Pathways of resistance: from mercury to methicillin

Posted on February 18, 2015   by Jemima Hodkinson

In a climate of rising fear over the diminishing efficacy of antibiotics, microbiologists from the Universities of Nottingham and East Anglia have looked back at the bacteria-killing substances of the pre-antibiotic era: metals. Dr Jon Hobman and Dr Lisa Crossman's review, published in the Journal of Medical Microbiology, concludes that the ancient pathways of resistance which bacteria have evolved against these metals may be intimately linked to the antibiotic resistance genes that are circulating in bacterial populations today.

Metals and metallic compounds have been used for medical and biological purposes for millennia: as antiseptics, diuretics, and dental fillings; cosmetics, tonics and chemical weapons. Most are indiscriminately toxic, and you wonder whether some of these historical cures were actually worse than the ailments they were intended to treat – mercury-laced teething powder, anyone?

Metals and their ions can damage cells in multiple ways: binding to enzymes, DNA and membranes, disrupting their function; taking part in reactions that generate harmful free radicals; or binding to the cell’s pool of antioxidants that usually protects against free radicals. It is the lethal damage that these mechanisms can inflict on bacterial cells that underlies the utility of metal compounds in controlling infections in plants, animals and humans.

However, as with modern antibiotics, bacteria have evolved their own defences against the toxic effects of antimicrobial metals. Some methods are generic, such as stress response mechanisms and efflux pumps, which try to bail toxic molecules out of the cell faster than they can come in. Others are specific weapons against particular metals or ions: these are controlled by a response regulator, a neat signaling system that turns on the genes for the cell’s defensive response when it senses the ion present in the environment. For example, the method that bacteria use to protect themselves against mercury ions involves a protein which ferries the ion into the cell, then hands it over to an enzyme that converts it into non-toxic mercury molecules, which can then diffuse out of the cell. Scientists have identified related mechanisms for several other metals; many are ancient, evolved over millennia in response to metal ions present naturally in the environment.

Today, use of all but a few metals in medicine has now been phased out, superseded by safer, more effective modern antibiotics. Should we care that E. coli is resistant to arsenic, or that mercuric chloride might no longer cure your syphilis? Thanks to a dramatic increase in available microbial genome sequences, there is increasing evidence that metal ion resistance and antibiotic resistance are linked by being carried on the same mobile genetic elements that are capable of being moved between bacterial species and strains. Antimicrobial metal resistances could be contributing to the more pressing problem of resistance to modern antibiotics.

When mercury resistance was beginning to be reported in clinically important bacteria in the 1960s, it was found to be genetically linked to penicillinase plasmids in S. aureus. Comparing these clinical isolates with samples from the ‘pre-antibiotic era’ – some from 10,000 year old Siberian permafrost, others from the first half of the 20th century – leads the authors of this review to conclude that the Tn21 family of mercury resistance transposons – a type of mobile genetic element – could have evolved stepwise into multi-drug resistance transposons, eventually carrying genes conferring resistance to streptomycin, chloramphenicol and tetracycline as well as mercury. This evidence for the co-carriage – and potential for co-selection – of metal ion resistance and antibiotic resistance genes could be important when thinking about approaches to combat antibiotic resistance, particularly given the increasing use of metals with antimicrobial properties in consumer products, from plasters to water filters.

It could also provide a worrying glimpse into the future of resistance to modern antibiotics. Current advice emphasises the need to limit use of antibiotics, on the assumption that reducing the pressure for bacteria to carry resistance genes will lead to their loss by natural selection. However, mercury resistance has persisted despite the fact that antimicrobial use of mercury compounds has all but stopped – a phenomenon that the authors admit is surprising. Could antibiotic resistance genes persist in the bacterial populations in a similar way, even if use declines?

It also reminds us that microbiology can often take a human-centric view. While antibiotic resistance to modern antibiotics is usually seen as a problem of treatment failure, the way that resistance genes spread is an ecological problem.

Jemima is a member of the Wellcome Trust’s Graduate Development Programme

Hobman, JL., & Crossman, L. (2014). Bacterial antimicrobial metal ion resistance Journal of Medical Microbiology DOI: 10.1099/jmm.0.023036-0

Image: Luca Savettiere on Flickr under CC BY-NC-ND 2.0