Min-maxing Microbes

Many researchers are busy discovering ways to mitigate the deadly effects of the growing antibiotic resistance crisis. One such person is Craig MacLean, Professor of Evolution and Microbiology at the University of Oxford. MacLean’s lab recently published a paper exploring how genes are evolving to maximize their effectiveness (1).

“The main mechanism for bacteria to become resistant to antibiotics is by acquiring new resistance genes that protect them against antibiotics,” says MacLean. “It is well established that the acquisition of resistance genes imposes fitness costs on bacteria.”

This can be seen, MacLean explains, when bacteria have a worse rate of growth as a byproduct of acquiring resistance genes. In theory, a reduction in antibiotic consumption should turn the heat down on the boiling pot of bacteria, but so far measures to do so have not delivered the results we might expect.

MacLean’s previous work has examined the use of the antibiotic colistin in agriculture. Its heavy use as a growth promoter led to the emergence of MCR-1 resistance gene in E.coli. Now widely banned, it offers researchers like MacLean a unique opportunity to see how regulation can affect resistance.

“The main questions that we set out to answer in this project were as follows: Has MCR-1 evolved to offset the huge fitness burden that it imposes on E.coli? And, if so, has the evolution of the gene impacted the efficacy of the colistin ban?” says MacLean.

The team’s major finding was that MCR-1 has evolved in such a way that it has “tweaked” the level at which E.coli expresses it – meaning it has minimal cost impact on the bacteria. “These new low cost, high resistance variants of MCR-1 then spread across strains of E.coli that are associated with different ecological niches,” MacLean adds.

Colistin’s ban did show a dramatic decline in MCR-1 presence in agriculture, but the team found that the prevalence of low cost, high resistance variants didn’t drop so sharply. “The findings provide some of the clearest evidence showing how evolution mitigates the costs of resistance genes and stabilizes resistance in pathogen populations,” MacLean explains.

Most surprising of all was the discovery that mutations that dial back the expression of MCR-1 actually boost colistin resistance. “This surprising result (which is supported by multiple lines of evidence) is completely counterintuitive,” says MacLean. “We still don’t fully understand why this is the case, but we think that it probably reflects the fact that high levels of MCR-1 activity lead to changes in the cell membrane that make bacteria more sensitive to colistin; for example, by increasing membrane permeability.”

The paper’s results suggest a need to explore methods beyond reducing antibiotic consumption. “Under these conditions you probably need interventions that are going to directly remove resistance from pathogen populations or that are going to provide a big advantage to antibiotic sensitive bacteria,” concludes MacLean.