Reversing Resistance: How to teach old antibiotics new tricks

It’s an all-too-common refrain nowadays, but antibiotic resistance remains one of the world’s most severe public health threats.  Bacteria have developed resistance to nearly every antibiotic drug in our arsenal, and the Healthcare Infection Society has estimated that 10 million people will die annually from antibiotic-resistant bacteria by 2050.

Hoping to reverse these worrying trends, researchers from Oregon State University and Sarepta Therapeutics have developed a new method for killing antibiotic-resistant bacteria with drugs that we already have.  The technique uses a molecule called a PPMO to directly target and suppress bacterial genes that confer resistance, which re-sensitizes bacteria to existing drugs.  Initial experiments have only re-sensitized bacteria to a single drug (meropenem), but the general strategy can be extended to resistance mechanisms that deactivate many antibiotics at once; think “two birds, one stone.”

Therapies that “reverse” antibiotic resistance have been in use for decades, but most have been created via traditional drug discovery methods that are expensive and time-consuming.  A PPMO, however, can be easily modified to target different resistance genes.  This feature can bypass years of work because identifying these key genes is often easier, faster, and cheaper than building new molecules from scratch.  Antibiotic resistance is growing so rapidly that having multiple ways to kill the same pathogen is becoming more and more valuable; think “one bug, many stones.”

PPMOs are nowhere near the clinic yet and will eventually confront resistance themselves, but they embody a promising strategy that aims to be as adaptable as the microbes they’re designed to kill.

Acknowledgments: Many thanks to Tracy Kambara, a graduate student in the Biological & Biomedical Sciences Ph.D. program at Harvard University, for providing her expertise and commentary on the topic.

Managing Correspondent: Christopher Gerry

Original Research: Peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) restores carbapenem susceptibility to NDM-1-positive pathogens in vitro and in vivo – Journal of Antimicrobial Chemotherapy

Media Coverage: Scientists develop molecule that reverses antibiotic resistance – The Independent; Scientists just announced our best shot at ending antibiotic resistance to date – Science Alert