Plasmid pRUM in E. faecium → carries tcrB (Cu²⁺ resistance) with vanA (vancomycin resistance).11 Result: Heavy metal exposure → maintenance of multi-ARG plasmids within bacterial populations.
Cross-resistance (shared mechanism	One biochemical mechanism imparts resistance to both metal and antibiotic 11. A single adaptive change protects against both stressors.	Basis: Metal exposure → activates multidrug efflux pumps or induces target modification → lowers intracellular antibiotic levels. Examples:Listeria MdrL pump → exports Zn²⁺, Co²⁺, CrO₄²⁻, macrolides; Campylobacter CmeABC pump → expels Cu²⁺, Co²⁺, fluoroquinolones; B. cepacia DsbA-DsbB system → resists β-lactams, aminoglycosides, Zn²⁺, Cd²⁺. 11 Result: Metal exposure → efflux pump upregulation → decreased antibiotic accumulation → higher MIC (enhanced resistance).
Co-regulation (regulatory linkage)	A shared regulator or signaling pathway controls both metal resistance and antibiotic resistance genes. 11 Metal triggers a regulatory response that affects antibiotic susceptibility.	Basis: Metal exposure → activates two-component systems or repressors with dual regulons → coordinates metal efflux and antibiotic resistance. Examples:P. aeruginosa CzcR–CzcS senses Zn²⁺/Cd²⁺/Co²⁺ → induces czcCBA metal efflux → represses oprD porin (carbapenem entry) → Zn²⁺ exposure → carbapenem resistance via porin loss. E. coli BaeSR system → responds to metals → upregulates multidrug efflux pump MdtABC.11
Metal-induced HGT (gene transfer)	Heavy metals enhance horizontal transfer of ARGs and maintenance of resistance plasmids/ integrons.	Basis: Metal exposure → induces SOS response and cellular stress → stimulates integrase activity and conjugation machinery. Biofilm formation under metal stress → enhances cell-to-cell contact and gene exchange. Examples:intI1 integrase frequency ↑ in metal-polluted microbiomes → promotes ARG capture; sub-lethal Cu/Zn → increases F-plasmid conjugation; Cd + antibiotic co-exposure → upregulates plasmid transfer genes in P. putida → higher ARG transmission rates.
Stress responses & mutagenesis	Metals cause oxidative and metabolic stress, promoting error-prone DNA repair and selection of stresstolerant mutants.	Basis: Metal exposure → ROS generation → DNA damage → SOS mutagenesis → emergence of resistance mutations. Metals also activate global stress regulons (e.g., oxidative stress defenses) → cross-protection against ROS-inducing antibiotics2. Examples:E. coli exposed to sub-lethal Cr(VI) → increased rifampicin resistance via ROS-mediated mutations. Under metal stress, glyoxalase system ↑ → detoxifies methylglyoxal → enhances survival under metal and immune stress. Streptococcus with active Ni-dependent GloA → tolerated MG better → exhibited greater virulence.21

Table 2: Major mechanisms by which heavy metals co-select for antibiotic resistance. Each mechanism is defined, with its molecular basis and an example. Co-resistance = physical linkage of genes; Cross-resistance = one mechanism, two resistances; Co-regulation = one regulator controls multiple resistance genes; HGT = horizontal gene transfer processes; Stress responses = indirect selection via general stress and mutation. References illustrate specific cases

Table 3. Examples of Bacterial Taxa and Elements with Co- or Cross-Resistance to Metals and Antibiotics:

Bacterium / Plasmid	Implicated Metal(s)	Antibiotic Resistance Trait(s)	Mechanism
Enterococcus faecium (pig isolate)	Copper (Cu) via tcrB operon	Vancomycin (VanA), erythromycin (ErmB) on same plasmid	Co-resistance (plasmidborne gene linkage)11
Staphylococcus aureus ST398 (LA-MRSA)	Zinc (Zn), Cadmium (Cd) via czrC efflux22	Methicillin (mecA on SCCmec); also tetracycline is often co-selected. 9	Co-resistance (genetic linkage on SCCmec element)
Pseudomonas aeruginosa	Cobalt (Co), Zinc (Zn), Cadmium (Cd) sensed by CzcRS	Carbapenems (imipenem) – via loss of OprD porin ; multidrug efflux (Mex pumps) also contribute	Co-regulation (twocomponent system CzcRS controlling metal efflux & antibiotic uptake).11
Burkholderia cepacia	Zinc (Zn), Cadmium (Cd)	β-lactams, aminoglycosides, fluoroquinolones 11	Cross-resistance (broad-spectrum DsbA-DsbB efflux pump)
Campylobacter jejuni	Cobalt (Co), Copper (Cu)	Fluoroquinolones (e.g. ciprofloxacin), macrolides (erythromycin)	Fluoroquinolones (e.g., ciprofloxacin), macrolides (erythromycin) 11
Listeria monocytogenes	Arsenic (As), Copper (Cu), Mercury (Hg), Silver (Ag) 11	Chloramphenicol, Tetracycline, Kanamycin (all encoded on same plasmid) 11	Co-resistance (multiple resistance genes colocated)
Salmonella enterica (Typhi and others)	Mercury (Hg) via mer operon	Multi-drug: e.g. Chloramphenicol (cat), β-lactams (bla_TEM), Sulfonamides (sul1), Trimethoprim (dfr)	Co-resistance (transposon with mer and ARGs) 11
Integrative Conjugative Element ICEpMER (Klebsiella pneumoniae)	Mercury (Hg), Tellurite (Te)	Extended-spectrum β-lactamases (CTXM), quinolone resistance (qnr)	Co-resistance (ICE with metal + drug genes)
Escherichia coli (lab strain with plasmid pRP4)	Chromium (Cr), Silver (Ag) experimentally	Ampicillin, Tetracycline, Kanamycin (on RP4 plasmid)	HGT facilitation (metal-induced higher conjugation frequency)2

Table 3: Representative bacteria and genetic elements exhibiting linked heavy metal and antibiotic resistance. These examples illustrate the range of taxa (Gram-positive and Gram-negative) and mechanisms (plasmid co-resistance, efflux-mediated cross-resistance, co-regulatory systems) involved in metal-driven antibiotic resistance. LA-MRSA = livestock-associated MRSA. (Note: This is not exhaustive; many other examples exist in literature.)

Conclusion

Heavy metal contamination has emerged as a significant and underappreciated force driving the global rise of antibiotic resistance. Through long-term persistence in the environment, heavy metals impose a selective pressure that enriches bacterial populations for metal resistance, and by various co-selection mechanisms, this often results in enrichment for antibiotic resistance as well. Environmental, agricultural, industrial, and clinical data all converge on this point. In the environment, non-antibiotic pollutants like metals can create antibiotic-resistant reservoirs in soils and waters that ultimately threaten human and animal health. In agriculture, heavy metal usage sustains multidrug-resistant organisms in livestock and crop systems, complicating efforts to curb AMR via antibiotic stewardship alone. Industrial emissions and
Urban pollution with metals similarly contributes to a backbone of resistance in microbial communities.
Clinically, metal-driven co-selection (e.g., via copper or arsenic resistance genes linked to drug resistance) means that hospitals and war zones alike must contend with pathogens whose multidrug resistance may have been incubated by exposure to metals rather than therapeutic antibiotics.

Mechanistically, heavy metals and antibiotics are intertwined in microbial evolution. Co-resistance (genes carried together on plasmids or integrons) and cross-resistance (common efflux pumps or protective enzymes) create direct molecular links between metal tolerance and antibiotic resistance. Coregulatory circuits demonstrate that bacteria’s response to a toxic metal can automatically induce antibiotic resistance phenotypes. They trigger stress responses and mutagenesis pathways that can spawn new resistance mutations and favor hardy phenotypes like glyoxalase-rich, oxidative-stress-resistant cells. The special case of nickel highlights how an essential yet toxic metal can spur co-selection: nickel contamination selects for Ni-dependent enzymes (like glyoxalase I) and Ni-resistant efflux systems, indirectly arming bacteria against multiple stresses, including antibiotics.

In light of these insights, combating antibiotic resistance demands an integrated approach. Environmental regulations should limit heavy metal pollutants, and remediation of contaminated sites could help diminish the environmental reservoir of ARGs. In agriculture, finding alternatives to heavy metal feed additives (or judiciously limiting their use) is key to preventing co-selection of superbugs at the source. Improved waste management – treating metal-rich industrial and hospital wastewater – may reduce the collateral selection for resistance in downstream ecosystems. From a research perspective, there is a need for continued surveillance of metals in high-risk environments (e.g. densely populated urban soils, aquaculture ponds, conflict zones) and how they correlate with resistomes, as well as mechanistic studies into novel co-regulatory or cross-resistance pathways (for instance, the role of other metal-responsive regulators, or the impact of nanomaterials and metalloid pollutants on AMR gene mobility).

Overall, heavy metals and antibiotic resistance are two sides of the same coin in microbial ecology. Heavy metal contamination is not just an environmental toxicology issue – it is directly linked to the public health challenge of AMR. Addressing one without the other would be a half-measure. A One Health strategy that encompasses environmental metal pollution control, sustainable agricultural practices, and prudent antibiotic use is essential to stem the tide of resistance. By recognizing heavy metals as silent drivers of antibiotic resistance, we can design more effective interventions to protect the efficacy of life-saving antibiotics for future generations.

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