Impact of Environmental Sub-Inhibitory Concentrations of Antibiotics, Heavy Metals, and Biocides on the Emergence of Tolerance and Effects on the Mutant Selection Window in E. coli

Author:

Chukwu Kelechi B.1,Abafe Ovokeroye A.123ORCID,Amoako Daniel G.14ORCID,Ismail Arshad56ORCID,Essack Sabiha Y.1ORCID,Abia Akebe L. K.17ORCID

Affiliation:

1. Antimicrobial Research Unit, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa

2. Residue Laboratory, Agricultural Research Council, Onderstepoort Veterinary Research Campus, Onderstepoort 0110, South Africa

3. School of Geography, Earth and Environmental Sciences, University of Birmingham, Birmingham B15 2TT, UK

4. Department of Integrative Biology and Bioinformatics, University of Guelph, Guelph, ON N1G 2W1, Canada

5. Sequencing Core Facility, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg 2192, South Africa

6. Department of Biochemistry and Microbiology, University of Venda, Thohoyandou 0950, South Africa

7. Environmental Research Foundation, Westville 3630, South Africa

Abstract

Bacteria’s ability to withstand the detrimental effects of antimicrobials could occur as resistance or tolerance with the minimum inhibitory concentration, the mutant prevention concentration, and the mutant selection window as salient concepts. Thus, this study assessed the impact of exposure to extremely high doses of ampicillin on the level of persistence and tolerance development in isolates previously exposed to different concentrations of selected antibiotics, biocides, and heavy metals. These isolates were previously exposed to oxytetracycline (OXYTET), amoxicillin (AMX), copper (Cu), zinc (Zn), benzalkonium chloride (BAC) 10, dimethylammonium chloride (DADMAC) 12 and a combination of all the individual pollutants (ALL). The isolates were exposed to very high concentrations (25 × MIC) of ampicillin, and their tolerance was calculated as the time required to kill 99.9% of the bacterial population (MDK99.9). The MDK99.9 increased by 30 to 50% in test isolates (DADMAC, OXYTET, Zinc = 28 h; BAC, Copper = 30 h; amoxycillin, ALL = 26 h) compared to the untreated control. BAC-exposed isolates decreased from 2.5 × 108 CFU/mL to 2.5 × 104 CFU/mL on the second day, displaying the highest tolerance increase. The tolerance appeared to originate from two sources, i.e., stochastic persistence and genetic-induced persistence, involving multiple genes with diverse mechanisms. The mutant selection window of the isolates to ampicillin, amoxicillin, and oxytetracycline also slightly increased compared to the control, indicating the selective survival of persister cells during the 30-day exposure. These findings indicate that bacterial exposure to sub-inhibitory concentrations of environmental chemical stressors may not always result in the development of antimicrobial resistance but could initiate this process by selecting persisters that could evolve into resistant isolates.

Funder

South African Research Chair Initiative of the Department of Science and Technology and the National Research Foundation of South Africa

South African Medical Research Council

Publisher

MDPI AG

Subject

Virology,Microbiology (medical),Microbiology

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