Table 3.

Mechanisms of co-selection of AMR by heavy metals.

Mechanism	Microorganism	Example	Reference
Co-resistance	MRSA	Plasmids carrying resistance genes for Cu and Cd (copA, mco, and cadDX) and multiple antimicrobials including macrolides, lincosamides, streptogramin B, tetracyclines, aminoglycosides, and trimethoprim (erm(T), tet(L), aadD, and dfrK)	[62]
	MRSA	Physical presence of the Zn resistance gene (czrC)on the methicillin resistance-encoding SCCmec element	[63,64]
	Pseudomonas sp.	A number of ARGs such as aadA2, qacEΔ1, and sulI (resistance against streptomycin, spectinomycin, quaternary ammonium, and sulfonamide) located in Tn5045, where chromate resistance genes chrBACF are obtained	[65]
	monophasic S. Typhimurium	Heavy metal resistance genes ((silver/copper (silA-silE), mercury (merA)) and ARGs exist on chromosomes or plasmids in S. Typhimurium strains from different sources	[66]
	Enterococcus faecium and Enterococcus faecalis	Co-transfer of tcrB and erm(B) genes between E. faecium and E. faecalis strains	[67]
	E. faecalis	The antibiotic resistance gene tetM (resistance to tetracycline), vanA (encoding vancomycin resistance), streptothricin acetyltransferase gene, and aminoglycoside adenylyltransferase gene was identified in Cu-resistant E. faecalis	[68]
Cross-resistance	L. monocytogenes	A multidrug efflux pump MdrL found in L. monocytogenes confers a resistant phenotype against a range of antimicrobial compounds and heavy metals, such as Zn, Co, and Cr	[69]
	E. coli	The membrane stress-responsive two-component system (TCS) CpxRA that is linked to resistance to a variety of cell envelope-targeting drugs in Gram-negative bacteria, is also Cu-responsive and contributes to Cu tolerance	[70]
	P. aeruginosa	TCS CscRS found in P. aeruginosa not only influences the transcription of the czcCBA operon that encodes an RND-type efflux pump, which confers resistance to Zn, Cd, and cobalt (Co), but also reduces the expression of a specific porin OprD through which imipenem enters the bacterium	[71]
	E. coli	The envelope stress response sigma factor RpoE activated by polymyxin B and linked to polymyxin B resistance in a number of Gram-negative bacteria is also activated by Zn in E. coli and contributes to Zn and Cu tolerance in E. coli	[72]
	E. coli	Exposure to Cu increases expression of the oxidative stress-responsive soxS regulatory gene that has been linked to expression of the acrAB multidrug efflux operon	[73]
Biofilm formation	S. aureus	The biofilm matrix enables bacteria to survive under stress conditions, such as exposure to heavy metals, and this in turn drives the frequency of mutation in the bacterial genomes, some of which may co-select for AMR	[74]
Facilitation of HGT	E. coli	Sub-inhibitory concentrations of heavy metals accelerate the horizontal transfer of plasmid-mediated ARGs in water environment by promoting conjugative transfer of ARGs between E. coli strains	[75]