Brand-new class of antibiotic kills drug-resistant

superbug
A newly discovered antibiotic can sidestep the defenses of a dangerous, drug-resistant bacterial
species.
The drug targets CRAB, or carbapenem-resistant Acinetobacter baumannii, which shows
resistance to most existing antibiotics. However, the newfound antibiotic kills CRAB using an
attack strategy that's never been seen before in antibacterial drugs, and this strategy is highly
targeted, affecting only the one species of bacteria.
"The advantage of a novel class of fully synthetic antibiotic is that bacteria have never seen
this," said Kenneth Bradley, one of the drug's developers and head of infectious diseases
discovery at Roche Pharma Research and Early Development in Basel, Switzerland. Thus, the
existing shields that CRAB uses to fend off antibiotics can't block the new drug's attacks.

Bradley and collaborators at Roche and Harvard University published a pair of papers
describing the discovery and workings of the new antibiotic on Jan. 3 in the journal Nature. The
drug, named zosurabalpin, is currently being tested in early-stage safety trials in humans.
"This is very promising in that this is a new drug class and a new drug target," Paul
Hergenrother, a professor of chemistry at the University of Illinois Urbana-Champaign who
wasn't involved in the research, told Live Science. "One would not expect cross-resistance with
antibiotics that hit other targets."
A brand-new antibiotic
CRAB has been flagged as an "urgent" threat in the U.S. due to its extensive resistance. The
microbe causes blood, urinary tract, lung and wound infections, most often in people in health
care settings, and it poses a particular threat to people with weak immune systems and those
who need catheters or ventilators.
The bacterium is "gram-negative," meaning it has a cell wall that's surrounded by a
membrane. It's been more than 50 years since a new class of antibiotic that works against
gram-negative bacteria was brought to market. That's partly because it's difficult to find drugs
that can penetrate the microbes' outer membranes and stay inside long enough to do their job,
Hergenrother said.
The study authors aimed to help close this gap by hunting for new types of antibiotics. "Instead
of making new versions of the existing antibiotic scaffolds … we wanted to start with something
completely different," Bradley said.
They began by broadly screening a library of nearly 45,000 chemical compounds for signs of
activity against different bacteria, including A. baumannii. Crucially, the library included synthetic
compounds with unique properties unlike many seen in drug companies' standard libraries,
which likely opened a door for discovery, Hergenrother noted.
This screen revealed a compound that they would modify to create the drug zosurabalpin. The
initial compound showed similar potency against strains of A. baumannii with different degrees
of resistance, and it didn't work on other types of disease-causing bacteria. The team tweaked
the compound to be even more potent against A. baumannii, and it proved effective at clearing
infections in mice and rats.
"But at the same time, we identified safety flags," Bradley noted. In addition to killing A.
baumannii, the compound reacted with fat bubbles called lipids in the rodents' blood, harming
the animals. The researchers solved this problem by adjusting the compound's electrical
charge.
How the new drug works
While working toward the final version of zosurabalpin, the team investigated exactly how the
compound kills CRAB: The drug disrupts machinery that's key to building the bacterium's outer
membrane.
Bacteria need lipopolysaccharide (LPS) to make the membrane, and machinery transports LPS
to the microbe's surface. Zosurabalpin gums up that machinery, but only when it's bound to
LPS. The Harvard collaborators also showed that the drug works only on A. baumannii because
of the specific component of the machinery it targets.
"They were able to solve an actual atomic-resolution structure of the target bound to
zosurabalpin," Bradley explained. "There are actually molecular differences that would prevent
the compound zosurabalpin from binding to other species [of bacteria]."
Antibiotics with narrow targets have less chance of disrupting the gut microbiome and other
helpful bacteria in the body, Hergenrother said. "A lot of your broad-spectrum antibiotics will
really wipe out the gut microbiome," so hopefully, zosurabalpin will prove to be "microbiome-
sparing," though that needs to be shown, he said. In addition, by targeting certain microbes,
narrow antibiotics don't place widespread pressure on a bunch of bacteria to develop new
resistance, Hergenrother added.
That said, CRAB will still be pressured to evolve new resistance strategies against zosurabalpin.
"We fully expect that evolution will lead to the emergence of resistance at some point, but at
least we're not starting behind the ball on this one," Bradley said. Plus, sometimes to gain
resistance to one drug, bacteria become more vulnerable to another or lose some ability to
cause disease. This is something that will need to be studied more in trials.
The ongoing human trials of zosurabalpin are assessing the drug's safety profile in healthy
volunteers, Bradley said. Looking beyond zosurabalpin, the drug's advent raises the idea that
LPS could be a promising new target for future antibiotics that work on other gram-negative
bacteria, he added.