Researchers discover that anti-malaria drugs can fight pulmonary disease


Date:
March 21, 2022
Source:
Colorado State University
Summary:
A research team has discovered that drugs used to treat malaria
are also effective at treating a pulmonary disease similar to
tuberculosis.



FULL STORY ==========================================================================
A research team at Colorado State University has discovered that drugs
used to treat malaria are also effective at treating a pulmonary disease similar to tuberculosis.


========================================================================== Their findings were featured on the cover of the Feb. 23 issue of Science Translational Medicine.

The study is a significant development in the fight against infections
caused by non-tuberculous mycobacteria, or NTM, which are now more common
than tuberculosis in the United States and often attack people who have a weakened immune system or preexisting conditions like chronic obstructive pulmonary disease or cystic fibrosis.

"There are currently very few antibiotics available to treat NTM
infections, and some patients fail to respond to any treatment,"
said Professor Mary Jackson of CSU's Department of Microbiology,
Immunology and Pathology, one of the lead authors. "The perspective
that antimalarial drugs that already have undergone advanced clinical
trials may become part of the arsenal of drugs available to fight these infections could have an immediate impact in the clinic." The research,
which was led by Jackson and lead author Juan Manuel Belardinelli, a
research scientist in CSU's Department of Microbiology, Immunology and Pathology, targeted an NTM known as Mycobacterium abscessus. Few drugs
are effective against this mycobacterium, and the ones that are tend to
be toxic and cause bad side effects, Jackson said.

Targeting disease's defense mechanism Jackson and Belardinelli worked
with other members of CSU's Mycobacteria Research Laboratories to target
one of the key defense mechanisms that this mycobacterium deploys to
fight off our immune system and antibiotics.



==========================================================================
The researchers believe that the bacterium is capable of sensing
and responding to threats in its environment, such as lowered oxygen
levels, oxidative stress and acidic pH, which are our body's natural
ways of fighting disease. It does so by activating, among other things,
a regulator known as DosRS which controls many essential functions in
the bacterium such as its respiration, ability to form biofilms and
ability to enter a dormant state when the conditions are not favorable
to bacterial multiplication.

They found that in mice, two existing antimalarial drugs were able to
prevent DosRS from responding to stresses, meaning that the bacterium
struggled to fight off antibiotics and the immune system's natural
disease response.

"It blocked the regulator and kept it from doing its job," Jackson
explained.

"One of the things the treatment did, in particular, was to lower the bacterium's ability to form biofilms, thereby reducing its ability
to resist killing by antibiotics." The treatment alone was just as
effective at dropping bacterial loads in the lungs as the combination
of antibiotics currently used to treat the disease.

The lead authors are now working with doctors at National Jewish Health
to administer the drug that proved most effective -- OZ439 -- to humans, particularly those with cystic fibrosis.

"Treatment of M. abscessus is especially challenging because a minimum
of three to four antibiotics are needed in combination, and there
are few available options," said Dr. Jerry Nick, a pulmonologist at
National Jewish Health. "The repurposing of antibiotics developed for
other infections for use in the treatment of M. abscessus has proven
to be the most successful route to increasing available therapies for
this serious disease. This report is especially exciting because these compounds were both effective against the infection and also increased
the effectiveness of other antibiotics. The repurposing strategy reduces
the time needed to test these compounds in clinical trials, as often
there is a proven track record of safety and clinical experience."

========================================================================== Story Source: Materials provided by Colorado_State_University. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Juan Manuel Belardinelli, Deepshikha Verma, Wei Li, Charlotte
Avanzi,
Crystal J. Wiersma, John T. Williams, Benjamin K. Johnson, Matthew
Zimmerman, Nicholas Whittel, Bhanupriya Angala, Han Wang, Victoria
Jones, Ve'ronique Dartois, Vinicius C. N. de Moura, Mercedes
Gonzalez-Juarrero, Camron Pearce, Alan R. Schenkel, Kenneth
C. Malcolm, Jerry A. Nick, Susan A. Charman, Timothy N. C. Wells,
Brendan K. Podell, Jonathan L.

Vennerstrom, Diane J. Ordway, Robert B. Abramovitch, Mary Jackson.

Therapeutic efficacy of antimalarial drugs targeting DosRS signaling
in Mycobacterium abscessus. Science Translational Medicine, 2022;
14 (633) DOI: 10.1126/scitranslmed.abj3860 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220321162717.htm

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