New mechanisms of antibiotic resistance discovered in Escherichia coli

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A team of experts from the Institute of Microbiology and Infection at the University of Birmingham (UK) have mapped the multiple antibiotic resistance (mar) regulon using whole-genome DNA sequencing, identifying new information about antibiotic resistance in Escherichia coli.

Lead author of the study David Grainger, from the University of Birmingham, explained: “We investigated a gene found in bacteria that is involved in resistance to multiple antibiotics.

“Although we have known about this gene for many decades, the ‘nuts and bolts’ of how it provides resistance to antibiotics has been difficult to pick apart.

“Our research identified previously unknown roles for this gene in controlling processes that provide drug resistance.

“We found two completely unexpected mechanisms that bacteria use to protect themselves from antibiotics. One protected their DNA from the harmful effects of fluoroquinolone antibiotics, and the other prevented doxycyline getting inside bacteria.”

The mar operon identified in E. coli is a chromosomally-encoded system that confers antimicrobial resistance, shared by most enteric bacteria.

The locus was already recognized for its dual antibiotic resistant mechanisms: 1) ability to control drug efflux via pumps and 2) ability to reduce porin production. These processes are controlled via two encoded transcription factors, MarR and MarA.

However, not all mar phenotypes can be explained through these mechanisms, for example, minocycline resistance, which is maintained in mutant marR cells. Previous attempts to complete the marR and marA regulons have been unsuccessful.

Using chromatin immunoprecipitation and DNA sequencing (ChIP-seq) the team mapped genome-wide DNA binding of both marR and marA.

The study, published in Nature Communications, was the end result of a decade-long research project carried out by the University. The results illustrate the extensive coverage on the mar regulon, which encompasses both lipid trafficking and DNA repair mechanisms.

These uncovered pathways of the mar locus include quinolone-induced DNA repair and the blockade of tetracyclines across the outer membrane.

Co-author Laura Piddock, from the University of Birmingham, concluded: “Antibiotics underpin modern medical, veterinary and farming practices world-wide. However, the efficacy of antibiotics is decreasing as more bacteria become resistant.

“Research such as ours that provides greater understanding of drug resistance mechanisms is vital if we are to address the global crisis of antibiotic resistance.”

Sources: Sharma P, Haycocks JRJ, Middlemiss AD et al. The multiple antibiotic resistance operon of enteric bacteria controls DNA repair and outer membrane integrity. Nat. Comms. doi:10.1038/s41467-017-01405-7 (2017); www.birmingham.ac.uk/news/latest/2017/11/new-mechanism-bacteria-antibiotic-resistance.aspx

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