Name : Erra Setya Hasana

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Narrow-Spectrum Antibiotic Could Spare the

Microbiome
It may be possible to treat a type of bacterial infection with an antibiotic without disturbing the
normal microbiota, according to a study published today (May 9) in Antimicrobial Agents and
Chemotherapy. Researchers at St. Jude Children’s Research Hospital in Memphis, Tennessee,
have found that when administered orally at high does, a drug that targets Staphylococcus aureus
called Debio1452 (formerly AFN-1252) has little impact on intestinal bacterial communities in
mice.

“It’s a really exciting new way to target pathogens,” said Kristie Keeney, a microbiologist at the
University of British Columbia, who was not involved in the work. Keeney said Debio1452 falls
into a much-needed class of drugs that narrowly target gram-positive bacteria like multidrug-
resistant S. aureus.

Historically, antibiotics have been designed to kill off many different species of bacteria, giving
clinicians an efficient and inexpensive way to treat a range of infections. But these broad-
spectrum drugs can wreak havoc on a patient’s gut microbiome. In the case of oral antibiotics,
“the bacteria in the intestine get a huge dose,” said study coauthor Charles Rock, an infectious
disease specialist at St. Jude.

Disrupting gut microbiota can lead to complications such as an overgrowth of resident species
like Clostridium difficile, one major cause of healthcare-related infection. And scientists are only
beginning to understand the long-term effects of microbiome alterations on metabolism and
immune function, among other things. Narrow-spectrum antibiotics that target a pathogen
selectively could help prevent such complications.

Debio1452, which is currently being developed by the Swiss pharmaceutical company

Debiopharm, is designed to inhibit an enzyme called FabI in Staphylococcus species only. FabI
controls the rate of fatty acid synthesis, a process required for bacterial cell membrane
production and cell division. Although some other bacterial groups use FabI, Debio1452 targets
an active site unique to the staphylococcal version of the enzyme. Rock, who studies bacterial
fatty acid synthesis, wanted to test whether this specificity would allow Debio1452 to do its job
while leaving the gut microbiome intact.

Rock and colleagues treated mice in groups of five with large doses of Debio1452 or one of four
broad spectrum antibiotics every day for 10 days. They then performed 16S ribosomal DNA
sequencing on stool samples taken throughout the experiment and for 27 days following the
treatment. When they compared the phylogenetic compositions of the microbiomes of each
group of mice, the researchers found that samples from the Debio1452-treated group more
closely resembled samples from the untreated controls than any other treatment group.

At the taxa level, Debio1452 caused one bacterial family called S24-7 to drop from making up
30 percent to 50 percent of the bacteria to just 0.2 percent after 10 days of treatment. The S24-7
family fully recovered after two days off the drug. All of the other antibiotic-treated groups
experienced substantial changes in major and minor taxa, which persisted anywhere from one to
four weeks after the treatment ended.

David Relman, a Stanford University microbiologist who was not involved in the study, noted
that even a very narrowly targeted drug will have some unanticipated effects on the complex
ecosystem of the gut microbiome. “The story will always be more complicated than we’d like to
think,” he told The Scientist.

The story may be further complicated when the drug is used during an ongoing infection, rather
than in healthy mice, Keeney said.

Rock said that the presence of an infection shouldn’t affect the study’s results because his team
used antibiotic doses beyond what would be needed to clear an infection (as previously
determined).

Keeney noted that testing the drug’s effects on human microbiomes will be the only way to know
whether the results hold up in the clinical setting.

Although Debio1452 is currently being tested in clinical trials, Rock said there are no plans to
test its effects on human microbiomes, which differ from those of mice. Agencies like the US
Food and Drug Administration currently don’t require drug companies to examine how new
antibiotics affect gut microbiota.

Rock said that as the long-term effects of microbiome disruption become better understood, this
may change and narrow-spectrum drugs may become more desirable. “Meanwhile,” he added,
“we’ll go back to the bench and see if we can come up with something similar that we can use
against gram-negative [bacteria].”

Source : http://www.the-scientist.com/?articles.view/articleNo/46051/title/Narrow-Spectrum-
Antibiotic-Could-Spare-the-Microbiome/