[Pharmwaste] The hunt for new antibiotics grows harder as resistance builds

[Deborah DeBiasi]

https://cen.acs.org/pharmaceuticals/antibiotics/hunt-new-antibiotics-grows-harder/96/i49



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*The hunt for new antibiotics grows harder as resistance builds *



Scientists keep fighting the microscopic arms race, even though it’s one we
might eventually lose



by  Megha Satyanarayana





December 16, 2018 | APPEARED IN  VOLUME 96, ISSUE 49



As the summer of 2016 wound down in Colorado, public health officials in
two counties issued alerts: people drinking raw milk from a local dairy
were getting sick from bacteria called Campylobacter jejuni.





By the end of the outbreak, about a dozen people had fallen ill with
diarrhea, fever, and vomiting. One person was hospitalized. Several were
sick for more than 10 days, despite the fact that Campylobacter infections
typically resolve quickly. Months later, federal public health officials
revealed why the infection might have persisted for so long: bacteria they
isolated had developed resistance to the antibiotics normally used to treat
them.





It’s a story that has become increasingly common. Infections that were once
easily treatable now require extraordinary doses of one or more
antibiotics. Meanwhile, intravenous antibiotics with nicknames like “last
resort” come off the shelf more and more often. These stories portend a
bleak future, one in which small wounds could lead to death, a common
occurence of a bygone era, say scientists who spoke to C&EN about the
antibiotic crisis.





“The real worry is what our world is going to be like for our kids” if
antibiotics stop working, says Floyd Romesberg, who researches natural
antibiotics at Scripps Research in California. “We risk living in a
postantibiotic era.”



Finding new medicines to kill pathogenic bacteria is getting harder and
harder, Romesberg says. Some teams are urgently trying to tweak
tried-and-true antibiotics to squeeze a few more usable treatments out of
them. Some researchers are looking for new compounds that can be used as
templates to develop medicines. And still others are plumbing the
unexplored crevices of bacterial physiology, hoping to unearth targets that
could lead to whole new classes of antibiotics.





Future generations of bacteria-fighting drugs will be more targeted, likely
more expensive, and, researchers hope, more quickly approved and deployed.





But antibiotic hunters are worried. Bacteria are smart. They will keep
developing resistance to anything scientists throw at them, and eventually,
they will win, Romesberg and many of his colleagues say.





“We’re buying time,” Romesberg says. “You just have to keep running as fast
as you can to stay in place.”





Bacteria’s tricks





Antibiotic development seems to drive in two lanes of traffic: one relies
on tweaking the molecular scaffolds of tried-and-true medicines, like the
β-lactam ring found in penicillin; the other involves the search for
entirely new compounds to disrupt both known and novel targets.





In either case, says Lynn Silver, an antibiotic expert who consults for
industry, antibiotic hunters face three big challenges: getting their
compound into bacteria, especially Gram-negative species, which have
tough-to-penetrate outer membranes; staving off resistance; and preventing
toxic side effects in the person taking it.





Pathogens have a laundry list of ways to neutralize antibiotics. Some
multidrug-resistant bacteria produce a high level of efflux pumps as a
means to regurgitate antibiotics that find their way inside cells. Some
develop enzymes that modify the drug, reducing its efficacy. And others
find ways to produce redundancy. For example, if an antibiotic attacks a
protein in a bacterium’s cell wall, that bacterium may simply replace the
target protein with a different one that is immune to the antibiotic but
preserves the target’s function.





These challenges are why the well has been fairly dry of truly new
antibiotics for decades, says Eric Gordon, CEO of Arixa Pharmaceuticals,
and why the pharmaceutical industry has virtually walked away from the
search.





“The entire pharmaceutical industry, coming out of World War II, was an
antibiotic industry,” Gordon says. Scientists have been building on the
molecular scaffolds of the antibiotics from that era for the past 50 years
and have reached the point of diminishing returns. “You might be able to
squeeze one or two compounds out of these classic scaffolds, but they just
don’t have much more to give.”





Gordon’s company is working on an oral version of a β-lactamase inhibitor,
a compound administered along with antibiotics to try to overcome
resistance. Bacteria produce enzymes called lactamases that disable
antibiotics containing the classic β-lactam ring scaffold. When given with
β-lactam antibiotics, lactamase inhibitors can overcome resistance
mechanisms, at least for a little while. Over the years, pathogens have
evolved thousands of enzymes—to date, scientists know of about 2,700 of
them—that neutralize β-lactams.





Arixa’s drug is an oral version of an already US Food and Drug
Administration–approved β-lactamase inhibitor called avibactam, which is
given intravenously in conjunction with an antibiotic. The pill would allow
consumers to take the medication outside the hospital.



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Some bacteria produce enzymes called β-lactamases to destroy antibiotics
containing β-lactam rings. One tactic employed by industry is building
β-lactamase inhibitors. Clavulanic acid was the first, approved in the
1980s. Oral avibactam, developed by Arixa, is one of the latest.





Reformulating an existing drug means the company has fewer regulatory
hurdles to jump through, making it a more reasonable pursuit, financially,
than building a novel antibiotic, Gordon says.





Efforts like Arixa’s are going to work for a while, Gordon says, but “it
still doesn’t answer the question about what is going to be the source of
the antibiotics of the future,” he says.





With so many ways to neutralize a β-lactam antibiotic, which works by
preventing bacteria from building their cell walls, the field is running
out of ways to use this structure to build antibiotics. And with few novel
targets he can point to that researchers have successfully built
antibiotics against, Gordon struggles to be optimistic.







Related: The hunt for new antibiotics grows harder as resistance builds





“Most people think that with a big cash infusion into the area, maybe
catalyzed by the government or something like that, we’d be, you know,
sailing along again, making antibiotics. But the fact is, nobody knows how
to make them anymore,” he says.





Searching for new scaffolds





Eventually, tweaking known antibiotics will stop yielding new drugs. This
is why several scientists, including Romesberg, have turned to natural
products as a source of new building material. Like penicillin, “virtually
all of the good antibiotics that we have came from nature,” he says. “It’s
proven to be extraordinarily difficult for a chemist to come up with new
scaffolds.”





Antibiotic resistance mechanisms

Pathogens have evolved several mechanisms to neutralize antibiotics: They
can use inactivating enzymes such as β-lactamases to destroy antibiotics
containing β-lactam rings. They can increase the production of efflux pumps
to spit antibiotics back out of the cell. They can alter the composition of
their cell wall to decrease antibiotic uptake. They can alter the genetic
targets of some antibiotics, and they can replace enzymes targeted by
antibiotics with alternative enzymes that carry out the same function.





Romesberg’s lab investigates natural compounds to take advantage of their
ready-made scaffolds. One class of molecules his team studies is a group of
bacterially secreted antibiotics called arylomycins, which were first
isolated in 2002. Different bacterial species use arylomycins to fight each
other, but because people thought the antibiotics would work on only a
small number of species, they garnered little initial interest as possible
medicinal compounds, Romesberg says.





In general, he explains, companies are looking for certain assurances from
a new antibiotic scaffold before they will pursue it as a possible
medicine. Among these assurances is that the scaffold has a target that is
conserved—meaning present in many species—so that the antibiotic has a
broad spectrum of activity.





Romesberg thinks this prerequisite is misguided.





He describes a scenario in which a narrow-spectrum compound is simply one
that once could kill or maim many species of bacteria, until those species
figured out how to outsmart it. That resistance put the pressure back on
the creature producing the antibiotic to tweak its weapon, creating a
compound that is once again broad spectrum. That broad-and-narrow cycle
then continues.





All the natural products that became successful antibiotics are probably
ones that were found at the point in their activity cycle where they were
the most broad spectrum, Romesberg argues. Picking up compounds at the
narrow part of their cycle isn’t wasted time, he insists. When his team
discovered arylomycin, which inhibits the activity of a signal peptidase
that allows for bacteria to secrete proteins and lodge them in their
membranes, the group found that despite a conserved target sequence, it was
a narrow-spectrum compound.





The researchers tested it against several bacterial species, found one that
was susceptible, and watched what happened during an experiment enabling
that species to develop resistance in the lab. The species, Staphylococcus
epidermidis, was changing its signal peptidase in a specific way, via a
serine-to-proline substitution. A number of other bacteria that are
resistant to arylomycins use the same trick to evade the antibiotics. From
this finding, the team concluded that although arylomycins are currently
narrow spectrum, they were once powerful, broad-spectrum killers
(Antimicrob. Agents Chemother. 2012,DOI: 10.1128/AAC.00785-12).





So to turn arylomycins into a broad-spectrum antibiotic once again,
Romesberg’s team and others have focused on tweaking the natural scaffold
to overcome the destabilizing effect of that proline.





RQx Pharmaceuticals, a biotech founded by Romesberg, partnered with
Genentech in 2013 to take on that challenge. In September, Genentech
scientists published early data on an arylomycin-based compound that can
kill pathogens associated with some hospital-acquired infections. It works
by covalently binding a lysine in the signal peptidase. This strong link,
in theory, will thwart the effects of a proline being swapped in for a
serine somewhere in the peptidase structure (Nature 2018, DOI:
10.1038/s41586-018-0483-6).





Novel targets and novel products





In the 1990s, with the advent of gene sequencing, pathogen scientists were
sure that sequencing bacterial genomes would yield a treasure trove of
proteins that bacteria couldn’t live without. Aiming at these targets with
new drugs, either from known compounds or from libraries of untested
compounds, seemed like it would energize the field.



It wasn’t the easy victory some had anticipated. Many of the genes
described were already known and had already been through compound screens,
antibiotic industry consultant Lynn Silver says. And Arixa’s Gordon adds
that bacteria seemed to be able to compensate for antibiotic activity
against those targets.





But some researchers are undeterred and say that they just need more time.
“Exploring novel targets gives you an opportunity to surprise the
bacteria,” says Concepción González-Bello, an organic chemist at the
University of Santiago de Compostela.



I can’t imagine that society would let things go back to the times when we
could die from a minor flesh wound.



---Manos Perros, CEO, Entasis Therapeutics





González-Bello studies some of bacteria’s essential genes, including two in
the metabolic shikimate pathway that are critical for survival. She
believes that designing antibiotics for new targets will lead to medicines
that could elude resistance strategies longer than medicines being
developed for known targets.





While researchers continue to plug away at sussing out novel targets,
González-Bello says some of the most intriguing work that could deliver
sooner focuses less on building new antibiotics and more on what can be
administered alongside them to make them work better.





The classic additive is the β-lactamase inhibitor, but newer research is
looking at immune-boosting compounds called adjuvants. In the presence of
pathogens, the human immune system goes to work immediately, recognizing
chemical patterns on the surface of bacteria. The immune cell receptors
that do this work are now targets for natural and synthetic compounds that
can be paired with antibiotics to stoke the immune response.





Other promising ways to attack pathogens through the immune system include
antimicrobial peptides, which are released by the human immune system in
response to infection. Like antibiotic compounds, these peptides interfere
with the cell membrane of bacteria, or nucleic acid and protein formation,
both of which are required for survival. Medicinal antimicrobial peptides,
which include vancomycin and daptomycin, are among last-resort treatments.





But a number of bacterial species are resistant even to last-resort
treatments, so some members of industry are bucking the search for
broad-spectrum antibiotics and focusing instead on these highly resistant
species, which are the narrowest of targets. Genentech, for example, has a
drug-antibody conjugate in Phase I trials, in partnership with Seattle
Genetics and Symphogen. The antibody is engineered to attach to the cell
wall of MRSA—methicillin-resistant Staphylococcus aureus—a common
health-care pathogen that is resistant to all known β-lactam antibiotics,
as well as some last-resort antibiotics like vancomycin.





On top of its resistance to antibiotics, MRSA hides inside circulating
cells, allowing it to move from the site of initial infection to elsewhere
in the body. The Genentech antibiotic is a spin on rifamycin that is
inactive until it gets inside mammalian or human cells. The conjugate seems
to work by binding MRSA before it invades cells. Once a cell takes up the
pathogen, the conjugate is cleaved, and the antibiotic is activated.





Some narrow-spectrum antibiotics are already showing progress in clinical
use. In mid-November, a small biotech called Entasis Therapeutics released
tantalizing clinical trial findings of zoliflodacin, a narrow-spectrum
antibiotic that inhibits DNA synthesis in people with gonorrhea infection.
It’s a needed advance: the sexually transmitted infection in some people
has persisted, even after multiple rounds of antibiotics, including those
of last resort.





While most people will still be able to use broad-spectrum antibiotics,
Entasis Therapeutics CEO Manos Perros says that for a small group of
people, “bacterial antibiotics are going to become like orphan-disease
drugs, tailored to the resistance mechanism.”







Related: Antibiotics developer Entasis Therapeutics seeks to go public





That narrowness will come at a price. Although the FDA and Congress have
created programs to fast-track antibiotics through approvals, and nonprofit
groups, like Carb-X, provide financial support to promising programs,
companies hint that developing drugs for specific uses will be expensive.





“You can do the math. If your market size is 5 million patients versus
50,000,” then you’ll have to adjust the price for the lower volume you will
sell, Perros says. But he stresses that any high cost would be for a
onetime treatment. People will get well, he says, and become productive
again.





But like other scientists, Perros tempers optimism with the reality that
any approved antibiotics are short-term gains. “Every battle is going to be
a losing battle,” he says. “We have to change how we do things. We have to
change how we fight that war if we want to prevail. I can’t imagine that
society would let things go back to the times when we could die from a
minor flesh wound.”

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