Scientists Blend Old Drugs In New Ways

Researchers behind a new study from the Emory Antibiotic Resistance Center at the Emory
University School of Medicine, in Atlanta, GA, believe that old drugs could be used in new ways
to win the race against superbugs.
The study's authors explain that many superbug bacteria have a type of resistance called
heteroresistance," which many researchers still struggle to define precisely.
However, by and large, heteroresistance refers to a phenomenon in which, within a larger
bacterial population, a subpopulation develops resistance to the antibiotic (or antibiotics) to
which other bacteria in the same population respond.
Moreover, since only a few bacteria within a population are drug-resistant, in the case of
heteroresistance, doctors may find it hard to detect these instances using regular laboratory tests.
We can think of heteroresistance as bacteria that are half resistant,'" explains study co-author
David Weiss, Ph.D. When you take the antibiotic away, the resistant cells go back to being just
a small part of the group. That's why they are hard to see in the tests that hospitals usually use," he
Weiss and colleagues believe that successfully identifying heteroresistance could help doctors
and researchers identify which antibiotic combinations would work best in defeating a mixed
the population of susceptible and drug-resistant bacteria.
So far, laboratory experiments and research in mouse models — which the investigators present
in Nature Microbiology — suggest that this approach could indeed help turn the tables against
hard-to-track antibiotic-resistant bacteria.
In the current study, the research team analyzed 104 bacterial samples (isolates) obtained through
the Multi-site Gram-negative Surveillance Initiative, a program run by the Centers for Disease
Control and Prevention (CDC), with a focus on carbapenem-resistant Enterobacteriaceae.
The researchers used the samples to identify multidrug-resistant bacteria. Among their samples,
over 85% of the bacteria showed resistance to at least two different antibiotics.
However, Weiss and colleagues found that in the heteroresistance lay the solution: When they
combined the two antibiotics that a bacterial population was resistant to, the mix was more
effective in killing the population.
Why? Because within that multidrug-resistant population, different subpopulations were resistant
to different antibiotics, which meant that distinct drugs were able to successfully target different

The researchers also tested their method on two isolates of pan-resistant Klebsiella pneumoniae
bacteria, one of which had been collected from a patient who died in the hospital in 2016 from
infection with the superbug.
The case caused alarm at the time, since that strain of K. pneumoniae, later named Nevada-2016,
demonstrated resistance to 26 antibiotics, including the extremely strong drug colistin.
In laboratory experiments, a culture of Nevada-2016 showed heteroresistance to two antibiotics.
Yet when the investigators attacked the bacteria with a combination of those antibiotics, the
bacteria receded.
The team also performed some tests in mice that they had infected with another heteroresistant
— and deadly — strain of K. pneumoniae, AR0040. The researchers identified the drug
combination that matched AR0040's heteroresistance, then treated the mice with it, curing them
of the dangerous infection.
Looking more closely at heteroresistance could illuminate more aspects of antibiotic resistance
and help identify promising ways to fight it.
The idea of using antibiotic combinations to fight stubborn bacteria is by no means new, but
studies such as the current one shed fresh light on why and how this strategy can be effective.
Thus, the authors explain in their paper, Multiple heteroresistance may explain a significant
proportion of antibiotic combinations previously identified as synergistic [working in unison]."
Should heteroresistance to more than one antibiotic become combined within a bacterial strain,
however, Weiss notes that the approach in the current study would be ineffective.
Yet, for the time being, the researchers mean to take their experiments further and see how
successful their approach can be in the case of other bacteria with heteroresistance.
We are saying: Don't toss those drugs in the trash, they may still have some utility. They just
have to be used in combination with others to do so. While we can't tell beforehand what
the combination will work [since] there isn’t any magic combination, Weiss says, testing bacterial
strains to figure out effective drug mixes isn’t so much different from testing bacterial strains for
resistance to individual antibiotics anyway, rendering this strategy pragmatically viable.


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