A new platform for combinatorial drug discovery to combat antibiotic resistance

A new platform for combinatorial drug discovery to combat antibiotic resistance


Antibiotics were first discovered and deployed
more than 75 years ago. But development of new antibiotics largely
stalled by the 1980s, and over the past 30 years a disturbing trend has emerged. According to the World Health Organization
more than a 1/4 of healthcare associated infections in long term acute settings exhibit some form
of antibiotic resistance. This means that with antibiotic resistance on the rise The antibiotics we’ve relied
on for nearly a century are becoming less effective. One solution is to develop new antibiotics. Here in the Blainey Lab at the Broad Institute
believe an alternative solution is to combine antibiotics with existing drugs. In particular, gram-negative bacteria like
E. coli feature a thick outer membrane which keeps antibiotics from getting in and effectively
treating infection. Recent studies have revealed that combining
antibiotics with other existing drugs can give those antibiotics a fighting chance. One example is Loperamide. It’s a drug typically used to treat diarrhea,
but has shown the ability to disrupt gram-negative cell envelopes. There are around 2000 FDA-approved drugs used
in hospitals and doctors’ offices today. To test every one of these
drugs against a single bacteria would take millions of tests and require complex and
expensive robotic equipment. We want to make this easier. So we designed a microwell array device that
right now lets us rapidly test about 1,000 pairs of antibiotics and drugs We make tiny droplets that each contain bacteria
as well as a single antibiotic or drug. We load pairs of these droplets into each
microwell on the microwell array. We color code these droplets, we can also
tell which antibiotic-drug pair went into each microwell. Then we use microscopy to track the growth of the bacteria in each microwell And we are looking for instances where the bacteria didn’t grow. In these cases it might mean that we have discovered a synergy
between the antibiotic and the drug. For our first full-scale test we screened
10 antibiotics and more than 4,000 compounds from the Broad Institute’s drug repurposing
library, a collection of compounds in development or clinical use for other diseases. After 10 days of testing against E. coli we
found more than 10 promising combinations for further study. We think that with time we can scale this
technology up such that almost any lab can test 10 times as many drug combinations at much lower costs than a
industrial robotic facility. Our lab and our collaborators are working
to adapt this technology to a wide range of disease areas in addition to infectious disease.

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