by Thea Singer

Reports of the arrival in the U.S. of a new superbug that is resis­tant to an antibi­otic of last resort have set off alarm bells among public health officials.

The new superbug, which was found last month in the urine of a woman from Penn­syl­vania, is an Escherichia coli bac­terium that car­ries a gene called mcr-​​1. It has been found to confer resis­tance to the antibi­otic colistin—often the only treat­ment left for people infected with a lethal family of bac­teria known as carbapenem-​​resistant Enter­obac­te­ri­aceae, or CRE. Tom Frieden, director of the Cen­ters for Dis­ease Con­trol, has called CRE “night­mare bac­teria.”

For­tu­nately, the Penn­syl­vania woman’s infec­tion was sus­cep­tible to other antibi­otics, according to news reports. How­ever, the mcr-​​1 gene is car­ried on a cir­cular piece of DNA, or “plasmid,” that can be trans­ferred from one bac­terium to another. The great fear is that it could end up in a bac­terium that is resis­tant to all other antibi­otics, resulting in a “pan resis­tant” superbug.

We asked Uni­ver­sity Dis­tin­guished Pro­fessor Kim Lewis, who is a leader in the field of antibi­otic dis­covery, to describe the extent of the threat posed by the emer­gence of mcr-​​1. Last year a team led by Lewis, who is also the director of Northeastern’s Antimi­cro­bial Dis­covery Center, dis­cov­ered the antibi­otic teixobactin, which kills bac­teria without encoun­tering any detectable resis­tance. That dis­covery cap­tured head­lines worldwide.

The mcr-​​1 gene was recently found in E. coli in the U.S. In late 2015 researchers around the world—in China, then Den­mark, the Nether­lands, France, and Thailand—began reporting that bac­teria with the gene were resis­tant to col­istin, a last resort antibi­otic. What do these dis­cov­eries mean regarding antibi­otic resis­tance overall?

Col­istin is a much more impor­tant antibi­otic than many others. For example, we are one step away from a totally resis­tant Pseudomonas aerug­i­nosa, one of the tougher bugs to hit that causes life-​​threatening infec­tions in people with com­pro­mised immune sys­tems. Col­istin is an antibi­otic of last resort for that and it has been very effec­tive. It is an old antibi­otic with a high level of tox­i­city to the kid­neys, which is why it had not been used for a while. But with the devel­op­ment of these strains of resis­tant P. aerug­i­nosa, it became promi­nent in the arsenal of doc­tors. Another example is the bac­terium Acine­to­bacter bau­mannii. Wound infec­tions from resis­tant strains of A. bau­mannii emerged in hos­pi­tals among sol­diers returning from Iraq and Afghanistan, and col­istin became the treat­ment of last resort for them. The saving grace, if you will, of col­istin is that resis­tance to it has hereto­fore not been easily trans­mis­sible. Now with the mcr-​​1 gene, which is on a plasmid and can hop around from one bac­terium to another, that equa­tion has changed.

Bac­teria with the mcr-​​1 gene may be resis­tant to col­istin. But are they resis­tant to all other antibi­otics as well?

That depends. If the gene hops into a bac­terium that is resis­tant to every­thing else, we have a serious problem. But con­sider the case of the woman in Penn­syl­vania: She had a strain of E. coli that did respond to other antibiotics.

Where does teixobactin fit into the pic­ture? Antibi­otic resis­tance occurs when a bac­terium acquires a genetic muta­tion that allows it to code for a pro­tein that no longer binds the antibi­otic. Would bac­teria with the mcr-​​1 gene likely be resis­tant to teixobactin?

Teixobactin inhibits the biosyn­thesis of two impor­tant cell wall “polymers”—sugary mol­e­cules needed to build the cell wall. Nei­ther of those poly­mers are pro­teins, so they’re not coded directly by genes, which means there’s nothing to mutate. That’s the beauty of teixobactin—it hits immutable targets.

On a big-​​picture level, teixobactin points us in a new direc­tion. It shows us that we can have antibi­otics where devel­op­ment of resis­tance will be exceed­ingly unlikely. Our tra­di­tional approach to resis­tance has been trying to intro­duce antibi­otics faster than the bac­teria can develop resistance—we’re kind of in a rat race with them. Another, smarter approach is to focus on com­pounds where the bac­teria won’t develop resistance.

Now, teixobactin has its own lim­i­ta­tions: It only acts against “gram pos­i­tive” bac­teria. Gram neg­a­tive bac­teria have an addi­tional mem­brane restricting pen­e­tra­tion of most drugs into the cell. E. coli is gram neg­a­tive, so in that par­tic­ular case teixobactin would not be helpful. But it would be helpful against an anal­o­gous sce­nario with gram pos­i­tive bac­teria such as methicillin-​​resistant Staphy­lo­coccus aureus (MRSA) or vancomycin-​​resistant ente­ro­cocci (VRE), both of which are resis­tant to almost every­thing and for which we are run­ning out of options.

Col­istin, too, has its lim­i­ta­tions, in the other direc­tion: It acts only on gram neg­a­tive bacteria.

A news article in the December 2015 issue of Nature noted that ear­lier find­ings regarding col­istin resis­tance were “con­cerning” but “they may not be as cat­a­strophic as many media reports have sug­gested, because col­istin is only one of sev­eral antibi­otics that are rarely used in humans.” Should alarm bells be sounding?

Yes, absolutely. The alarm has been sounded very prop­erly. Con­sider again the case of P. aerug­i­nosa. With some strains we are only one step away from pan resis­tance; once they acquire col­istin resis­tance, that’s it.

Originally published in news@Northeastern on June 7, 2016.

Kim Lewis, University Distinguished Professor and Director of the Antimicrobial Discovery Center in the College of Science