Sub-lethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis

By Michael A. Kohanski, Mark A. DePristo, James J. Collins. Molecules and Cells, 2010

959 citations recorded by the source corpus.

Summary Antibiotic resistance arises through mechanisms such as selection of naturally occurring resistant mutants and horizontal gene transfer. Recently, oxidative stress has been implicated as one of the mechanisms whereby bactericidal antibiotics kill bacteria. Here we show that sub-lethal levels of bactericidal antibiotics induce mutagenesis, resulting in heterogeneous increases in the minimum inhibitory concentration for a range of antibiotics, irrespective of the drug target. This increase in mutagenesis correlates with an increase in ROS, and is prevented by the ROS scavenger thiourea and by anaerobic conditions, indicating that sub-lethal concentrations of antibiotics induce mutagenesis by stimulating the production of ROS. We demonstrate that these effects can lead to mutant strains that are sensitive to the applied antibiotic but resistant to other antibiotics. This work establishes a radical-based molecular mechanism whereby sub-lethal levels of antibiotics can lead to multidrug resistance, which has important implications for the widespread use and misuse of antibiotics.

Subfields: Molecular Biology, Molecular Medicine, Pharmacology

View Paper: https://www.semanticscholar.org/paper/f66174b9c041e5c8c3d06de7cfc8ed21720b9d88

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Citations in the corpus

Antibiotics and the gut microbiota. (2014, positive): “…at levels believed to be pres-ent in natural environments such as soil elicit nonlethal responses that lead to altered physiology and behavior (5–7); thus, antibiotics and a wide variety of small molecules that display growth-inhibitory properties at high concentrations may have evolved long…”
Review of Antimicrobial Resistance in the Environment and Its Relevance to Environmental Regulators (2016, background): “The induction of this DNA damage and repair cascade by low levels of antibiotics leads to an increase in mutation rates, which can result in the emergence of multidrug resistance (Kohanski et al., 2010).”
Antibiotics induce redox-related physiological alterations as part of their lethality (2014, background): “Accordingly, these and previous data point to hydroxyl radicals as agents of antibiotic mutagenesis, and this notion is supported by observations that anaerobic growth or thiourea addition reduces mutation rates to near normal levels (77).”
Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics (2014, background): “Furthermore, bacteria may produce hydroxyl radicals when exposed to sublethal concentrations of antibiotics (169).”
Antimicrobial use in aquaculture re-examined: its relevance to antimicrobial resistance and to animal and human health. (2013, background): “Mutants and bacteria tolerant to antimicrobials can clearly be selected by inhibitory and subinhibitory concentrations of antimicrobials (Miller et al., 2004; Dorr et al., 2009; Kohanski et al., 2010).”
Selection of Resistant Bacteria at Very Low Antibiotic Concentrations (2011, background): “time and thereby increase the rate of mutant take-over [18].”
Antibiotic Resistance Is Prevalent in an Isolated Cave Microbiome (2012, background): “Resistance can emerge relatively quickly in the case of some mutations in target genes and there is evidence that antibiotics themselves can promote such mutations [43,44,45,46]; however, resistance to most antibiotics occurs through the aegis of extremely efficient enzymes, efflux proteins and othe”