Development and selection of low-level multi-drug resistance over an extended range of sub-inhibitory ciprofloxacin concentrations in Escherichia coli

Carly Ching,Muhammad H Zaman

doi:10.1038/s41598-020-65602-z

Carly Ching, Muhammad H Zaman

Open Access

https://doi.org/10.1038/s41598-020-65602-z

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Abstract

To better combat bacterial antibiotic resistance, a growing global health threat, it is imperative to understand its drivers and underlying biological mechanisms. One potential driver of antibiotic resistance is exposure to sub-inhibitory concentrations of antibiotics. This occurs in both the environment and clinic, from agricultural contamination to incorrect dosing and usage of poor-quality medicines. To better understand this driver, we tested the effect of a broad range of ciprofloxacin concentrations on antibiotic resistance development in Escherichia coli. We observed the emergence of stable, low-level multi-drug resistance that was both time and concentration dependent. Furthermore, we identified a spectrum of single mutations in strains with resistant phenotypes, both previously described and novel. Low-level class-wide resistance, which often goes undetected in the clinic, may allow for bacterial survival and establishment of a reservoir for outbreaks of high-level antibiotic resistant infections.

Highlights

Antibiotic resistant infections can undermine effective treatments on which we typically rely on
We systematically reviewed the literature on sub-inhibitory fluoroquinolone antibiotic exposure and resistance
We investigated the impact of a wide range of sub-inhibitory concentrations of ciprofloxacin, from 0% to 110% of the minimum inhibitory concentration (MIC), on stable antibiotic resistance acquisition in Escherichia coli

Summary

Introduction

Antibiotic resistant infections can undermine effective treatments on which we typically rely on. While focus is often given to genetic determinants and mechanisms associated with high-level and clinically-relevant antibiotic resistance during lethal selection[1], bacteria are often exposed to lower, sublethal concentrations of antibiotics. This occurs in the environment during agricultural activities and wastewater treatment[2,3]. It occurs in the clinic due to low-dose prophylactic treatment, incorrect dosing, poor patient adherence and use of poor quality or substandard medicines, which often do not have the stated amount of active pharmaceutical ingredient (API)[4,5] This prevalent, and often inadvertent, exposure of bacteria to sub-inhibitory levels of antibiotics may serve as an important driver of antibiotic resistance[6]. This has broad health implications, from agriculture to poor quality antibiotic usage, as this may result in strains of bacteria that are pre-disposed to evolve further resistances

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