Associations between sensitivity to antibiotics, disinfectants, and heavy metals in natural, clinical and laboratory isolates of Escherichia coli

Bacteria in nature often encounter non‐antibiotic antibacterials (NAAs),
such as disinfectants and heavy metals, and they can evolve resistance via
mechanisms that are also involved in antibiotic resistance. Understanding
whether susceptibility to different types of antibacterials is
non‐randomly associated across natural and clinical bacteria is therefore
important for predicting the spread of resistance, yet there is no
consensus about the extent of such associations or underlying mechanisms.
We tested for associations between susceptibility phenotypes of 93 natural
and clinical Escherichia coli isolates to various NAAs
and antibiotics. Across all compound combinations, we detected a small
number of non‐random associations, including a trio of positive
associations among chloramphenicol, triclosan and benzalkonium chloride.
We investigated genetic mechanisms that can explain such associations
using genomic information, genetic knockouts and experimental evolution.
This revealed some mutations that are selected for by experimental
exposure to one compound and confer cross‐resistance to other compounds.
Surprisingly, these interactions were asymmetric: selection for
chloramphenicol resistance conferred cross‐resistance to triclosan and
benzalkonium chloride, but selection for triclosan resistance did not
confer cross‐resistance to other compounds. These results identify genetic
changes involved in variable cross‐resistance across antibiotics and NAAs,
potentially contributing to associations in natural and clinical bacteria.