Understanding human health risks caused by antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARG) in water environments: Current knowledge and questions to be answered

Figures & data

Table1. Examples on various ARGs, MGEs and antibiotics found in different water environments.

Environment	ARGs*	MGEs*	Antibiotics*	Remarks	Reference
South China Sea	macB, acrB			Pristine environment with minimal human activity	(Chen et al., 2013)
Polar marine sediments	sul1, tet(D), qnrB	intI1		sul gene abundance in polar sediments were 2-5 orders lower than the human impacted Haihe river, China.	(Tan et al., 2018)
Marine environment coastal areas of Bohai bay, China	blaTEM, sul1, sul2, tet(B),	intI1			(Zhang, Niu, Zhang, & Zhang, 2018)
Sediments from 18 estuaries along over 4,000 km of coastline in China	aacC, aadA5, mphA, oprD, oprJ, qacEΔ1	intI1	Macrolides, TC		(Zhu et al., 2017)
Manilla Bay water	sul1, sul2, sul3			Bay water contained sul genes with high copy numbers, even though the inlet river water didn’t, suggesting marine non-culturable bacteria are the reservoir of the three sul genes	(Suzuki et al., 2013)
Maricultural site sediments	bacA, mexF, mexB, sul1, tet(C)		CIP, ENR, OTC, SDZ, SMX, TC	Samples were taken from sites to represent the complete Chinese coastline	(Gao et al., 2018)
Maricultural site water and sediments	sul2>sul1, tet(W), tet(Q)>tet(O)		SDZ (water) OTC (sediments)		(Chen, Zheng, Zhou, & Zhao, 2017)
Estuarine lake water	sul1		NOR, OTC, SDZ, SMX, TC		(Yuan, Ni, Liu, Zheng, & Gu, 2019)
Estuarine lake sediments	tet(C)
Urban sewage pipes	FCA and MLSB resistance genes	tnpA (IS6 group)	SMX		(Huang et al., 2019)
Activated sludge reactors	aadA, bacA, chloramphenicol exporter, sul1, tet(C)		ERY, KAN, LIN, SMT, TC, TMP	Minimum antibiotic concentration of 20 mg /L was used in this study	(Zhao et al., 2019)
Full-scale municipal WWTP influent	blaTEM, ermf, qnrS	intI1		Several treatment process chains were used including activated sludge process, oxidation ditch and A2O treatment	(Tong et al., 2019)
WWTP (activated sludge) effluent	sul1, tet(O), tet(W)		AMX, TC		(Proia et al., 2018)
WWTP (activated sludge + nutrient removal) effluent	sul1, sul2, qnrS, tet(O), tet(W)		AMX, TC
activated sludge TP influent	aac(6')-1b, blaCTX-M, ermB, sul1, sul2, tet(M)	intI1	AMX, CTC, CIP, OTC, TC, VAN		(Le, Ng, Ngoc, Chen, & Gin, 2018)
Membrane bioreactor influent	aac(6')-1b, blaCTX-M, dfrA, ermB, sul1, sul2, tet(M)
Hospital WWTP effluent	aacC2, blaSHV, floR, mefA, sul1, sul2, tet(A), tet(B), tet(C), tet(W)	tnpA	AMP, FEP, CAZ, TMP, VAN		(Szekeres et al., 2017)
WWTP effluent	sul1, sul2, tet(A), tet(C), tet(G), tet(M), tet(O), tet(W), tet(X)	intI1, intI2			(Ben et al., 2017)
Urban WWTP effluent	FCA and Aminoglycoside resistance genes	tnpA (IS6 group), IS613, Tp614, tnpA (IS4 group)	SMX		(Huang et al., 2019)
Waste stabilization pond effluent			CEF, CIP, ERY, SMX		(Azanu, Styrishave, Darko, Weisser, & Abaidoo, 2018)
Recycled water	vanA, ermF, sul2			A broader range of ARGs were detected after the reclaimed water passed through the distribution systems	(Fahrenfeld, Ma, O’Brien, & Pruden, 2013)
Full-scale municipal WWTP sludge	blaTEM, ermF	intI1		Several treatment process chains were used including activated sludge process, oxidation ditch and A2O treatment	(Tong et al., 2019)
Dewatered sludge	ermC, qnrB, sul1, sul2, tet(A), tet(B), tet(E), tet(G), tet(H), tet(S), tet(T), tet(X)		Sulfonamides, TC	Concentrations are higher than the influent values	(Mao et al., 2015)
Urban river discharge	FCA and MLSB resistance genes	tnpA (IS6 group), IS613, Tp614, tnpA (IS4 group)	SMX		(Huang et al., 2019)
Freshwater biofilms	ermB			After notable runoff event	(Winkworth, 2013)
	vanB, tet(B)			Swimming spot
River water from upstream until the estuary	sul1, sul2, tet(W)				(Jiang, Zhou, Yang, et al., 2018)
River surface water	blaOXA-21, emrA, ereA, mdtK, tet(G)	52 integrons and 39 plasmids		Unique ARGs to different water systems were marked	(Jiang, Zhou, Zhang, et al., 2018)
River water			CEF, CIP, ERY, SMX		(Azanu et al., 2018)
River sediments	lsa, vanM, vanS, vanY, vanZ	18 integrons and 105 plasmids			(Jiang, Zhou, Zhang, et al., 2018)
River water and sediments	sul1, sul2			Sediments contained 120 to 2000-fold higher concentrations of sul1 and sul2 genes compared to river water	(Luo et al., 2010)
Recreational lake water	blaSHV, blaTEM, ampC, ermA, ermB, cat, cmr				(Fang, Wang, Cui, Rogers, & Dong, 2018)
Lake surface sediments	blaOXY, blaSHV, blaTEM, sul1, sul3, tet(O)	intI1	NOR, TC		(Ohore, Addo, Zhang, Han, & Anim-Larbi, 2019)
Recreational water and sediments	blaTEM, sul1, sul2, tet(X), tet(W)	intI1			(Dong, Cui, et al., 2019)
Irrigation water			CIP, ERY		(Azanu et al., 2018)
Fish intestine, Finland	aadA1, aadA2, dfrA1, sul1, tet32, tet(M), tet(O) tet(W),	intI1, tnpA01, tnpA04, tnpA06, tnpA07		Antibiotics are not used in the fish farm	(Muziasari et al., 2017)
Fish gills and intestinal contents, Concepcion Bay, Chile			AMP, CHL, STR, TET	ARB mainly belonged to Vibrionaceae and Enterobacteriaceae	(Miranda & Zemelman, 2001)
Spleen tissue of Carp, Czech Republic	tet(A), tet(E), qnrS1, qnrS2, sul2,	intI1	OTC	OTC was used to treat carp erythrodermatitis	(Syrova et al., 2018)
Intestinal mucus of wild freshwater fish species, Spain	blaTEM			Brown trout and Ebro barbel from La Llosa del Cavall reservoir	(Marti et al., 2018)
Intestinal mucus of wild freshwater fish species, Spain	qnrS, sul1			Common carp from Foix reservoir
Seafood products, Japan	blaTEM-1, blaCMY-2, blaCMY-13, blaCMY-39, qnrB2, qnrB6, qnrS1	intI1		Products were made in Japan or imported from Chile, China, India, Indonesia or North Pacific	(Ahmed, Maruyama, Khalifa, Shimamoto, & Shimamoto, 2015)
Active and closed down landfills			CEP, CIP, ERY, SMX, TMP	Antibiotics in leachate from active landfills were significantly greater than in closed landfills in the wet season	(Chung, Zheng, Burket, & Brooks, 2018)
Landfill leachate	ampC, blaCTX-M, qnrA, qnrB, qnrS	intI1, intI2, tnpA01, tnpA03	AMX, INN-d4, CEP, ENR, NOR, NOR-d5 OFX, PEF		(You, Wu, Wei, Xie, & Lu, 2018)
Neglected MSW landfill leachate	sul1, sul2	intI1, tnpA, traA, IS-CR3, IS-26			(Yu et al., 2016)
MSW landfill groundwater	171 ARGs	tnpA01, intI1			(Chen et al., 2017)
Urban residential land discharge	FCA and beta-lactamase resistance genes	tnpA (IS6 group), Tp614, tnpA (IS4 group)	OTC		(Huang et al., 2019)
Urban public land discharge	FCA and beta-lactamase resistance genes	tnpA (IS6 group), Tp614, tnpA (IS4 group)	SMX		(Huang et al., 2019)
Urban tap water	Aminoglycoside and MLSB resistance genes	IS613, tnpA (IS4 group)	SMX		(Huang et al., 2019)
Tap water (Extracellular ARG)	blaTEM, sul1, sul2, tet(C)			Monthly variations of ARGs has been performed	(Hao et al., 2019)
Tap water (Intracellular ARG)	sul1, sul2
Groundwater (Closer to urban areas)	sul1, tet(C), tet(O), tet(W)	intI1	ERY, TMP		(Szekeres et al., 2018)
Piggery WWTP effluent	ampC, blaOXA-1, blaTEM-1			Higher abundance of ARGs in winter	(Yang et al., 2019)
Aquaculture/ livestock wastewater			SMT, OTC, LIN, SMX	Piggery, shrimp culture and other livestock wastewater from Thailand and Vietnam	(Shimizu et al., 2013)
Hospital sewer outlet	blaTEM, sul1, tet(W)		SMX, TC		(Proia et al., 2018)
Hospital wastewater	sul1, tet(O)	intI1			(Qiang Wang et al., 2018)
Hospital wastewater			CIP, ERY, CEF, SMX		(Azanu et al., 2018)
Hospital effluents	blaSHV > blaNDM-1> blaCTX> blaKPC			Predominant ARB taxa were Pseudomonas spp., Klebsiella spp., Enterobacter spp. and Citrobacter spp.	(Haller et al., 2018)
Pharmaceutical manufacturing plant A WWTP effluent	lmrA		CLI, LIN		(Guo et al., 2018)
Pharmaceutical manufacturing plant B WWTP effluent	aac, aadD		PM, RSM
Pharmaceutical manufacturing plant CWWTP effluent	qnrD		LVX
Pharmaceutical manufacturing plant D WWTP effluent	ermB		AZM, CIP, CLR, ENR, ROX
Pharmaceutical manufacturing plant E WWTP effluent	blaOXA		CEP, INN

* Most abundant ARGs, MGEs and antibiotics were reported when data are available. AMX: Amoxicillin, AMP: Ampicillin, AZM: Azithromycin, CAZ: Ceftazidime, CEF: Cefuroxime, CEP: Cephalexin, CHL: Chloramphenicol, CIP: Ciprofloxacin, CLR: Clarithromycin, CLI: Clindamycin, CTC: Chlortetracycline, ENR: Enrofloxacin, ERY: Erythromycin, FEP: Cefepime, INN: Cefradine, KAN: Kanamycin, LIN: Lincomycin, LVX: Levofloxacin, NOR: Norfloxacin, OFX: Ofloxacin, OTC: Oxytetracycline, PEF: Pefloxacin, PM: Paromomycin, ROX: Roxithromycin, RSM: Ribostamycin, SDZ: Sulfadiazine, SMT: Sulfamethazine, SMX: Sulfamethoxazole, STR: Streptomycin, TET: Tetracycline, TMP: Trimethoprim, VAN: Vancomycin. A2O: Anaerobic-Anoxic-Oxic, FCA: fluoroquinolone, quinolone, florfenicol, chloramphenicol, and amphenicol, MLSB: Macrolide-Lincosamide-Streptogramin B resistance genes, MSW: Municipal solid waste, WWTP: Wastewater treatment plant.

Table 2. Sub-inhibitory concentrations of selection pressures induce antibiotic resistance.

Bacterial strain	Selection pressure	Concentration	MIC	Remarks	Reference
(a) Mutation
E. coli MG1655	Ampicillin	1 µg/ml		Significant increases in the mutation rate relative to an untreated control associated with increased production of reactive oxygen species. Multidug cross-resistance was observed	(Kohanski et al., 2010)
	Kanamycin	3 µg/ml
	Norfloxacin	15 ng/ml
	Norfloxacin	50 ng/ml
Staphylococcus aureus	Ampicillin	35 ng/ml
E. coli J93 and derived strains	Ciprofloxacin	1/5 of MIC		Some derived strains, result in a loss of fitness relative to that of the wild type in the absence of antibiotic	(Liu et al., 2011)
	Tetracycline	1/20 of MIC
Pseudomonas aeruginosa, Pseudomonas protegens	Ciprofloxacin	1/10 of MIC		Genome architucture chnages were observed in as low as 5 serial passages in the presence of sub-MIC antibiotics. After 4 passages, MIC of aome P. protegens strains was increased	(Chow, Waldron, & Gillings, 2015)
	Kanamycin	1/10 of MIC
	Tetracycline	1/10 of MIC
E. coli MG1655	Ag(I)	1.79 mg/l	8.95 mg/l	Mutation rate of E. coli resistant to ciprofloxacin increased by 14.6 1538.2 folds for Ag(I), 4 -27 fold for Zn (II) and 7 -20 fold for Cu(II). Resistance to ciprofloxacin occurred via adaptive mutations	(Li et al., 2019)
	Zn (II)	26.81 mg/l	134 mg/l
	Cu (II)	11.5 mg/l	575 mg/l
E. coli MG1655	Sodium Chlorite (NaClO2)	10 mg/l		MIC to ciprofloxacin was increased by 4 – 8-fold	(D. Li et al., 2016)
	Iodoacetic acid	10 mg/l
E. coli MG1655 wild type	Ciprofloxacin		0.023 µg/ml		(Gullberg et al., 2011)
E. coli MG1655 mutants			0.047–0.38 µg/ml	Ratio of resistant: susceptible strains changed as a function of number of generations and the antibiotic concentration. Minimum selective concentration (fitness cost of the resistance and antibiotic-conferred selection for the resistant mutant are in balance), varied between 1/4 (Streptomycin) and 1/230 (Ciprofloxacin)
Salmonella enterica serovar Typhimurium LT2	Tetracycline		1.5 µg/ml
	Streptomycin		4 µg/ml
S. enterica serovar Typhimurium LT2 wild type	Streptomycin	1 mg/l	4 mg/l	After 900 generations, high-level resistance up to >1024 mg/l was observed. Several small-effect resistance mutations combined and conferred high-level resistance via alteration of ribosomal RNA target, reduction in aminoglycoside uptake and induction of an aminoglycoside modifying enzyme.	(Wistrand-Yuen et al., 2018)
(b) Horizontal gene transfer
From bacterial community to E. coli CV 601	Gentamicin	0.1 mg/l	0.125 mg/l		(Jutkina et al., 2018)
	Sulfamethoxazole	1mg/l	16 mg/l
	Chlorhexidine digluconate	24.4 µg/l	4.8 mg/l
	Triclosan	0.1 mg/l	2 mg/l	Two-fold increase in relative transfer frequency
From E. coli K12 LE392 to E. coli K12 MG1655	Triclosan	0.02 µg/l–2 mg/l		2 µg/l Triclosan increased the intra-genera conjugation frequency by 6.2-fold	(Lu, Wang, et al., 2018)
From E. coli K12 LE392 to Pseudomonas putida KT 2440				3 µg/l Triclosan increased the inter-genera conjugation frequency by 2.3 - fold
From E. coli S17-1 to E. coli K12 MG1655	Free chlorine	0.1–1 mg/l		Conjugative transfer efficiency increased by 3.4–6.9-fold	(Zhang, Gu, He, Li, & Chen, 2017)
	Chloramine	0.1–1 mg/l		Conjugative transfer efficiency increased by 1.9–7.5-fold
	Hydrogen peroxide	0.24–3 mg/l		Conjugative transfer efficiency increased by 1.4–5.4-fold
From E. coli S17-1 to Salmonella typhimurium TA1535	Free chlorine	0.1–1 mg/l		Conjugative transfer efficiency increased by 1.4–2.3-fold
	Chloramine	0.1–1 mg/l
	Hydrogen peroxide	0.24–3 mg/l
From E. coli S17-1 to E. coli K12 MG1655	Ag (I)	0–0.1 mg/l	0.39 ± 3.54 mg/l	All ions promoted the conjugation frequency. The ability of heavy metal ions to facilitate conjugative transfer varied in Cu (II) > Ag (I) > Cr (VI) > Zn (II) order. Reactive oxygen species formation, SOS response, increased cell membrane permeability and altered expression of conjugation-relevant genes contributed to the increased conjugation efficiency.	(Ye Zhang et al., 2018)
	Zn (II)	0–100 mg/l	135 ± 4.50 mg/l
	Cu (II)	0–0.5 mg/l	410 ± 6.65 mg/l
	Cr (VI)	0–20 mg/l	77 ± 5.93 mg/l
Acinetobacter baylyi ADP1	Bromoacetic acid (BAA)	600 µM		Natural transformation rates were increased by 2 -fold as a result of BAA induced DNA damage.	(Mantilla-Calderon et al., 2019)

Figure 1. Quantitative microbial risk assessment (QMRA) procedure for assessing the human health risks by ARB and ARGs in aquatic environment. The diagram briefly describes the process and provide summarizes the current knowledge.

Figure 2. Hypothesis for new antibiotic resistance hotspots. (a) Attachment of antibiotics to EPS can increase the antibiotic concentration in the biofilm surface layer and can act as a selective pressure, (b) Elevated concentration of chemicals in the vicinity of ultrafiltration and reverse osmosis treatment systems membrane surface can act as mutagens and can lead to the development of antibiotic resistance in the bacteria in gel/cake layer and surroundings via mutation.

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